Biochemistry - Genetics

hixeruwe's version from 2016-05-12 18:03

Basic Genetics

Question Answer
Codominanceneither of 2 alleles is dominant (ie blood types)
incomplete penetrancenot all individuals with mutant genotype show mutant phenotype
Pleiotropy1 gene has >1 effect on phenotype (PKU can cause retardation to hair/skin change)
Imprintingdifferent phenotypes depend on whether mutation is of maternal/paternal origin
anticipationseverity of disease worsens or age of onset of disease is earlier in succeeding generations (huntingtons)
Loss of heterozygosityif parent inherits/develops mutation in tumor suppressor gene, complementary allele must be deleted/mutated also before cancer (retinoblastoma)
linkage disequilibriumtendency for certain alleles at 2 linked loci to occur together more often than expected by chance, measured in a population
mosaicismcells in body have different genetic makeup, can be germ-line, (lyonization-random x inactivation in females)
locus heterogeneitymutations at different loci can give same pheno (marfans, MEN2B, homocysinturia all cause marfanoid habitus)
heteroplasmypresence of both normal/mutated mtDNA--> variable expression in mito inherited disease
Uniparental disomyoffspring receives 2 copies of chromosome from 1 parent and no copies from other

Basic Genetics

Question Answer
Hardy-weinberg assumptionsno mutations, no selection for any genotypes, random mating, no migration
hardy weinberg equationp^2 + 2pq+ q^2= 1, 2pq= heterozygote, p+q=1
Prevelance of x-linked recessive disease in males/females based on Hardy-Weinberg population geneticsmales=q, females=q^2
Prader-williPaternal allele is not expressed - the normal maternal allele is silenced - chromosome 15
Findings: mental retardation, hyperphagia, obesity, hypogonadism, hypotonia
AngelMan syndromeMaternal allele is not expressed - the normal paternal allele is silenced - chromosome 15
Findings: mental retardation, seizures, ataxia, inappropriate laughter
Imprintingat single locus only 1 allele is active, the other is inactive (imprinted by methylation), if active allele is deleted-->disease
Auto dominantmostly due to defect in structural genes, many generations both M/F affected, often pleiotropic, family hx crucial to dx
Auto recessive25% of offspring from 2 carriers affected, usually due to enzyme deficits, usually only seen in 1 generation, usually more severe than dominant disorders, will see in childhood
x-linked recessivesome of heterozygous moms have 50% chance of being affected, no male-male transmission, more severe in males
X-linked dominanttransmitted thru both parents, either M/F offspring of affected mother may be affected while ALL female offspring of affected father are diseased
Hypophosphatemic ricketsVit-d resistant rickets, inherited disorder (x-linked dom) resulting in increase phosphate wasting at proximal tubule, rickets-like presentation
Mitochondrial inheritancetransmitted thru mom, all offspring of affected females may show disease, variable expression due to heteroplasmy
Mitochondrial myopathies (Leber's hereditary optic neuropathy)mito inheritance, degeneration of retinal ganglion cells/axons-->acute loss of central vision; RED RAGGED FIBERS

Autosomal-Dominant Diseases

AchondroplasiaAD, cell signaling defect of FGF receptor 3dwarfism, short limbs but head/trunk are normal size, assoc. w/advanced paternal age
Autosomal dominant polycystic kidney diseasemutations in PKD1 on chr 16**always bilateral** massive enlargement of kidneys due to multiple cysts, flank pain, hematuria, HTN, progressive renal failure
assoc w/polycystic liver disease, *berry aneurysms*, mitral valve prolapse
Familial adenomatous polyposisAD, deletion of chr 5 (5 letters in polyp) the APC genecolon covered with polyps after puberty, progression to colon cancer if no resection
Familial hypercholesterolemiaAD, elevated LDL & chol. due to absent/defective LDL receptorheteros = 300mg/dL, homo = 700+ mg/dL of cholesterol, severe atherosclerotic disease early and tendon xanthomas (in achilles usually), MI possible before age 20
Hereditary hemorrhagic telangiectasia (aka Osler-weber-rendu syndrome)AD disorder of blood vesselstelangiectasia, recurrent epistaxis, skin discolored, AVMs
Hereditary spherocytosisAD, spectrin/ankyrin defectspheroid erythrocytes, hemolytic anemia, increased MCHC, splenectomy = curative
Huntington'sAD, trinucleotide CAG repeat on chr 4depression/dementia/choreiform mvmts/caudate atrophy/decreased GABA/Ach in brain, sxs b/t 20-50 y.o.
Marfan's syndromeAD, fibrillin gene mutation-->connective tissue disorder affects skeleton, heart, eyestall/long extremities, pectus excavatum, hyperextensive joints, long tapering fingers/toes, cystic medial necrosis of aorta-->aortic incompetence/dissecting aorta aneurysm
MEN (multiple endocrine neoplasias)AD, MEN 2A/2B assoc. w/ ret geneMEN1: Pancreatic, pituitary, parathyroid tumors (diamond)
MEN2a: Thyroid and parathyroid tumors, pheochromocytoma (square)
MEN2b: Thyroid tumors, pheochromocytoma, ganglioneuromatosis (triangle)
Medullary Thyroid Carcinoma!
Neurofibromatosis type 1 (von recklinghausens disease)AD, on long arm of chr. 17 (17 letters in von Recklinghausen)cafe-au-lait spots, neural tumors, lisch nodules (pigmented iris hamartomas), skeletal disorders (scoliosis), optic pathway gliomas, pheochromocytomas
Neurofibromatosis type 2AD, NF2 gene on chr. 22 (type 2=22)bilateral acoustic schwannomas, juvenile cataracts...NO NEUROFIBROMAS
Tuberous sclerosisAD, incomplete penetrance and variable presentationfacial lesions, hypopigmented "ash leaf spots" on skin, cortical/retinal hamartomas in ventricles (brain), retardation, renal cysts & angiomyolipomas, cardiac rhabdomyomas, astrocytomas, seizures
von Hippel-Lindau diseaseAD, deletion of VHL tumor suppressor gene on chr. 3-->constitutive expression of HIF (T.F.) and activation of angiogenic growth factorshemangioblastomas of retina/cerebellum/medulla, 1/2 develop multiple bilateral renal carcinomas --> clear cells

Autosomal Recessive & X- Linked Diseases

Question Answer Column 3
AR diseases.albinism, ARPKD, cystic fibrosis, glycogen storage diseases, hemochromatosis, mucopolysaccaridoses (except Hunter), pku, sicle cell, thalassemias, spingolipidoses (except Fabry's)
Cystic fibrosisAR defect in CFTR gene on chr. 7 (delF508) which actively secretes Cl- in lungs/GI tract and actively reabsorbs Cl- from sweatdefective Cl- channel secretes thick mucus plugging lungs/pancreas/liver-->recurrent infxns/chronic bronchitis/pancreatic insufficiency, mutation causes abnormal protein folding-->degradation of channel before reaching cell surface
Complications: infertility due to bilateral absence of vas deferens
Diagnostic test of cystic fibrosis.increased [Cl- ions] in sweat
Treating CF.N-acetylcysteine to loosen mucous plugs-->cleavage of disulfide bonds within mucous glycoproteins
X-linked recessive disorders.Be Wise, Fool's GOLD Heeds HOpe: bruton's agammaglobulinemia, Wiskott-aldrich, Fabry's disease, G6PD def, Ocular albinism, Lesch-Nyhan, Duchenne's, Hunter's syndrome, Hemophilia A and B, Ornithine transcarbamoylase
Duchenne'sXR frameshift mutation which deletes dystrophin gene --> frameshift mutationaccelerated m. breakdown, weakness begins in pelvic girdle and goes up, cardiac myopathy, pseudohypertrophy of calf mm. due to fibrofatty replacement of m., use of Gower's maneuver to stand up, onset before age 5
Becker'sXR mutated dystrophin gene (no frameshift)less severe than Duchenne's, onset in adolescence/early adult
Diagnosing muscular dystrophies.increased CPK (creatine phosphokinase) and m. biopsy
Dystrophin geneDMD, longest human gene-->high rate of spontaneous mutationdystrophin helps anchor m. fibers primarily in skeletal/cardiac m.
Gower's maneuver.characteristic of Duchennes, use upper extremities to stand up
Fragile X syndromeX-linked dominant defect affecting methylation/expression of FMR1 gene2nd most common cause of mental retardation, find "Xtra large testes (macro-orchidism), jaw, ears", autism, mitral valve prolapse, trinucleotide repeat disorder (CGG)

Additional Genetic Abnormalities

Question Answer
Trinucleotide repeat disordersHuntingtons (CAG), Myotonic dystrophy (CTG), Fragile X (CGG), Friedrichs ataxia (GAA)
Down syndrome featuresMR, flat facies, prominent epicanchal folds, simian crease, duodenal atresia, congenital heart disease, increased risk of ALL/Alzheimers
Pregnancy quad screen and Down syndromedecreased alpha-fetoprotein and estriol, increased b-HCG and inhibin A, ultrasound shows increased nuchal translucency
Cause of Down Syndromemeiotic nondisjunction of homologous chr. 21 (assoc. with advanced maternal age), some cases due to robertsonian translocation or Down mosaicism
Pregnancy quad screen: Decresed a-fetoprotein, estriol. Increased B-hCG, inhibin A
Edward's syndrometrisomy 18, severe retardation, rocker-bottom feet, micrognathia (small jaw), low-set ears, clenched hands, death w/in 1 yr of birth;
Pregnancy quad screen: Decreased AFP, b-HCG, estriol, normal inhibinA
Election age = 18
Patau's syndrometrisomy 13, severe retardation, cleft lip/palate, holoprosencephaly, polydactyly, death w/in 1 yr of birth;
1st trimester pregnancy screen: Decreased free B-hCG, PAPP-A, and increased nuchal translucency
Puberty = 13
robertsonian translocationswhen 2 acrocentric chromosomes (centromeres near ends) fuse at centromere and 2 short arms are lost, balanced translocations usually dont have abnormal phenotype
Most commonly involving chromosomes 13, 14, 15, 21, 22
Peri vs paracentric inversionsperi involves centromere and proceeds through meiosis, para doesn't involve centromere and doesnt go thru meiosis
Cri-du-chat syndromecongenital microdeletion of short arm of chr. 5, high pitched crying/mewing, epicanthal folds, cardiac abnormalities (VSD), microcephaly, mod-severe MR
Cri du chat = cry of the cat
Williams syndromecongenital microdeletion of long arm of chr. 7, distinctive "elfin" facies, MR, hypercalcemia (increased sens to vit D), well-devel verbal skills, extreme friendliness with strangers, cardio problems
22q11 deletion syndromesCATCH 22- cleft palate, abnormal facies, thymic aplasia (t cell def), cardiac defects, hypocalcemia (2o to parathyroid aplasia), microdeletion at chr. 22q11, can be DiGeorge or velocardiofacial
Due to aberrant development of 3rd and 4th branchial pouches
Digeorge syndromemicrodeletion of chromosome 22q11: thymic aplasia, parathyroid, and cardiac defects
Velocardiofacial syndromemicrodeletion fo chromosome 22q11, palate, facial, cardiac defects [PFC]