Sex-Linked and Nontraditional Inheritance Flashcards
Sex chromosomes
Humans have X and Y sex chromosomes, males XY, females XX
Lyon hypothesis
One X chromosome in each XX cell is inactive, seen in nucleus as Barr body, basis for dosage compensation, inactivation is random, fixed, incomplete
X-inactivation patterns
Two cell types result from X-inactivation, may express different alleles, all normal females are mosaics
X-inactivation center
Specific region of X chromosome, contains at least one gene XIST, transcribes 17kb RNA from inactive X, coats inactive X to maintain inactivation, methylation and histone deacetylation may be important
Sex-linked inheritance
Due to X-linked genes, different patterns in males and females, in females is similar to autosomal recessive, in males recessive X-linked genes are expressed
Sex-linked disorders
Hemophilia A, Duchenne’s muscular dystrophy, red-green color blindness
X-linked recessive females
Frequency of affected females is low, requires affected father or new mutation, heterozygotes express mutation in half their cells, normal cells compensate
X-linked recessive pedigrees
No father-son transmission, affected males are much more common, passage through females show “skipped” generations, afected father and normal mother will have no affected children
Hemophilia A
Defect in Factor VIII gene on X, affects 1:5,000 to 10,000 males, prolonged or severe bleeding from wounds, hemorrhages in joints and muscles
Factor VIII gene in hemophilia
Half of patients have severe form (<1% normal Factor VIII activity), moderate forms (1-5%, 5-15% activity), gene is 186 kb long, 26 exons, 9kb mRNA
Duchenne muscular dystrophy
Severe progressive muscular atrophy, affects 1:3500 males, shows before age 5, in wheelchair by 11, heart and respiratory muscles impaired, death by cardiac/respiratory failure by 25, creatine kinase is early diagnostic indicator
DMD gene
Dystrophin gene, 2.5 Mb, 14 kb mRNA, 3685 amino acid protein, largest known gene, may be involved in cytoskeletal integrity, binds F-actin and dystroglycan, usually absent in DMD
Color blindness
Red-green color blindness is x-linked, normal visition is trichromatic, missing one color is dichromatic
Reason for color blindness
Opsin protein absorbs colors, responsible for color vision, red and green opsins adjacent on X, affected people have abnormal arrangement (no green = deuteranopia, no red = protanopia), unequal crossing over
X-linked dominant inheritance
Much less common than recessive disorders, heterozygote females may be less affected than homozygotes (mating of affected not likely), females twice as likely to be affected than males, vertical transmission, seen in every generation, males from mother, females from either parent
Hypophosphatemic rickets
X-linked dominant, kidneys unable to reabsorb phosphate, abnormal ossification, bones bend and distort
Incontinentia pigmenti
X-linked dominant, abnormal skin pigmentation and teeth, neurological and ocular abnormalities, males lost in utero
Rett syndrome
X-linked dominant, autism, ataxia, mental retardation, some males survive to term
X-linked dominant pedigree
More females affected, present in all generations, no father-son transmission
Y-chromosome inheritance
Strictly father-son, holandric inheritance, most genes involved with sex determination, spermatogenesis, and testicular function
Mitochondrial inheritance
Mitochondria have circular chromosome, produce own ribosomes and tRNA, inheritance is maternal, mutation rate is high (lack of repair systems, free radicals from oxidative metabolism)
Variable expression
Many mitochondria per cell, mutation may be present in only some (heteroplasmy), percentage of mutant molecules determines status of mitochondrial function
Leber hereditary optic neuropathy (LHON)
Mitochondrial disorder, optic nerve death in 3rd decade, heteroplasmy uncommon, missense mutation in protein coding genes
Myoclonic epilepsy with ragged red fibers (MERRF)
Mitochondrial disorder, single base changes in tRNA, epilepsy, ataxia, dementia, myopathy, heteroplasmic, highly variable expression
Mitochondrial encephalomyopathy and stroke-like episodes (MELAS)
Single-base mutations in tRNA, heteroplasmic with variable expression
Mitochondrial disorders due to duplications and deletions in mitochondrial chromosome
Kearns-Sayre disease, Pearson syndrome, chronic progressive external opthalmoplegia
Fragile X syndrome
Most common inherited form of mental retardation, fragile refers to effect in cultured cells (long arm of X breaks in low folic acid), affects 1:4000 males, 1:8000 females, not recessive, not fully dominant, odd inheritance
Sherman paradox
Normal transmitting males (NTM)- normal male with affected descendants, daughters of NTMs are never affected but grandchildren of NTM may be affected, does not appear to be normal inheritance
Resolving Sherman paradox
Cloned FMR1, find CGG repeat in 5’ UTR, normal is 6-50 copies, abnormal >230, transmitting males have 50-230, repeat expands only in female meiosis, offspring of transmitting males have same number as father
Molecular biology of FMR1
Normal amount in normal, more mRNA in expanded repeats up to 230, then none, highest expression in brain
Disruption of FMR1
Large repeats have high methylation, may explain loss of transcription, small percentage have structural mutation, affects mRNA distribution in neurons, glutamate receptor is key
Fragile X phenotype
Long face, prominent jaw, large ears
Genomic imprinting
Chromosomal regions methylated differently in sperm vs. ova, causes different expression level from paternal vs. maternal chromosome, sum of levels if normal, if one is mutated, level depends on activity of other, can cause two different disorders from same region
Prader-Willi syndrome
Paternal deletion, maternal imprinting
Angelman syndrome
Maternal deletion, paternal imprinting
