Biochem 2.3 Taylor

Explain the molecular defects, clinical manifestations, and treatments of Wilson's Disease

-Brown ring on outer part of eye- kayser-Fleischer

Explain the molecular defects, clinical manifestations, and treatments of Cholesteryl Ester Storage Disease

-Can live into adulthood -No cure

Explain the molecular defects, clinical manifestations, and treatments of PKU

-Carriers protected from ochratoxin A produced fungi like Aspergillus found associated with foods (grapes, beans) water damaged houses and heating/cooling ducts neurotoxin, carcinogen -New Variant PKU - Dihydrobiopterin reductase deficiency; very rare

Explain the molecular defects, clinical manifestations, and treatments of Carnitine Uptake Deficiency

-Defect involves renal tubules have defective carnitine transporter

Explain the molecular defects, clinical manifestations, and treatments of Hereditary Hemochromatosis

-HFE gene-high iron (Fe) gene

DAX1

Testis formation supressor.

_ _12. Cystinuria is a major cause of kidney stones in children.

True

Isochromosomes

-2 P arms or 2 Q arms -Turners disease if you have 2 X q arms -Edwards disease if you have 2 chromosome 18 q arms

Review Williams Syndrome.

"Cocktail behavior"aka train wreck behavior. 26 different genes involved in the deletion that effects elastin gene. Associated with the increased risk of stenosis. Also effects LIMK1 a kinase transcription factor that is correlated with visual and spatial orientation.

Compare and contrast a base pair mutation with a missense mutation.

- base pair or point mutations represent over 60% of single gene causing mutations - additional noteworthy mutations often result from deletion or insertion of one or more base pairs -frameshift mutations (Tay-Sach's and CF), promoter mutations (pyruvate kinase deficiency), & splice site mutations (beta thalassemia)

Prader-Willi Syndrome

-Maternal genes are imprinted and silenced -paternal genes are lost (chromosome 15) -Mothers DNA cannot compensate -Small nucleoribo protein-N=SNRP-N causing defective mRNA processing, increases grehlin causing excessive hunger and obesity, hypogonadism, hypotonia.

Angelman Syndrome

-Paternal DNA are imprinted and silenced -maternal DNA (chromosome 15) lost -Paternal DNA cannot compensate -Cells affected in hippocampus and cerebellum Defective ubiquitin ligase, key proteins are not targeted for destruction. Causes mental retardation, laughing and flapping, ataxia, seizure and short stature.

Define population genetics.

-Stratification-choose mate due to socioeconomic reasoning -Positive assortive mating-similar characteristic-like height -Consanguinity and inbreeding- -Heterozygote Advantage-sickle cell or PKU, keeping carriers of heterozygote gene around

Contrast de la Chapelle Syndrome with Swyer Syndrome.

-XX female with male phenotype (testis)-XX MALE -XY male with female phenotype (ovary)-XY FEMALE

Discuss genome/chromosome abnormality.

-alteration in # or structure of chromosomes -observed microscopically; large -Occur on average in between 1/100 and 1/200 (<1%) of live births -Most autosomal abnormalities diagnosed at birth -Most sex chromosome abnormalities not recognized until puberty -Frequency of chromosome abnormalities in spontaneous abortion is at least 40-50% -Most common chromosome abnormality in abortuses is Turner Syndrome (20% abortuses) -Polyploidy conditions (15% abortuses) -also noted in neoplasms; Philadelphia Chromosome and CML, translocation of region on 9 (ABL)-->22 BCR

Explain the molecular defects, clinical manifestations, and treatments of Phocomelia

-morning sickness pill -Flipper syndrome

Explain the molecular defects, clinical manifestations, and treatments of Oculocutaneous Albinism

..EXAMPLES OF AUTOSOMAL RECESSIVE DISEASES Oculocutaneous Albinism -Complete or partial absence of pigment in eyes, skin, and/or hair -Photosensitivity, decreased visual acuity (20/200), and increased risk of melanomas -1/17,000: chromosome 11 or chromosome 15 -Defect in OCA1 and/or OCA2 genes -OCA1 gene codes for tyrosinase which is used to synthesize melanin (pigment) from tyrosine -OCA2 gene contains the information to make P protein, an integral membrane protein in melanocytes; transports tyrosine into cells; blue eyes; more common -Sunglasses, glasses, and avoidance of long term exposure to sunlight

2. A 40 year old husband is a carrier for both Carnitine Uptake Deficiency and Wilson's Disease. The wife is also a carrier for both diseases. What is the probability that one of their children will have both Carnitine Uptake deficiency and Wilson's Disease?

1/16 dihybrid cross Cc Ww back into 2 monohybrid crosses end up with 1/4 for both and add them together.

3. Peter and Susan have two boys and now they are expecting identical twins. What is the probability of having another 2 boys? A. 1/2 B. 1/4 C. 1/8 D. 1/16 E. 1/32

1/2

What can you learn from a maternal blood sample? Ultrasound? Ausculation?

1st Trimester Screening, 10 -14 weeks into Gestation, Noninvasive Methods Maternal Serum Screening: hCG, AFP, uE3, Inhibin, and PAPPa. Ultrasound: Determination of sex, age, number of fetuses, basic anatomy, nucal translucency, heart defects, etc. Asculation and Heart Rate: Doppler or Fetal Stethoscope: Normal 120-160 bpm, too fast or too slow can indicate a number of fetal stressors/emergencies

List 2 ways to classify chromosomes.

2 main classifications for humans. 1) Metacentric centromere is in the center (chromosomes 1,3 and 19,20) 2) Acrocentric centromere near the end (chromosomes 13,14,15,21,22)

Reciporcal Translocations

2 non-homologous chromosomes (usually 3&6 or 6&20) interchange genetic material. The first generation is usually just a carrier but when they reproduce the mutation will be expressed. Exp: Trisomy 6P syndrome---hypotonic muscles and mental delay.

Define Dominance

A trait that is phenotypically expressed in both homozygotes and heterozygotes.

Describe Array Comparative Genome Hybridization (aCGH).

3. ARRAY COMPARATIVE GENOME HYBRIDIZATION -Fluorescent imaging technique useful for diagnosing deletions and duplications of very small (< 100kb) DNA segments -Measures difference between 2 different samples (patient vs control) with regard to copy number or dosage -Patient DNA is labeled red dye -Control DNA is labeled green dye -Mixed in equal proportions and hybridized to an array of unique genomic sequences on chip -Yellow/orange signal means equal amounts -Red indicates increased; gain or duplication -Green indicates decreased ; loss or deletion -Limitation includes balanced rearrangements-doesn't give info on rearrangement.

How many genes are in the mitochondrial chromosome?

37 genes that code for 14 proteins, tRNAs and ribosomal subunits.

XYY Syndrome

47, XYY Syndrome - male; 1/1000 - taller than average; 10-15 point reduction in IQ - 1/30 incidence in prison population - hyperactivity, attention deficit disorder, impulsive, and frustration - fertile -Super male

Why would a gene defect in the mitochondrial genome cause a disease?

A defect in the mitochondrial genome can still cause disease because it could effect e- transport and ATP production, thus cells that require ATP for function would be affected.

Amniocentesis?

A needle is inserted transabdominally into the amniotic cavity and 20-40 ml of fluid is removed. The fluid contains loose embryonic cells that can be cultured for karyotyping, DNA analyses and biochemical analyses. More than 600 tests possible. Risk increases fetal loss 0.5% above baseline (1/300).

Two parents who are carriers for cystic fibrosis have children. What is the probability that one of their children will have the disease? A. 25% B. 50% C. 75% D. 100%

A. 25%*** B. 50% C. 75% D. 100%

A XY male with a female phenotype including the presence of ovaries may occur due to: A. 5-ARD deficiency B. SRY gene deletion C. SOX9 gene duplication D. DAX1 gene deletion

A. 5-ARD deficiency B. SRY gene deletion*** C. SOX9 gene duplication D. DAX1 gene deletion

A Caucasian patient that presents with respiratory difficulty, salty sweat, sticky mucous, pancreatic malfunctions, intestinal obstructions, and a chloride ion channel mutation most likely has: A. Albinism B. PKU C. Polycystic Kidney Disease D. Cystic Fibrosis

A. Albinism B. PKU C. Polycystic Kidney Disease D. Cystic Fibrosis***

Blaschko's lines are an example of: A. Aneuploidy B. Imprinting C. Gene rearrangement D. Mosaicism

A. Aneuploidy B. Imprinting C. Gene rearrangement D. Mosaicism***

The fusion of two acrocentric nonhomologous chromosomes near the centromere region that results in the loss of the p arms is a(n): A. Deletion B. Duplication C. Isochromosome D. Robertsonian Translocation

A. Deletion B. Duplication C. Isochromosome D. Robertsonian Translocation***

A gain of genetic material that results from unequal crossing over is a(n): A. Deletion B. Duplication C. Inversion D. Reciporcal Translocation

A. Deletion B. Duplication*** C. Inversion D. Reciporcal Translocation

A one year old female child that demonstrates a meowing cry, mental retardation, a chromosome 5 deletion, and defective Semaphorin F function most probably has: A. Down Syndrome B. Charcot-Marie-Tooth Disease C. Cri du Chat Syndrome D. Williams Syndrome

A. Down Syndrome B. Charcot-Marie-Tooth Disease C. Cri du Chat Syndrome*** D. Williams Syndrome

A patient that presents with hypertonia, unusual clenching of fists, rocker-bottom feet, growth retardation, and trisomy of chromosome 18 may have: A. Down Syndrome B. Edward Syndrome C. Patau Syndrome D. Klinefelter Syndrome

A. Down Syndrome B. Edward Syndrome*** C. Patau Syndrome D. Klinefelter Syndrome

A young child that presents with mental retardation, elf-like appearance, aortic stenosis, dental malformations, and altered elastin production may have: A. Down Syndrome B. Charcot-Marie-Tooth Disease C. Cri du Chat Syndrome D. Williams Syndrome

A. Down Syndrome B. Charcot-Marie-Tooth Disease C. Cri du Chat Syndrome D. Williams Syndrome***

A patient that presents with peripheral limb weakness, high feet arches, abnormal PMP22 production, and a chromosome 17 duplication most likely has: A. Down Syndrome B. Charcot-Marie-Tooth Disease C. Cri du Chat Syndrome D. Williams Syndrome

A. Down Syndrome B. Charcot-Marie-Tooth Disease*** C. Cri du Chat Syndrome D. Williams Syndrome

A 5 year old male patient that exhibits hypotonia, a low nasal root, short neck, loose nape skin, a simian crease in palms, mental retardation and trisomy of chromosome 21 most likely has: A. Down Syndrome B. Edward Syndrome C. Patau Syndrome D. Turner Syndrome

A. Down Syndrome*** B. Edward Syndrome C. Patau Syndrome D. Turner Syndrome

The situation in which genes on different chromosomes behave independently during gamete formation is known as: A. Mendel's First Law B. Mendel's Second law C. Chromosome Theory of Heredity D. Genetic Imprinting

A. Mendel's First Law B. Mendel's Second law*** C. Chromosome Theory of Heredity D. Genetic Imprinting

A chromosome with the centromere located near the end is termed: A. Metacentric B. Acrocentric C. Submetacentric D. Telocentric

A. Metacentric B. Acrocentric*** C. Submetacentric D. Telocentric

Down Syndrome may arise due to: A. Nondisjunction B. Robertsonian Translocation C. Mosaicism D. Isochromosome Formation E. All of A-D F. Three of A-D G .Two of A-D

A. Nondisjunction B. Robertsonian Translocation C. Mosaicism D. Isochromosome Formation E. All of A-D*** F. Three of A-D G .Two of A-D

The extent or severity to which a given phenotype is expressed can be termed: A. Penetrance B .Expressivity C. Pleiotropy D. Allelic Heterogeneity

A. Penetrance B .Expressivity*** C. Pleiotropy D. Allelic Heterogeneity

What is anticipation?

Anticipation: Age of onset decreases with each generation, severity may increase and number of triplet repeats increase.

___9. is a urea cycle disorder.

Argininosuccinic acidemia

A patient that presents with growth retardation, low IQ, rigidity, and is thought to have had a reciprocal translocation involving chromosome 3 or chromosome 20 most likely has: A. Recombinant 8 Syndrome B. Angelmen Syndrome C. Prader-Willi Syndrome D. 6p Syndrome

A. Recombinant 8 Syndrome B. Angelmen Syndrome C. Prader-Willi Syndrome D. 6p Syndrome *** (trisomy)

A patient that exhibits obesity, hypogonadism, hypotonia, small hands, defective SNRNP-N activity, and loss of paternal chromosome 15 expression probably has: A. Recombinant 8 Syndrome B. Angelmen Syndrome C. Prader-Willi Syndrome D. Down Syndrome

A. Recombinant 8 Syndrome B. Angelmen Syndrome C. Prader-Willi Syndrome*** D. Down Syndrome

A patient showing mental retardation, ataxia, short stature, uncontrolled laughter, defective ubiquitin protein ligase activity, and loss of maternal chromosome 15 expression most likely has: A. Recombinant 8 Syndrome B. Angelmen Syndrome C. Prader-Willi Syndrome D. Down Syndrome

A. Recombinant 8 Syndrome B. Angelmen Syndrome*** C. Prader-Willi Syndrome D. Down Syndrome

A Hispanic couple from the San Luis Valley give birth to a child suffering from cardiac abnormalities and mental deficits. The parents are carriers for an inversion mutation. The child may have: A. Recombinant 8 Syndrome B. Angelmen Syndrome C. Prader-Willi Syndrome D. Down Syndrome

A. Recombinant 8 Syndrome*** B. Angelmen Syndrome C. Prader-Willi Syndrome D. Down Syndrome

A male patient showing a reduced IQ, thin appearance, tall stature, hypogonadism, enlarged breasts, and a XXY karyotype most likely has: A. Turner Syndrome B. Angelmen Syndrome C. Klinefelter Syndrome D. Down Syndrome

A. Turner Syndrome B. Angelmen Syndrome C. Klinefelter Syndrome*** D. Down Syndrome

A female patient that presents with a short stature, webbed neck, sunken chest, infertility, and a X or XO karyotype may have: A. Turner Syndrome B. Angelmen Syndrome C. Klinefelter Syndrome D. Down Syndrome

A. Turner Syndrome*** B. Angelmen Syndrome C. Klinefelter Syndrome D. Down Syndrome

A dark band of G Banding Karyotype Analysis: A. refers to high GC content regions of DNA B. corresponds to regions that brightly fluoresce with quinacrine mustard C. contains about 1000 genes D. is stained lightly by Giemsa stain

A. refers to high GC content regions of DNA B. corresponds to regions that brightly fluoresce with quinacrine mustard*** C. contains about 1000 genes D. is stained lightly by Giemsa stain- because it's darkly stained

Describe the phenotype and organ involvement of Li-Fraumeni syndrome. What does SBLA stand for?

AD; chromosome 17; very rare; 400; inherited cancer Predominately due to missense mutations in p53 protein, especially in regions that are involved in DNA binding. With some mutations, tetramers containing Mutp53 and WTp53 do not recognize the DNA binding sequence. This is an example of a Dominant Negative Mutation where only one allele needs to be mutated, to phenotypically express the trait. This is true autosomal dominant inheritance. p53 tumor suppressor protein regulates cell cycle, repair of DNA damage and apoptosis. 25-fold increased cancer risk multiple tumors (SBLA, sarcomas, breast, leukemia, adrenal gland)

Compare and contrast polyploidy with aneuploidy.

Abnormalities of Chromosome # A. Polyploidy - presence of a complete set of EXTRA chromosomes in a cell (a lethal condition except for skeletal muscle cells that are multinucleated) 1. Triploidy - 69 chromosomes 2. Tetraploidy - 92 chromosmes *Most polyploidy conceptions are aborted B. Aneuploidy - presence or ABSENCE of individual chromosomes in cells; 45 or 47 for example -Autosomal monosomies tend to be lethal; whereas sex chromosome monosomy is viable (Turner Syndrome)

Describe the gene, mutation, protein product, altered biochemistry, and phenotype of: A. Achondroplasia

Achondroplasia- where protein tyrosine kinase activity of a mutated receptor is constantly active rather than controlled. Gain of function mutation. This is the most common form of human dwarfism. It is most frequently caused by a G to A mutation (98%) at nucleotide position 1180 in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene located on Chr4. This mutation results in a glycine to arginine amino acid substitution at AA 380. Affected individuals have short limbs, but more normal torsos. Growth Hormone will not correct the condition. Sporatic mutation during spermatogeneis is observed in 80% of cases (somatic cells of the parents don't have the mutated allele) and is associated with increasing paternal age. Therefore only 20% of cases are from a pre-exisiting allele. Homozygous inheritance is lethal!

___12. is a fluorescent imaging technique useful for diagnosing deletions and duplications of very small (< 100kb) DNA segments.

Array compartive gene

Robertsonian translocations.

Acrocentric chromosomes, 1 chromosome hitches a ride with another, non-homologous. The p arm becomes part of another chromosome. Accounts for 4% of Down's Genes on the short arm are usually rRNA so not much of a deal if a few are lost, in contrast to losing p arms. Williams Roberstson 14-yellow 21-green

Explain Charcot-Marie-Tooth Disease.

Adult onset of symptoms. PMP22 gene is a gene involved with the myelin sheath and how it interacts with gap junctions, when duplicated it impairs nutrient delivery to myelin sheath leading to demyelination.

_ _6. is characterized by black urine, osteoarthritis, and heart valve defects.

Alkaptonuria

Complete Penetrance

All individuals who have the disease-causing mutation have full clinical symptoms of the disease.

The State of Washington provides for neonatal screening for 24 genetic diseases. What is the significance of the particular diseases being tested?

Almost all are autosomal recessive and all can be treated with diet and or supplements significantly decreasing the phenotypic expression of the disease if intervention is initiated in infant hood.

AZFs

Also made by Leydig cells. Azospermia factors produces the mRNA factors needed for spermatogenesis.

Define and give an example of aneuploidy.

Aneuploidy examples: Turners (X) or Downs (21) or Edwards (18) or Pateau (13) all trisomies -Gain or loss of individual chromosomes -Nondisjunction stage-Anaphase I or II is defective

Review Triple X, Klinefelter, and Turner Syndromes.

Autosomal trisomies are viable (Down, Edward, Patau) Sex chromosome trisomies and tetrasomies are viable (XXY, XXX, XYY, XXXX) *As most common cause of abnormalities involving chromosome number is nondisjunction during meiosis, please refer to Gametogenesis lecture for details concerning Down, Edwards, Patau, Turner, and Klinefelter Syndromes. Additional Chromosome Number Disorders: Triple X Syndrome: - 1/1000 births; 5 to 10 born every day in U.S. - female - 47 chromosomes, XXX - majority not diagnosed; X inactivation; mosaics - tall, thin, epicanthal folds (upper part of the eye-asian eye), microcephaly, dyslexia, lower IQ, abnormal offspring

E. Huntington's Disease

Autosomal‑dominant disorder with almost complete penetrance is a frequent neurodegenerative disorder. The gene is located on the short arm of Chr4 and undergoes unstable expansion of CAG (glutamine codon) on the 5ʹ terminal section of the gene (IT15) that encodes huntingtin protein (Htt). Pathophysiology of HD is unclear. The striatum appears especially vulnerable despite similar expression of the mutated protein in other brain regions. Clinical manifestations are chorea (spasms), cognitive impairment and psychiatric disorders. Aggregation of mutated Htt, transcriptional dysregulation, altered energy metabolism, excitotoxicity, impaired axonal transport and altered synaptic transmission culminate in neuronal dysfunction and death. No effective treatment for prevention or slowing disease progression Death usually occurs at about 20 years after diagnosis.

Describe the potential metabolic, immunologic, social, economic, and health benefits of breast feeding for mom and baby.

Benefits of Breastfeeding for Baby favorable balance of nutrients improve cognitive development protects against infections protect against chronic diseases Impacts gene expression protect against food allergies Benefits of Breastfeeding for Mom contracts the uterus delays return of regular ovulation* conserves iron stores protects against breast cancer (especially pre-menopausal forms) aids in return of pre-pregnancy weight

Clarify Wolf-Hirschhorn Syndrome.

C. Wolf-Hirschhorn Syndrome -Deletion in short arm of chromosome 4 -Wide spaced eyes, high forehead, and flat nasal bridge; "Greek Warrior Helmet" appearance, mental and physical retardation; cleft lip; short stature; seizures -1/50,000; 2X more females -WHSC1, LETM1, and MSX1 genes are deleted -WHSC1 codes for histone methyltransferase that inhibits gene expression; is associated with facial appearance and delays, leads to over expression of other genes. -LETM1 codes for a mitochondrial Ca2+/H+ anti porter (alters how Ca2+ gets in and out of skeletal muscle cells); associated with seizures -MSX1 makes a transcriptional repressor; involved with cleft lip and palate

Use the risk factors of coronary artery disease as an example of factors that can and cannot be controlled.

CAD has low concordance with MZ at 19% and DZ at 9%, therefore there is more of an environmental cause and most risk factors can be controlled or modified. Controllable risk factors include: Fatty diet, Hypertension, Smoking, High serum cholesterol, Low serum HDL, High serum LDL, Stress, Insufficient exercise, Obesity, Diabetes Uncontrollable risk factors: Family history (genetics), Age, Male sex

What can be learned from: Chorionic Villus Sampling?

CVS increases fetal loss by 1.5% (1/175 loss rate). The method can be performed transcervically or transabdominally. Collected cells are cultured, then analyzed for karyotype and by various DNA methodologies.

__10. results in defective beta fatty acid oxidation.

Carnitine uptake deficiency

1. If a wife and husband who are both carriers for cystic fibrosis have children, what is the probability that one of their children will have the disease?

Cc -genotype of both parents -probability is 1/4, 25%

What is meant by a multifactorial disease?

Characteristics: Most diseases with a genetic component are not inherited in Mendelian fashion but display multifactorial inheritance. Multifactorial disease are usually polygenic with small additive effects. Major effort to identify common disease susceptibility genes is ongoing. Identification of SNPs associated with disease susceptibility may help in identifying gene linkages. Genetic predisposition: likely to be due to a particular combination of genes. The combinations of genes and environmental factors causing a particular multifactorial trait may vary from person to person.

Comparing children with RB in one eye versus two eyes, which condition is much more likely to occur when inheriting one mutated allele? Why?

Children with the inherited allele will most likely develop RB in one eye, and will be the only children to express the phenotype in both eyes. Children with 2 sporadic mutations will almost always have only one eye affected. All of this has to do with the probability of the sporadic mutation occurring.

Contrast a mosaic with a chimera.

Chimera - single organism composed of genetically distinct cells from two different individuals (not a mosaic). -Formed by merger of multiple fertilized eggs (stick together and form a 2 cell stage that will give rise to an individual or organ with 2 sets of chromosomes) or organ transplantation (bone marrow)

What are several Invasive Diagnostic Methods?

Chorionic Villus Sampling (CVS) Amniocentesis Percutaneous Umbilical Blood Sampling

___8. states that genes are carried on chromosomes.

Chromosome theory of heredity

Describe the Chromosome Theory of Heredity.

Chromosomes are the carrier of genes

Discuss karyotype analysis.

Colchicine-binds to dimer and caps it, microtubules fall apart and cell division stops.

Name some of the important proteins expressed from this chromosome.

Complex 1,3,and 4 of the e- transport chain, ATP synthase, ribosomal RNAs and tRNAs.

What is the importance of Barr Bodies in Females?

Condensed X chromosome that has been inactivated by XIST, but this X still carries many active genes that are expressed as autosomes after the inactivation.

List some common MF diseases, both congenital and adult onset.

Congenital: Cleft lip/palateCongenital hip dislocation Congenital heart defectsNeural tube defectsPyloric stenosisTalipes (club foot) Adult onset: Diabetes mellitus I and II Epilepsy Glaucoma Hypertension Ischemic heart disease Manic depression Schizophrenia Alzheimers Rheumatoid arthritis Cancer Obesity

___5. can be due to inhibition of the Sonic Hedgehog (SHH) gene.

Cyclopia

___3. codes for a nuclear protein receptor that down regulates other nuclear receptors and functions in male repression.

DAX1 gene-male gets the ax (trick)

___6. overexpression is associated with Down Syndrome.

DSCRI and DYRKIA genes

Explain Cri-du-chat Syndrome.

Deletion Syndromes A. Cri du Chat Syndrome -Deletion of short arm of chromosome 5 -more common in females -1/50,000 live births; survive to adulthood -meowing cat cry (before age 2); mental retardation (1%; IQ around 35); ears low and folded; microcephaly size of deletion is proportional to mental impairment -most cases are sporadic -involve Semaphorin F or 5A ( involved in axonal guidance and connectivity) and delta catenin (migration and cell adhesion), cells can't form proper synaptic associations.

___10. has been associated with Schizophrenia.

Deletion of chromosome 22

Female pseudohermaphroditism.

Different than XX Male, due to congenital adrenal hyperplasia. Salt-wasting syndrome due to lack of aldosterone. Deficiency in 21 hydroxylase that converts progesterone to aldosterone and other corticosteroids.

Male pseudohermaphroditism

Different than XY FEMALE, have testis but appear female. Deficiency in testosterone synthesis and metabolism involving 5alphaR (a reductase that converts testosterone to dihydrotestosterone). Increased risk for testicular cancer. A chromosome 2 defect.

Detail Charcot-Marie-Tooth Disease and duplication.

Duplication=gaining chromosome material by unequal crossing over or segregation. Leads to partial trisomy CMT-Charcot Marie Tooth disease-perpherial nervous disorder found on chromosome 17 -weakness and paralysis of limbs

Why are females considered mosaics relative to the X-chromosome?

Early in female embryonic development (at the blastocyst stage), one of the two X chromosomes in each cell is randomly turned off and forms a condensed Barr Body. As each of these cells divide, you get islands of cells representing the gene expression of that active X chromosome . This results in a tissue mosaic. The color patches of calico female cats are examples of X chromosomal mosaics.

Develop a nutrition prescription that addresses maternal nutrient needs during pregnancy and lactation.

Energy & Nutrient Needs During Pregnancy Energy - 300 kcal - 2nd & 3rd Protein - 10 extra grams per day Essential FA - omega-3, omega-6 Nutrients for blood production & cell growth Nutrients for bone development Nutrient Supplements Nutrient Needs During Lactation Energy intake, 500 kcal extra/day Vitamins & Minerals Balanced diet for Mom Prenatal supplement Water, Increased fluid needs!

Define medical genetics.

Genetics: the study of genes, heredity, and variation; concerned with the transmission and expression of traits from one generation to the next.

___5. is the genetic constitution of an organism

Genotype

___9. uses a fluorescently-labelled probe to rapidly diagnose large chromosome deletions, rearrangements, and aneuploidy.

FISH

__3. Colchicine arrests cells in interphase.

False

___10. The term locus refers to an alternate or variable state of a gene.

False

___6. Single gene disorders are primarily associated with the geriatric age range.

False

___2. Chromosome disorders are present in 20% of live births.

False-1-2% of live births

___4. is due to a deficiency of 21- hydroxylase.

Female pseudohermaphroditism

Females can be homozygous or heterozygous for the genes on their X-chromosomes, while males are termed hemizygous. EXPLAIN.

Females receive 2 X chromosomes and most genes on one of these are silenced except for those that require 2 copies for normal function. This creates a heterozygote like genotype for females. Males only receive 1 X chromosome and do not experience any silencing of the X chromosome genes under normal conditions. This creates a hemizygous genotype with 1 X rather than 2. Therefore females may show XaXa or XaXb genotypes and males are always XY with regard to the genes that are carried on the sex chromosomes.

At what gestational stages are these methods performed?

First Trimester Screening (10-14 weeks gestation)= maternal serum screening, ultrasound, auscultation. At 15-20 weeks gestation the quad screen is done. CVS is performed at 10-13 weeks gestation. Amniocentesis is performed at 14-20 weeks. Percutaneous umbilical blood sampling is performed at 17 weeks and greater.

Describe the molecular genetics of male pattern baldness.

For instance, male pattern baldness (androgenic alopecia, AGA) is linked to testosterone and more specifically dihydrotestosterone concentrations and androgen receptors proximal to hair follicles. DHT causes vasoconstriction and eventual loss of the follicles. The androgen receptor gene is located on the X-chromosome and 5-α-reductase is located on Chr2. Females with mutant high affinity AR can develop AGA. 5-α-reductase inhibitors (propecia) and folicle vasodilators (minoxidil) can sometime reestablish hair growth.

The cyst forming cells are undergoing hyperplasia but are not cancerous. EXPLAIN. What is the difference?

Functional failure of these proteins causes fluid retention and cell proliferation (hyperplasia). Note, PKD is not a cancer.

Compare G banding with Q banding.

G banding-trypsin makes the DNA more accessible to the stain, the stain is an intercalating agent that inserts between DS DNA and prefers the AT regions. Dark reddish/brown G band appears at these regions. Q banding- also intercalating but when it inserts in DS DNA it quenches the bright color and prefers GC rich regions. Therefore, bright Q bands appear at AT regions where the quenching does not occur.

Sickle cell anemia is a genetic human disorder that results in "sickle" shape red blood cells. The disease is caused by a mutated version of the gene that helps make hemoglobin — a protein that carries oxygen in red blood cells. DNA is double stranded, and only one strand serves as template for transcription into mRNA. If the bottom DNA strand below is the template for the mRNA, write the sequence of the mRNA in the corresponding boxes below:

GAG GUG-valine

What is meant by a "gain of function" or "loss of function" mutation? EXPLAIN in terms of tumor suppressors mutations or oncogene mutations.

Gain of Function: Mutations in control elements for signaling or metabolic pathways, often subject to activation/inactivation control (e.g., membrane receptors, signaling enzymes, G-proteins, etc.). p53 is an example, when it experiences mutations its regulatory functions are lost and tumors are allowed to proliferate when they would be destroyed under normal conditions. An apparent autosomal dominant disease at the pedigree level requires the mutation of both alleles at the cellular level for disease expression. These are Loss of Function Mutations. Tumor suppression is lost when both alleles are mutated.

Explain the molecular defects, clinical manifestations, and treatments of Galactosemia

Galactosemia -inability to metabolize galactose properly -1/50,000 to 1/60,000 -due to one of 3 three mutations, all are autosomal recessive -GALT, galactose-1-phosphate uridylyltransferase, chr. 9; classic -GALK, galactokinase, chr. 17 -GALE, UDP galactose epimerase; 1 -toxic levels of galactose, galactose-1-phosphate, byproducts -bacterial infection, brain damage, liver damage, jaundice kidney failure, and cataracts -no dairy, soy based formula, 75% infant mortality

Recognize the Inheritance Characteristics of an Autosomal Dominant Disease.

General Assumption: Most affected individuals are heterozygotes, and matings involve one partner heterozygous for the autosomal dominant trait and the other partner will be homozygous normal. Therefore, there are three hallmarks of autosomal dominant inheritance. Every affected individual has an affected biological parent, i.e., here is no skipping of generations (some exceptions, e.g., new mutations, non-penetrance). Males and females have an equal probability of inheriting the mutant allele and being affected. The recurrence risk of each child is 1/2. Normal siblings of affected individuals do not transmit the trait to their offspring.

What are some of goals of Genetic Screening?

Genetic screening is a systematic approach to identify individuals at sufficient risk for developing or transmitting a genetic disorder. These individuals may benefit from additional testing. Information from genetic screening may provide parents and physicians with information concerning: Life-saving Measures Diagnosis and Treatment Birthing Arrangements Emotional Preparation Pregnancy Management Reduction of Additional Testing

6-7. The figure below shows one karyotype from a human and one from a gorilla. Can guess which is which? Can you figure out the sex?

Gorilla-48 chromosomes-female

___3. is the father of modern genetics

Gregor Mendel

_ _7. is treated by phlebotomy and deferoxamine.

Hemochromatosis

Describe the mutation(s) (gene and protein product), altered biochemistry, and pathophysiology of: A. Hemophilia A

Hemophilia A is defective Factor VIII (1/5,000- 1/10,000) that causes incorrect RNA splicing and produces a truncated, nonfunctional protein. Leads to decreased thrombin therefore fibrinogen is not converted to fibrin and clots do not form.

6-7. The figure below shows one karyotype from a human and one from a gorilla. Can guess which is which? Can you figure out the sex?

Human-46 chromosomes-male

Many Dominant Mutations result in defective structural proteins (e.g., collagen) or activated signaling regulators ( FGFR3, etc). Explain why these mutations are consistent with autosomal dominant inheritance.

In autosomal dominant disorders, a 50% reduction in the normal gene product and/or a 50% presence of the mutated product is associated with clinical signs and symptoms.

B. Fragile X Syndrome

In males, a mutation in the only copy of the gene in each cell causes the disorder. In most cases, males experience more severe symptoms of the disorder than females. Most common "single gene" cause of autism. The FMR1 gene provides instructions for making a protein called fragile X mental retardation 1 protein, or FMRP. This protein helps regulate the production of other proteins and plays a role in the development of synapses, which are specialized connections between nerve cells. In people with fragile X syndrome, the expanded CGG segment is repeated more than 200 times. The abnormally expanded CGG segment turns off (silences) the FMR1 gene, which prevents the gene from producing FMRP.

Describe the 3 risks of maternal obesity on pregnancy outcomes in mom and baby.

Increases risk for: Gestational diabetes and macrosomia Delivery complications Obesity in the offspring later development of type 2 diabetes in the mother Stillbirth, preterm birth, and some congenital malformations

What are several factors that might prompt the utilization of one of these techniques?

Indications for performing invasive methods: Mother ≥ 35yo previous child with abnormalities family history of abnormalities previous miscarriages abnormal maternal serum screening abnormal ultrasound

Define genomic imprinting.

Inhibition and silencing of chromosome. Genomic imprinting=difference in expression of alleles, which happens before fertilization. Causes inhibition of gene silencing. 2 types: Epigenesis-no change in DNA sequence. DNA methylation at C regions decreasing gene activity likewise histone methylation or deacetylation inhibits gene expression. Imprinting is inhibited.

Describe a cause of cyclopia.

Inhibition of the SHH gene, pax 6 is not inhibited. Also ingestion of corn lilly plant, cyclopamine toxin can inhibit SHH signaling pathway.

MIF

Inhibits female reproductive organ development.

___7. can refer to a Giemsa stained display of chromosomes in metaphase.

Karyotype

Explain the molecular defects, clinical manifestations, and treatments of Niemann-Pick Disease

Lethal condition Niemann Type A lethal-usually live for a few month-no Niemann Type B-not lethal

Explain the molecular defects, clinical manifestations, and treatments of Zellweger Syndrome

Liver gets larger because you are trying to compensate. VLCFA-very long chain fatty acids

TDF

Located on Leydig cells between the seminiferous tubules where testosterone is produced. Testosterone---->dihydrotestosterone (more potent form).

Explain the molecular defects, clinical manifestations, and treatments of Alkaptonuria

Lower protein diet-treatment -defect in homogentisate 1, 2-dioxygenase

___8. is due to a deficiency of 5-alpha reductase.

Male pseudohermaphroditism

_ _5. is caused by a defective branched chain ketoacid dehydrogenase.

Maple syrup urine disease

What are several Noninvasive Diagnostic Methods?

Maternal Serum Screens Ultrasound Ausculation

___1. refers to the situation in which the two members of a gene pair separate during gamete formation.

Mendel first law

What are some of the common features of the mitochondrial diseases? Which gene products are commonly defective?

Mitochondrial myopathies are a group of neuromuscular diseases caused by damage to the mitochondria. Brain neuronal cells and muscle cells require a great deal of energy, and thus appear to be particularly affected when mitochondrial dysfunction occurs. The symptoms of mitochondrial myopathies include muscle weakness or exercise intolerance, heart failure or rhythm disturbances, dementia, movement disorders, stroke-like episodes, deafness, blindness, droopy eyelids, limited mobility of the eyes, vomiting, and seizures. Complexes I and IV, ATP synthase or coenzymes associated with e- transport (CoQ10) are often defective.

Explain how family studies and comparisons of disease incidence in monozygotic twins vs dizygotic twins help elucidate the genetic vs environmental influences in the expression of the disease.

Monozygotic twins share 100% of their gene arrays, whereas dizygotic twins only share 25%. Therefore comparing the incidence of disease in these two sets can indicate whether the genetic factor or environmental factor is more likely to cause disease.

___4. refers to when two different chromosome complements are present within a person.

Mosaicism

Define and give an example of mosaicism.

Mosaicism -An individual has cells containing 2 or more different chromosome complements -Some cells have normal chromosome complement, others do not -Usually caused by nondisjunction in early postzygotic mitotic divisions (at the 16-32 cell stage) Symptoms are usually less severe -46/47,+21=Down Syndrome Blaschko's Lines: -Named after Alfred Blaschko; German dermatologist -Are lines of normal cell development in the skin -Are believed to trace the migration of embryonic cells -Lines are invisible under normal conditions -Become apparent in some diseases of the skin; systemic lupus erythematosus; epidermal nevi (non-benign growth-mole) -Follow a "V" shape over the back, "S" shaped whorls over the chest, and sides, and wavy shapes on the head

B. Osteogenesis Imperfecta, Type I and Type II. Why are these mutations termed Dominant Negative?

Mutations in collagen (osteogenesis imperfecta) is dominant negative because mutations in individual subunits of polymeric structural proteins produces a subpopulation of mutated components that can interfere with the assembly of the normal multimer. The severity of OI varies. In addition to brittle bones in the survivable forms of OI, Individuals can have blue teeth and sclera discoloration. Treatment involves physical therapy, biphosphonate (fosamax), supportive equipment, and sometimes surgery. OI Type 1 is the most common and a relatively mild disorder caused by mutations that inactivate one of the two copies of the COL1A1 gene . The mutations usually involve premature stop signals, small insertions, or deletions. The mutated allele does not produce functional pro-alpha1(I) chains. Because only one allele generates pro-alpha1(I) chains, cells produce about half of the normal amount of Type I collagen, but all of the final product is normal. Decreased amounts of collagen fibrils results in bone fragility, decreased calcification, and other symptoms. OI Type II, III and IV are caused by mutations in the COL1A1 gene and less often the COL1A2 gene . These mutations are point mutations that occur in codons for essential glycines with substitutions by bulky amino acids. These protein chains incorporate into the triple helix but the chains are subject to proteolysis. There are fewer functional collagen fibers than in Type I. Type II is perinatally lethal.

___8. is due to a deficiency of acid sphingomyelinase.

Neimann pick disease type A

Describe single gene abnormalities along with types of mutations.

Nonsense Mutation: - produces a stop codon (UAG, UAA, AGA) in mRNA - Beta thalassemia major; Cooley's Anemia 2. Other Mutations - base pair or point mutations represent over 60% of single gene causing mutations - additional noteworthy mutations often result from deletion or insertion of one or more base pairs -frameshift mutations (Tay-Sach's and CF), promoter mutations (pyruvate kinase deficiency), & splice site mutations (beta thalassemia)

FGFR3 defect (gain of function)

Normal FGFR3 is an inhibitor of cartilage formation. The receptor is a protein tyrosine kinase and is activated by several Fibroblast Growth Factors. In the case of the mutated receptor, the kinase is constituatively active. The combination of a normal FGFR3 and the defective receptor results in decreased cartilage and long bone formation at the level of chondrocytes in the bone plate.

Using retinoblastoma as your model, what is the genotype and phenotype of the cells that are normal (two different genotypes can give a normal phenotype) and cancerous (one genotype).

Normal phenotypes can have no mutated alleles or 1 mutated allele with inheritance (rbrb or RBrb) the cancerous phenotype must have two mutated alleles (RBRB).

Describe the genetics and phenotype of polycystic kidney disease.

Numerous cystic growths associated with nephrons. This condition contributes to a significant fraction of endstage renal disease. Defects are located in the polycystin genes PKD1 (chr16, 85%) and PKD2 (chr4, 15%). Freq 1/400 to 1/1000. Polycystins are integral membrane proteins that are involved in sensing cell pressure/environment (PDK1) and as Ca2+ channels (PKD2). PKD1 is believed to regulate the channel activity of PKD2. Symptoms include UTIs, hematuria, flank pain, hyperteinsion, and enlarged kidneys. Eventually requires dialysis and, if lucky, a kidney transplant.

_ _4. is due to a lack of tyrosinase.

Oculocutaneous albinism

Why would the mutation of one allele coding for typical metabolic enzyme (e.g., glucose phosphate isomerase in glycolysis) be a recessive rather than dominant inheritance?

Ordinary enzymes/proteins usually require both allelic products to be nonfunctional to produce a mutant phenotype and are thus autosomal recessive.

Recite the Hardy-Weinberg Equation.

PKU disease autosomal recessive. q^2homozygote with 2 small pp -PKU disease 1/4,500 what is carrier frequency? q^2=1/4,500, q= 0.015 p=1-q=0.985 2pq=carrier frequency= 2(0.985)(0.015)=0.029 or 3 % -HW calucations yield valuable info for genetic counseling and public health.

___2. is due to trisomy of chromosome 13.

Patau Syndrome

Incomplete Dominance

Pattern of inheritance in which a heterozygous genotype expresses a phenotype intermediate between dominant and recessive phenotypes.

Codominance

Pattern of inheritance that corresponds to the equal, distinct, and simultaneous expression of 2 different alleles.

___7. refers to the observable properties of an organism.

Phenotype

Describe the molecular genetics of Sex Reversal Syndrome and Male Infertility.

Rare (1/40,000) Sex Reversal Syndrome where the Y-chromosome is missing the SRY gene due to unequal crossover with the X-chromosome. The male exhibits the female phenotype and lacks testes. The reciprocal X-chromosome would produce a XX male. Y-linked male infertility involving mutations (often deletions) associated with the azospermia factor genes (there are three AZF clusters) that when mutated disrupt production of functional sperm.

Nonpenetrance

Reduced or incomplete when some individuals fail to express the trait, even though they carry the allele.

Explain the molecular defects, clinical manifestations, and treatments of Friedreich's Ataxia

Rhabdomyolysis-urine turns reddish brown, jaundice caused from extreme training-breaking down muscle proteins-->myoglobin is released (color).

Debate MECP2 Duplication Syndrome.

Rhett's syndrome-over expression MECP2-female ( a mutation in MECP2 not a duplication). A duplication of the q arm on X chromosome, normally binds to methylated DNA, in this condition there is too much inhibition and under expression of genes. 2 different conditions, over expression=Rett and under expression due to duplication.

___6. a circular chromosome implicated in some epilepsy cases.

Ring Chromosome

Ring chromosomes.

Ring chromosomes are usually degraded, but sometimes not. Ring chromosome 20 is a form of epilepsy with recurrent seizures and is resistant to drugs and surgery. When the ring forms it is either a deletion or mutation in acetylcholine receptor genes or K+ voltage gated channel genes. 5% or more of the cells have to express the ring chromosome to get the disease.

Describe the general infant weight categories; define SGA, LBW, LGA, and VLBW.

SGA-small gestational age, below 10th percentile AGA-average gestational age, 10-90th percentile LBW-low birth weight, less than 5lb 8oz LGA-large gestational age, greater than 90th percentile VLBW-very low birth weight, less than 3lb 5oz

___1. codes for a transcription factor that stimulates Sertoli cells to produce ABR and MIF.

SOX9 gene

___9. codes for transcription factor, TDF, that stimulates testis formation.

SRY gene

SRY gene

Sex determining region on the Y chromosome, codes for testis determining factor, when this is made at an increased amount it surpasses DAX which is the suppressor for testis formation. It also up regulates SOX9 on chromosome 17 that is another transcription factor. When SOX9 is up regulated sertoli cells within the seminiferous tubules are stimulated and the androgen binding receptor is made. These receptors will bind and hold testosterone in the tubules. MIF is then activated and it inhibits female reproductive organs from developing.

Contrast Sex-linked traits and Sex-influenced traits.

Sex-linked traits are determined by the genes on the sex chromosomes, whereas sex- influenced traits are much more common in one of the sexes, but can occur in both. However, the responsible gene(s) are not located on the X or Y-chromosomes

B. Hemophilia B

Single-nucleotide change in the gene for clotting Factor IX (rare, 1/100,000) that causes incorrect RNA splicing and produces a truncated, nonfunctional protein. Leads to decreased thrombin therefore fibrinogen is not converted to fibrin and clots do not form.

What is meant by concordance?

When the % of monozygotic twins expressing a phenotype for disease the more the disease cause comes from inheritance rather than environment, and vice versa.

Tetrasomy and Pentasomy X Syndromes

Tetrasomy and Pentasomy X Syndromes - about 100 total cases known - female - 48, XXXX and 49, XXXXX - epicanthal folds, small mouths, flat nasal bridge, speech and motor delays, joint issues, dental impairments, mental retardation - reduced fertility; offspring abnormalities

A or B is dominant over O, which is considered recessive, while A and B are codominant. EXPLAIN.

The 'O' blood group is caused by a deletion of guanine-258 corresponding to a region near the N-terminus of the protein. This mutation results in a frameshift and expression of an almost entirely different protein, which is unable to modify oligosaccharides which end in fucose-galactose. This sugar combination is termed the H antigen. The A and B alleles of the ABO gene express enzymes with glycosyltransferase activities that differ by adding either N-acetyl galactosamine or galactose to the H antigen, thus forming the A or B antigen respectively. Heterozygotes express both proteins and make both A and B antigens. Their blood group is AB. Remarkably, the difference between the A and B glycosyltransferase enzymes is only four amino acids. Derived from Wikipedia, ABO Blood Group System A&B are codominant and O is recessive to A or B.

What enzyme activities determine ABO Blood Types?

The ABO gene encodes for glucosyltransferases related to the ABO blood antigen system. There are three alleles, two of which code for two distinct glycosyltransferses depending on the gene sequence.

Describe the different tumor suppressor functions that are activated by p53.

The Genetics of p53, an extremely important tumor suppressor. In humans, the most common cancer causing mutation(s) of a tumor suppressor gene product are defects in a protein called p53 (it's a protein with a molecular mass of 53,000, thus p53). Mutated forms of p53 are found in at least 50% of all cancerous cells. P53 is a transcription factor that binds to its obligate DNA sequences as homotetramer. It has several important domains, but the DNA-binding domain and the tetramerization domain (TD) seem to be targets for most of the oncogenic mutations. Approximately 75% of TP53 tumor-derived mutations are point mutations that change a single amino acid. With 95% of these missense mutations occurring in the DNA-binding domain. In many cases, the mutated p53 does not bind to DNA but rather associates with "good" copies of p53 to form tetramers that are non functional and thus allows cell division. This is a dominant negative mutation.

Relate why medical genetics is increasingly important.

The application of genetic principles in medical practice is becoming more and more important. 1/2-3/4 of all pediatric deaths are linked to genetics. Personalized and predictive medicine is based on genetics.

How does the Liability Curve for the general population differ from a familial predisposition for an MF disease?

The curve for the general population indicates a smaller percentage of people with the disease whereas the curve for familial incidence has a greater percentage of people with the disease, both occurring at threshold for the disease.

Recognize the characteristics of an X-linked recessive disease.

The disease is never passed from father to son. All affected males in a family received the mutation from their mothers. Males are much more likely to be affected than females. If an affected male can reproduce, all of his daughters will be carriers. If affected males cannot reproduce, only males will be affected.

Explain how the incidence within a family group changes upon closeness of family members and the severity of the disease and the number of close relatives affected.

The incidence of the condition is greatest among relatives of the most severely affected patients. The risk is greatest among close relatives and decreases rapidly in more distant relatives. If there is more than one affected close relative, then the risks for other relatives are increased.

How is this pedigree unique compared to the other single gene disorders that we have previously studied?

The mother passes the disease to all of her offspring, males and females equally and if she has the mutation the offspring will also have the mutation, no skipping generations and not sex dependent.

Explain why these diseases occur in the presence of one mutated allele and one normal allele.

The mutated allele is dominant over the normal recessive allele therefore, if one dominant allele is inherited the phenotype is expressed.

The mtChromosome codes for 14 proteins yet a functional mitochondrion contains as many as 3000 proteins. EXPLAIN

The other proteins associated with mitochondria are coded for by the nucleus (nuclear origin).

Explain the "Two Hit" Model and why a disease pedigree looks autosomal dominant, but the mutations are recessive at the cellular level.

The pedigree appears to be a dominant inheritance, but at the cellular level it is recessive. The affected individuals inherit one defective allele, but disease expression doesn't occur unless the normal allele undergoes mutation. This event become more likely once the one defective gene is inherited. The probability of a cell sporadically receiving mutation becomes nearly 100% once the defective allele is inherited, therefore disease expression is highly likely.

Explain the relative probability of developing retinoblastoma when inheriting one mutated allele versus inheritance of two normal alleles.

The probability greatly increases for developing RB when one mutated allele is inherited because RB follows the Two Hit pattern of inheritance. Therefore, the probability of developing RB with one inherited defective allele approaches 100% because only one sporadic mutation needs to occur in a cell and there are trillions of cells this could occur to. Whereas, when no mutated alleles are inherited the sporadic mutation has to occur twice as two separate incidences and the probability of this occurring is much lower.

Percutaneous Blood sampling?

The prodecure increases the risk of fetal loss by 3%. The isolation of blood cells enables rapid cytogenic analysis (Check time2-3 days) and screening for many hematological diseases.

Describe/list the steps in the formation of a Barr bodies from an X-chromosome.

The q-arm of an X-chromosomes contain an X-inactivation center. This region contains the XIST gene (X-inactive specific transcript) that is unmethylated on the X-chromosome to be inactivated. Thus, it is transcriptionally active and produces large quantities of RNA that coat that X-chromosome. The RNA recruits DNA methylases and de-acetylases and other factors that allow the DNA to condense into a compact structure (a Barr Body).

Which of the two scenarios is more likely to have RB in both eyes? Why?

The scenario where the child inherits one mutated allele would lend itself to have tumors in both eyes over sporadic mutation of both alleles for the same reasons as the probability of the mutations occurring at the normal allele. 70% of RBs are in one eye and this represents both sporadic and inherited forms. 30% have RB in both eyes and it is primarily the inherited form.

What are the characteristics of an X-linked dominant inheritance and contrast these features with X-linked recessive inheritance.

The trait is never passed from father to son. All daughters of an affected male and a normal female are affected. All sons of an affected male and a normal female are normal. Matings of affected females and normal males produce 1/2 the sons affected and 1/2 the daughters affected. Males are usually more severely affected than females. The trait may be lethal in males. In the general population, females are more likely to be affected than males, even if the disease is not lethal in males.

Why are these defect so important to muscle and neuron function?

These tissues absolutely require ATP to function.

SOX9

Transcription factor stimulates sertoli cells to make androgen binding receptors. chromosome 17

_ _13. Autosomal recessive inheritance is characterized by frequent skipping of generations.

True

_ _14. Penicillamine is an appropriate treatment for Wilson's Disease.

True

_ _15. Thalidomide can induce phocomelia.

True

___1. Ingestion of Veratrum californicum material by a pregnant woman may result in the birth of a child with cyclopia.

True

___11. Female Pseudohermaphroditism is most commonly due to congenital adrenal hyperplasia.

True

___5. Hemophilia A can be caused by an inversion mutation.

True

___7. The risk of having a Down Syndrome child increases significantly when the mother is over 35 years of age.

True

___8. The most common disorder of the peripheral nervous system is Charcot-Marie-Tooth Disease.

True

___9. TDF stimulates Leydig cells to produce testosterone and AZFs.

True

___4. The long arm of the human chromosome is called the q arm.

True, short arm=p arm

Discuss Velocardiofacial/DiGeorge Syndrome.

Velocardiofacial/DiGeorge Syndrome -Deletion in long arm of chromosome 22 (22q11) -Tall nasal root and bridge, cleft palate, poorly developed thymus, reduced parathyroid activity, decreased serum calcium and heart defects -Most common microdeletion syndrome; 1/3000 TBX1 gene - codes for transcription factor. This is the most common deletion syndrome.

List a danger of Veratrum californicum.

Veratrum contains cyclopamine and looks like the plant Hellebore (toxin free) which is a remedy for morning sickness. Therefore, the Veratrum plant could be ingested by mistake.

___11. is sometimes considered the father of genetic medicine.

Victor Mckusick-april 2008 award Japan prize-similar to nobel prize, died shortly after given award

Identify the 5 nutrient deficiencies which are most commonly seen in practice among pregnant/lactating women, and recommend how they can be prevented/treated.

Water-encourage hydration Magnesium-Prenatal or supplement Protein-Lean protein diet or alternative protein supplement Folate/B12-Supplement and diet Iron-Prenatal or supplement

ABR

Where testosterone binds within the seminiferous tubules.

There is strong evidence that the majority of cancer mutations are acquired rather than inherited. In addition, mutated alleles for tumor suppressor genes are much more likely to be inherited than oncogenic mutations. Explain.

With a few exceptions, most mutations that transform proto-oncogenes into oncogenes are acquired rather than inherited. Since a major role of proto-oncogenes is to drive the cell cycle and cell division in a controlled manner, having an allele that expresses an oncogene in many cell types cells would present a serious problem! Therefore, the formation of oncogenes (in addition to viruses, etc) most likely happens at the level of sporadic somatic mutations in the affected individual rather than as inherited alleles.

C. Familial Hypercholesterolemia

Xanthomas are indicative of extremely high cholesterol and they form on eyelids, knuckles, and joints.

4. The pedigree below traces the inheritance of alkaptonuria, a biochemical disorder. Affected individuals, indicated here by the filled-in circles and squares, are unable to break down a substance called alkapton, which colors the urine and stains body tissues. Alkaptonuria appears to be caused by a(n) _____________ allele. A. Autosomal dominant B. Autosomal recessive C. X-linked recessive D. X-linked dominant E. Y-linked dominant

autosomal recessive- dominant wiped out because Carla is recessive (y-linked) -Wilma-not X-linked

_ _3. is caused by a GAA triplet repeat and results in mitochondrial iron accumulation.

friedrich ataxia

___2. a chromosome in which one arm is missing and the other is duplicated in mirror-image fashion.

iSOCHROMOSOME

Discuss schizophrenia and chromosome deletion.

microRNAs-inhibit gene expression -if we don't have microRNAs-upregulate/increase gene expression-->neural/behavioral deficits -Deletion is more harmful than duplication-because it's a lose of function. Duplication-don't have to lose that function.

Describe the tumor suppressive mechanism of RB.

pRB, Tumor Suppression and Carcinogenesis- pRB is a tumor suppressor involved in the regulation of the cell cycle. The suppressor activity of pRB appears to be controlled by the regulation of phosphorylation levels. Cyclin D1-Cdk4 (cdk,cyclin-dependent kinase) appears to be the protein kinase that phosphorylates pRB. The dephospho-pRB binds transcription factor E2F, thus blocking gene-specific transcription. Phosphorylation of the pRB protein results in dissociation of pRB from E2F, thus allowing transcription. E2F transcriptional complexes induce synthesis of G1/S transition enzymes such as DNA polymerase-alpha and dihydrofolate reductase! RB gene mutations of both chromosomes #13 would remove replication constraints and E2F would be able to bind the appropriate promoters and induce transcription.

_ _2. exhibits saturated LNAATs, impaired neurotransmitter formation, and mental retardation.

phenylketonuria

Explain the molecular defects, clinical manifestations, and treatments of Homocystinuria

significant portion of individuals die around 30ish

_ _1. is characterized by a reduction or absence of peroxisomes.

zellweger syndrome