Atypical Patterns of Inheritance

Question 1

Dosage Compensation

Answer 1

equalizing the contribution of X-linked genes in males and females

Question 2

X Inactivation

Answer 2

random inactivation of one of the X chromosomes in females; results in natural mosaicism

Question 3

How is X inactivation carried out?

Answer 3

X chromosome binds X Inactive-Specific Transcript RNA that causes 1) altered chromatin structure 2) DNA methylation 3) Barr body formation

Question 4

How does mosaic X inactivation affect X-linked diseases?

Answer 4

-X-linked diseases are more clinically variable in females (recessive can be more potent, dominant can be less potent) -biochemical detection of carriers of X-linked mutations is more difficult -

Question 5

Anticipation

Answer 5

increased severity or earlier onset of disease in succeeding generations; caused by unstable mutations

Question 6

Unstable Mutations

Answer 6

• some genes have strands of tri-nucelotide repeats
• easy place for mistakes during repair, replication, or recombination
• repeating tri-nucleotides can be expanded (i.e. slipped mispairing during DNA replication)
• causes loss of protein funciton, gain of altered function, or RNA gain of function

Question 7

Premutation

Answer 7

intermediate-size expansion in unstable mutations that does not cause disease but is unstable and likely to be increased in size in the next generation

Question 8

Huntington’s Disease

Answer 8

• definition: genetic disorder of the muscles that shows anticipation inheritance pattern
• etipathogenesis: tri-nucleotide repeat disorder (CAG repeat expansion)
  
  • autosomal dominant
  • toxic gain-of-function
• clinical: jerky, involuntary movements, balance and coordination problems, slurred speech and swallowing problems, dementia
  
  • late onset
  • 100% penetrance by age 80

Question 9

Myotonic Dystrophy

Answer 9

• definition: genetic disorder affecting muscles that often shows anticipation inheritance pattern
• etipathogenesis: tri-nucleotide repeat disorder
  
  • autosomal dominant
  • RNA gain of function: not transported from nucleus, attracts RNA-binding splicing proteins
• clinical: muscle wasting, cardiac arrhythmia

Question 10

Fragile X Syndrome

Answer 10

• definition: genetic disorder causing mental retardation that shows anticipation inheritance pattern
• etipathogenesis: tri-nucleotide repeat disorder
  
  • X-linked recessive
  • CGG repeats occur, gene is shut off, loss-of-function
• clinical: mental retardation, characteristic facial features, not as severe in females, often see normal transmitting males who give mutated allele to daughters who are normal, expansion happens when daughters then pass to sons who show phenotype

Question 11

Describe the Mitochondrial Genome.

Answer 11

• circular genome
• 2 ribosomal RNAs
• 22 tRNAs
• 13 proteins involved in oxidative phosphorylation
• higher mutation rate than nuclear genome

Question 12

Mitochondrial Inheritance

Answer 12

• mutations in nuclear genes follow rules of mendelian inheritance
• mutations in mitochondrial genes are inherited maternally (ovum has organelles, sperm, not so much)

Question 13

Leber Hereditary Optic Neuropathy

Answer 13

• definition: genetic mitochondrial DNA disorder that results in optic nerve degeneration
• etipathogenesis: missense mutations in any of 3 genes encoding respiratory enzymes
• clinical presentation: optic nerve degeneration

Question 14

Heteroplasmy

Answer 14

presence of more normal and mutant mitochondrial DNA, resulting in variable expression in mitochondrial inherited disease

Question 15

MERRF: myoclonic epilepsy with ragged red fibers

Answer 15

• definition: genetic mitochondrial DNA disorder affecting the muscles
• etiopathogenesis: failure in oxidative phosphorylation due to mitochondrial DNA mutation
• clinical: myopathy, lactic acidosis, and CNS disease; muscle biopsy shoes ragged red fibers

Question 16

Imprinting

Answer 16

• certain genes have one allele which is inactive in somatic cells (some genes have paternal allele inactive, others have maternal allele inactive)
• deletion of active allele can cause disease b/c other allele is constitutively inactive/imprinted

Question 17

Prader-Willi Syndrome

Answer 17

• definition: genetic disorder of imprinted gene causing multi-system problems
• etipathogenesis: deletion in imprinted paternal 15q11-q13 gene
  
  • uniparental disomy: PWS can also occur if child receives both copies of chromosome from mother (no paternal genes)
• clinical: hypotonia, failure to thrive, mild mental retardation, hypogonadism, eating disorders

Question 18

Angelman Syndrome

Answer 18

• definition: genetic disorder of imprinted gene causing multi-system problems
• etipathogenesis: deletion in imprinted maternal 15q11-q13 gene
  
  • uniparental disomy: AS can also occur if child receives both copies of chromosome from father (no maternal genes)
• clinical: hypotonia, seizures, severe mental retardation, lack of speech, unprovoked smiling/ laughter