Biochemistry - Genetics

  1. Codominance
    • Both alleles contribute to the phenotype of the heterozygote
    • blood groups A, B, AB
  2. Variable expressivity
    • Phenotype varies among individuals with same genotype
    • 2 patients with neurofibromatosis type 1 (NF1) may have varying disease severity
  3. Incomplete penetrance
    • Not all individuals with a mutant genotype show the mutant phenotype
    • BRCA1 gene mutations do not always result in breast or ovarian cancer
  4. Pleiotropy
    • One gene contributes to multiple phenotypic effect
    • PKU causes many seemingly unrelated symptoms,  ranging from mental retardation to hair/skin changes
  5. Imprinting
    • Differences in gene expression depending on whether the mutation is of maternal or paternal origin
    • Prader-Willi and Angelman's syndromes
  6. Anticipation
    • Increased severity or earlier onset of disease in succeeding generations
    • Huntington's disease
    • Trinucleotide repeat disorders
  7. Loss of heterozygosity
    • If a patient inherits or develops a mutation in a tumor suppressor gene , the complementary allele must be deleted/mutated before cancer develops
    • NOT true of oncogenes
    • Retinoblastoma and the "two-hit hypothesis"
  8. Dominant negative mutations
    • Exerts a dominant effect
    • A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning
    • Mutation of a transcription factor in its allosteric site
    • Nonfunctioning mutant can still bind DNA, preventing wild-type transcription factor from binding
  9. Linkage disequilibrium
    • Tendency for certain alleles at 2 linked loci to occur together more often than expected by chance
    • Measured in a population, NOT in a family, and often varies in different populations
  10. Mocaisism
    • Occurs when cells in the body differ in genetic makeup due to postfertilization loss or change of genetic information during mitosis
    • Can be a germ-line mosaic (gonadal mosaicism), which may produce disease that is not carried by parent's somatic cells
    • Mutation in the embryonic precursor of the bone marrow stem cell → a hematologic mosaic individual
    • chimeric individual  is derived from 2 zygotes that subsequently fuse
  11. Locus heterogeneity
    • Mutations at different loci can produce the same phenotype
    • Marfan's syndrome, MEN2B and homocystinuria; ALL cause marphanoid habitus
    • Albunism
  12. Heteroplasmy
    Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease
  13. Uniparental disomy
    • Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent
    • Heterodisomy (heterozygous) indicates a meiosis I error
    • Isodisomy (homozygous) indicates a meiosis II error or postzygotic chromosomal duplication of one of a pair of chromosomes, and loss of the other of the original pair
    • Uniparental is eUploid (correct number of chromosomes)
    • Most occurrences of UPD → normal phenotype
    • Consider UPD in an individual manifesting a recessive disorder when only one parent is a carrier
  14. Hardy-Weinberg population genetics
    • If a population is in Hardy-Weinberg equilibrium and if p and q are the freqencies of separate alleles, then:
    • p2 + 2pq + q2 = 1 
    • p + q = 1
    • p2 = frequency of homozygosity for allele p
    • q2 = frequency of homozygosity for allele q
    • 2pq = frequency of heterozygosity (carrier frequency, if autosomal recessive)
    • The frequency of an X-linked recessive disease in males = q; in females = q2
  15. Hardy-Weinberg law assumes:
    • No mutation occurring at the locus
    • No selection for any of the genotypes at the locus
    • Completely random mating
    • No net migration
  16. Imprinting
    • At some loci, only 1 allele is active; the other is inactive (imprinted/inactivated by methylation)
    • With 1 allele inactivated, deletion of the active allele leads to disease
    • Prader-Willi, Angelman's syndromes due to inactivation or deletion of genes on chromosome 15 (Can also occur as a result of uniparental disomy)
  17. Prader-Willi syndrome
    • Prader-Willi syndrome
    • Paternal allele is not expressed
    • Presents: mental retardation, hyperphagia, obesity, hypogonadism, hypotonia
  18. AngelMan's syndrome
    • AngelMan's syndrome
    • Maternal allele is not expressed
    • Presents: mental retardation, seizures, ataxia, inappropriate laughter
  19. Modes of inheritance
    • Autosomal dominant/recessive
    • X-linked recessive/dominant
    • Mitochondrial inheritance
  20. Image Upload 1
    • Autosomal dominant
    • Often due to defects in structural genes.
    • Many generations
    • Both male and female affected
    • Often pleiotropic
    • Family history is crucial to diagnosis
  21. Image Upload 2
    • Autosomal recessive
    • 25% of offspring from 2 carrier parents are affected
    • Often due to enzyme deficiencies
    • Usually seen in only 1 generation
    • Commonly more severe than dominant disorders
    • Patients often present in childhood
  22. Image Upload 3
    • X-linked recessive
    • Sons of heterozygous mother have 50% chance of being affected
    • No male-to-male transmission
    • Commonly more severe in males
    • Females usually must be homozygous to be affected
  23. Image Upload 4
    • Transmitted through both parents
    • Either male or female offspring of the affected mother may be affected
    • All female offspring of the affected father are affected
    • Hypophosphatemic rickets: formerly known as vitamin D-resistant rickets
    • -inherited disorder resulting in ↑ phophate wasting at proximal tubule

    -Rickets-like presentation
  24. Image Upload 5
    • Mitochondrial inheritance
    • Transmitted only through mother
    • All offspring of affected females may show signs of disease
    • Often due to failures in oxidative phosphorylation
    • Variable expression in population due to heteroplasmy
    • Mitochondrial myopathies: group of rare disorders resulting from mutations affecting mitochondrial function
    • -Often present with myopathy and CNS disease
    • -Muscle biopsy shows "ragged red fibers"
  25. Autosomal-dominant disease
    • Achondroplasia
    • ADPKD
    • Familial adenomatous polyposis
    • Familial hypercholesterolemia (hyperlipidemia type IIA)
    • Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)
    • Hereditary spherocytosis
    • Huntington's disease
    • Marfan's syndrome
    • Multiple endocrine neoplasias (MEN)
    • Neurofibromatosis type 1 (von Recklinghausen's disease)
    • Neurofibromatosis type 2
    • Tuberous sclerosis
    • von Hippel-Lindau disease
  26. Achondroplasia
    • Cell-signaling defect of fibroblast growth factor (FGF) receptor 3
    • Presentation: dwarfism, short limbs, larger head, but trunk size normal
    • Associated with advanced paternal age
  27. Autosomal-dominant polycystic kidney disease (ADPKD)
    • Bilateral, massive enlargement of kidneys due to multiple large cysts
    • Presentation: flank pain, hematuria, hypertension, progressive renal failure
    • 855 of cases are due to mutation in PKD1 (chrom 16)
    • Associated with polycyctic liver disease, berry aneurysm, mitral valve prolapse
  28. Familial adenomatous polyposis
    • Colon becomes covered with adenomatous polyps at puberty
    • Progresses to colon cancer unless colon is resected 
    • Mutations on chromosome 5 (APC gene)
  29. Familial hypercholesterolemia (hyperlipidemia type IIA)
    • Elevated LDL due to defective or absent LDL receptor
    • Heterozygotes (1:500) have cholesterol ~ 300mg/dL
    • Homozygotes (rare) have cholesterol >700mg/dL:
    • -severe atherosclerotic disease early in life
    • -tendon xanthomas (classically the Achilles tendon)
    • -MI may develop before age 20
  30. Hereditary hemorrhagic telangiectasia
    (Osler-Weber-Rendu syndrome)
    • Inherited disorder of blood vessels
    • Findings: telangiectasia, recurrent epistaxis, skin discolorations, arteriovenous malformations (AVMs)
  31. Huntington's disease
    Trinucleotide repeat disorder: (CAG)n

    • Findings:
    • -Depression
    • -Progressive dementia
    • -Choreiform movements
    • -Caudate atrophy
    • -↓ levels of GABA and ACh in the brain

    • Sx manifest in affected individual s between the age of 20 and 50
    • Gene located on chromosome 4: "Hunting 4 food"
  32. Marfan's syndrome
    • Fibrillin-1 gene mutation → connective tissue disorder affecting skeleton, heart, and eyes
    • Findings:
    • -tall with long extremities
    • -pectus excavatum
    • -hypermobile joints
    • -long, tapering fingers and toes (arachnodactyly)
    • -Subluxation of lenses
    • -Cystic medial necrosis of the aorta → aortic incompetence and dissecting aortic aneurysms
    • -Floppy mitral valve
  33. Multiple endocrine neoplasias (MEN)
    • Several distinct syndromes (1, 2A, 2B) characterized by familial tumors of endocrine glands
    • -Pancreas
    • -Parathyroid
    • -Pituitary
    • -Thyroid
    • -Adrenal medulla

    MEN 2A and 2B are associated with ret gene
  34. Neurofibromatosis type 1
    von Recklinghausen's disease
    Mutation on long arm of chromosome 17

    • Findings:
    • -café-au-lait spots
    • -neural tumors
    • -Lisch nodules (pigmented iris hamartomas)
    • -Marked by skeletal disorders (e.g. scoliosis)
    • -Optic pathway gliomas
  35. Neurofibromatosis type 2
    • Bilateral acoustic schwannomas
    • Juvenile cataracts
    • NF2 gene on chromosome 22; type 2 = 22
  36. Tuberous sclerosis
    • Findings:
    • -Facial lesions (adenoma sebaceum)
    • -hypopigmented "ash leaf spots" on skin
    • -cortical and retinal hamartomas
    • -seizures
    • -mental retardation
    • -renal cysts
    • -renal angiomyolipomas
    • -cardiac rhabdomyomas
    • -↑ incidence of astrocytomas

    Incomplete penetrance, variable presentation
  37. von Hippel-Lindaue disease
    • Findings:
    • -hemangioblastomas of retina/creebellum/medulla
    • -multiple bilateral renal cell carcinomas and other tumors (most)

    Associated with deletion of VHL gene (tumor suppressor) on chromosome 3

    Constitutive expression of HIF (transcription factor) and activation of angiogenic growth factors

    **Von hippel-lindau = 3 words for chromosome 3
  38. Autosomal-recessive diseases
    • Albinism
    • ARPKD
    • Cystic fibrosis
    • Glycogen storage diseases
    • Hemochromatosis
    • Mucopolysaccharidoses (except Hunter's)
    • Phenylketonuria
    • Sickle cell anemias
    • Sphingolipidoses (except Fabry's)
    • Thalassemias
  39. Cystic fibrosis
    mechanism, findings, dx, tx
    • Autosomal recessive defect in CFTR
    • -Chromosome 7; most common is deletion of Phe508 (ΔF508)
    • -CFTR channel: secretes Cl- in lungs, GI tract; reabsorbs Cl- from sweat
    • -Most common lethal genetic disease of white population

    • Mechanism of disease:
    • Defective Cl- channel → secretions of thick mucus that plugs lungs, pancreas, liver → recurrent pulmonary infections, chronic bronchitis, bronchietasis, pancreatic insufficiency, nasal polys, meconium ileus
    • -Pseudomonas; S. aureus
    • -malabsortpion and steatorrhea

    • Presentation (other):
    • -infertility in males due to BAVD
    • -Fat soluble vitamin deficiencies (A, D, E, K)
    • -Failure to thrive in infancy

    • Dx:
    • -increased concentration of Cl- ions in swat test

    • Tx:
    • -N-acetylcystein to loosen mucous plugs (cleaves disulfide bonds within mucous glycoproteins
  40. X-linked recessive disorders
    • **BWise, Fool's GOLD Heeds Silly HOpe
    • Burton's aagammaglobulinemia
    • Wiskott-Aldrich syndrome
    • Fabry's disease
    • G6PD deficiency
    • Ocular albinism
    • Lesh-Nyhan syndrome
    • Duchenne's (and Becker's) muscular dystrophy
    • Hunter's Syndrome
    • Hemophilia A and B
    • Ornithine transcarbamoylase deficiency
  41. X-linked recessive disorders
    • Female carriers may be affected
    • May have less severe symptoms due to random X chromosome  inactivation in each cell
  42. Muscular dystrophies
    • X-linked frameshift mutation → deletion of dystrophin gene → accelerated muscle breakdown
    • -Weakness begins in pelvic girdle muscles and progresses superiorly
    • -Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle
    • -Cardiac myopathy
    • *Gower's maneuver to stand
    • -Onset: <5 years of age
    • **Duchenne's deleted dystrophin

    **Dystrophin gene (DMD) is the longest known human gene: ↑ rate of spontaneous mutation

    -Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle

    Diagnose: ↑CPK and muscle biopsy
  43. Becker's muscular dystrophy
    • X-linked mutated dystrophin gene
    • less severe than Duchenne's
    • Onset in adolescence or early adulthood
  44. Fragile X syndrome
    • X-linked defect affecting the methylation and expression of FMR1 gene
    • Trinucleotide repeat disorder (CGG)n
    • 2nd most common cause of genetic mental retardation (after Down syndrome)
    • Findings:
    • -macro-orchidism (enlarged testes)
    • -long face with large jaw
    • -large everted ears
    • -autism
    • -mitral valve prolapse
    • **Fragile X = eXtra large testes, jaw, ears
  45. Trinucleotide repeat expansion diseases
    Try (trinucleotide) hunting for my fried eggs (X): Huntington's disease, myotonic dystrophy, Friedreich's ataxia, fragile X syndrome

    • **X-Girlfriend's First Aid Helped Ace My Test
    • Fragile X syndrome: (CGG)n
    • Friedreich's ataxia: (CAA)n
    • Huntington's disease: (CAG)n
    • Myotonic dystrophy: (CTG)n

    May show genetic anticipation
  46. Autosomal trisomies
    • Down syndrome (trisomy 21): 1:700
    • Edwards' syndrome (trisomy 18): 1:8000
    • Patau's syndrome (trisomy 13): 1:15,000
  47. Image Upload 6
    Meiotic nondisjunction
  48. Down syndrome
    Cause, findings, QUAD screen, ultrasound
    • -Most common viable chromosomal disorder
    • -Most common cause of genetic mental retardation

    • 95% are due to meiotic nondisjunction of homologous chromosomes
    • -Associated with advanced maternal age (1:25 in women >45)

    • 4% are due to Robertsonian translocation
    • 1% are due to Down mosaicism (no maternal association)

    • Findings:
    • -mental retardation
    • -flat facies
    • -prominent epicanthal folds
    • -simian crease
    • -gap between 1st 2 toes
    • -duodenal atresia
    • -congenital heart disease (most commonly ostium primum type ASD)
    • --Associated with increased risk of ALL and Alzheimer's disease (for those >35 years of age)

    *Down syndrome (trisomy 21): Drinking age (21)

    • Results of pregnancy QUAD screen:
    • ↓ α-fetoprotein
    • ↑ β-hCG
    • ↓ estriol
    • ↑ inhibin A

    Ultrasound: ↑ nuchal in first trimester translucency
  49. Edwards' syndrome
    Findings, quad screen
    2nd most common trisomy resulting in live birth (after Down)

    • Findings:
    • -severe mental retardation
    • -rocker-bottom feet
    • -micrognathia
    • -low-set Ears
    • -clenched hands
    • -prominent occiput
    • -congenital heart disease
    • *Death usually occurs within 1 year of birth

    **Edwards'; trisomy 18Election age (18)

    • Pregnancy quad screen:
    • ↓ α-fetoprotein
    • ↓ β-hCG
    • ↓ estriol
    • Normal inhibin A
  50. Patau's syndrome
    Findings, 1st trimester pregnancy screen
    • Findings:
    • -Severe mental retardation
    • -Rocker-bottom feet
    • -microphthalmia
    • -microcephaly
    • -cleft liP/Palate
    • -HoloProsencephaly
    • -Polydactyly
    • -Congenital heart disease
    • *Death usually within 1st year of life

    Patau's syndrome (trisomy 13): Puberty (13)

    • First-trimester pregnancy screen:
    • ↓ free β-hCG
    • ↓ PAPP-A
    • ↑ nuchal translucency
  51. Robertsonian translocation
    • Nonreciprocal chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, and 22
    • Common type of translocation
    • Occurs when long arm of 2 acrocentric chromosomes fuse at the centromere and the 2 short arms are lost
    • Balanced translocations normally do not cause any abnormal phenotype
    • Unbalanced tranlsocations can result in miscarriage, stillbirth, chromosomal imbalance (e.g. Down syndrome, Patau's syndrome)
  52. Cri-du-chat syndrome
    • Congenital microdeletion of short arm of chromosome 5 (46,XX or XY, 5p-)
    • Findings:
    • -microcephaly
    • -moderate to severe mental retardation
    • -high-pitched crying/mewing
    • -epicanthal folds
    • -cardiac abnormalities (VSD)

    *Cri du chat = Cry of the cat
  53. Williams syndrome
    Congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene)

    • Findings:
    • -distinctive "elfin" facies
    • -intellectual disability
    • -hypercalcemia (↑ sensitivity to Vitamin D)
    • -Well-developed verbal skills
    • -extreme friendliness with strangers
    • -cardiovascular problems
  54. 22q11 deletion syndromes
    Microdeletion at chromosome 22q11; Due to aberrant development of 3rd and 4th branchial pouches

    • Variable presentation: **CATCH-22
    • -Cleft palat
    • -Abnormal facies
    • -Thymic aplasia → T-cell deficiency
    • -Cardiac defects
    • -Hypocalcemia 2° to parathyroid aplasia

    DiGeorge syndrome: thymic, parathyroid, and cardiac defects

    Velocardiofacial syndrome: palate, facial, and cardiac defects
Card Set
Biochemistry - Genetics
Biochemistry - Genetics