Sex-Linked and Nontraditional Inheritance

Question 1

Sex chromosomes

Answer 1

Humans have X and Y sex chromosomes, males XY, females XX

Question 2

Lyon hypothesis

Answer 2

One X chromosome in each XX cell is inactive, seen in nucleus as Barr body, basis for dosage compensation, inactivation is random, fixed, incomplete

Question 3

X-inactivation patterns

Answer 3

Two cell types result from X-inactivation, may express different alleles, all normal females are mosaics

Question 4

X-inactivation center

Answer 4

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

Question 5

Sex-linked inheritance

Answer 5

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

Question 6

Sex-linked disorders

Answer 6

Hemophilia A, Duchenne’s muscular dystrophy, red-green color blindness

Question 7

X-linked recessive females

Answer 7

Frequency of affected females is low, requires affected father or new mutation, heterozygotes express mutation in half their cells, normal cells compensate

Question 8

X-linked recessive pedigrees

Answer 8

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

Question 9

Hemophilia A

Answer 9

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

Question 10

Factor VIII gene in hemophilia

Answer 10

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

Question 11

Duchenne muscular dystrophy

Answer 11

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

Question 12

DMD gene

Answer 12

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

Question 13

Color blindness

Answer 13

Red-green color blindness is x-linked, normal visition is trichromatic, missing one color is dichromatic

Question 14

Reason for color blindness

Answer 14

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

Question 15

X-linked dominant inheritance

Answer 15

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

Question 16

Hypophosphatemic rickets

Answer 16

X-linked dominant, kidneys unable to reabsorb phosphate, abnormal ossification, bones bend and distort

Question 17

Incontinentia pigmenti

Answer 17

X-linked dominant, abnormal skin pigmentation and teeth, neurological and ocular abnormalities, males lost in utero

Question 18

Rett syndrome

Answer 18

X-linked dominant, autism, ataxia, mental retardation, some males survive to term

Question 19

X-linked dominant pedigree

Answer 19

More females affected, present in all generations, no father-son transmission

Question 20

Y-chromosome inheritance

Answer 20

Strictly father-son, holandric inheritance, most genes involved with sex determination, spermatogenesis, and testicular function

Question 21

Mitochondrial inheritance

Answer 21

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)

Question 22

Variable expression

Answer 22

Many mitochondria per cell, mutation may be present in only some (heteroplasmy), percentage of mutant molecules determines status of mitochondrial function

Question 23

Leber hereditary optic neuropathy (LHON)

Answer 23

Mitochondrial disorder, optic nerve death in 3rd decade, heteroplasmy uncommon, missense mutation in protein coding genes

Question 24

Myoclonic epilepsy with ragged red fibers (MERRF)

Answer 24

Mitochondrial disorder, single base changes in tRNA, epilepsy, ataxia, dementia, myopathy, heteroplasmic, highly variable expression

Question 25

Mitochondrial encephalomyopathy and stroke-like episodes (MELAS)

Answer 25

Single-base mutations in tRNA, heteroplasmic with variable expression

Question 26

Mitochondrial disorders due to duplications and deletions in mitochondrial chromosome

Answer 26

Kearns-Sayre disease, Pearson syndrome, chronic progressive external opthalmoplegia

Question 27

Fragile X syndrome

Answer 27

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

Question 28

Sherman paradox

Answer 28

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

Question 29

Resolving Sherman paradox

Answer 29

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

Question 30

Molecular biology of FMR1

Answer 30

Normal amount in normal, more mRNA in expanded repeats up to 230, then none, highest expression in brain

Question 31

Disruption of FMR1

Answer 31

Large repeats have high methylation, may explain loss of transcription, small percentage have structural mutation, affects mRNA distribution in neurons, glutamate receptor is key

Question 32

Fragile X phenotype

Answer 32

Long face, prominent jaw, large ears

Question 33

Genomic imprinting

Answer 33

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

Question 34

Prader-Willi syndrome

Answer 34

Paternal deletion, maternal imprinting

Question 35

Angelman syndrome

Answer 35

Maternal deletion, paternal imprinting