Week 3 TNR and imprinting disorders

Question 1

What is the recurrence rate of Duchenne muscular dystrophy resulting from maternal germline mosaicism?

Answer 1

15%

Question 2

What are the signs and symptoms of Prader-Willi syndrome?

Answer 2

Neonatal hypotonia and undescended testicles; hypothalamic disfunction leading to lack of satiety, obesity, hypogonadotropic hypogonadism, growth hormone deficiency, short stature, diminished muscle, cognitive/behavioral impairment

Question 3

What is the genetic mechanism of Prader-Willi syndrome?

Answer 3

Lack of expression of paternal genes at 15q11-13

Question 4

What are the signs and symptoms of Angelman syndrome?

Answer 4

Severe intellectual disability, limited speech, ataxic gait, spontaneously happy affect, seizures

Question 5

What is the genetic mechanism of Angelman syndrome?

Answer 5

Lack of expression of maternally inherited UBE3 gene at 15q11-13

Question 6

What is the inheritance pattern of mitochondrial disorders?

Answer 6

Mitochondrial DNA is maternally inherited

Question 7

What is the treatment for mitochondrial disorders?

Answer 7

No effective treatment; supplementation of cofactors can be minimally effective

Question 8

What are the signs and symptoms of Huntington disease?

Answer 8

Chorea (involuntary muscle twitching), ataxia (impaired ability to coordinate limb movement), cognitive decline, psychiatric disturbances

Question 9

What gene is affected in Huntington disease?

Answer 9

HTT on chromosome 4, encodes for huntingintin protein

Question 10

What is the mechanism of Huntington disease?

Answer 10

Aggregates of mHTT aggregate in the brain (though it’s not known whether or not the aggregates or the free protein cause the damage)

Question 11

What are the signs and symptoms of fragile X syndrome?

Answer 11

Developmental delay, intellectual disability, behavioral abnormalities (including ASD); in males features include joint laxity, large testes after puberty, and facial dysmorphism

Question 12

What gene is affected in fragile X syndrome?

Answer 12

FMR1 gene, encodes FMRP protein (familial mental retardation protein (ugh))

Question 13

What mutation occurs in the affected gene of Huntington disease?

Answer 13

CAG repeats in exon 1 of HTT gene, cause polyglutamine tracts

Question 14

What mutation occurs in the affected gene of fragile X syndrome?

Answer 14

CGG repeats in the promotor of the 5’ UTR of FMR1

Question 15

What are the differences in the incidence of fragile X syndrome between males and females?

Answer 15

Incidence is higher in males than females, males show more physical signs, cognitive and behavioral abnormalities are more severe in males

Question 16

What is the mechanism of fragile X syndrome?

Answer 16

Reduced expression of FMR1 causes decreases in dendritic spine maturation, synapse formation, and synaptic plasticity

Question 17

How does the mutation in fragile X syndrome silence the affected gene?

Answer 17

Hypermethylation of the promotor FMR1 promoter region recruits HDACs, which results in silencing of the promoter region via chromatin condensation and the inability of RNAP to bind to the promoter

Question 18

What are the signs and symptoms of Friedreich ataxia (FRDA)?

Answer 18

Progressive muscle weakness in the extremities, loss of coordination, vision and hearing impairment, slurred speech, scoliosis, high plantar arches, diabetes, heart disorders (atrial fibrillation, tachycardia, hypertrophic cardiomyopathy)

Question 19

What gene is affected in Friedreich ataxia?

Answer 19

FXN gene, encodes frataxin protein

Question 20

What mutation occurs in the affected gene in Friedreich ataxia?

Answer 20

GAA repeats in intron 1 of FXN gene on chromosome 9

Question 21

What is the inheritance pattern of Friedreich ataxia?

Answer 21

Autosomal recessive

Question 22

What is the mechanism of Friedreich ataxia?

Answer 22

Hypermethylation in mutant gene causes transcriptional repression of frataxin, which normally removes iron in the cytoplasm around the mitochondria. Iron build-up causes free radical damage to the mitochondrial membrane, which especially affects nerve and muscle cells

Question 23

What are the signs and symptoms of myotonic distrophy?

Answer 23

Affects multiple systems, variable presentation; most commonly causes cataracts, muscle dysfunction (myotonia, smooth muscle dysfunction, skeletal muscle wasting), cardiac conduction defects, central nervous system defects (hypersomnia, personality/cognitive changes, dementia)

Question 24

What is the inheritance pattern of myotonic dystrophy?

Answer 24

Autosomal dominant

Question 25

What gene is affected in myotonic dystrophy type 1?

Answer 25

DMPK gene, encodes myotonic dystrophy protein kinase

Question 26

What mutation occurs in the affected gene of myotonic dystrophy type 1?

Answer 26

CTG repeat in the 3’ UTR of DMPK gene on chromosome 19q

Question 27

What gene is affected in myotonic dystrophy type 2?

Answer 27

ZNF9, encodes zinc finger 9 protein

Question 28

What mutation occurs in the affected gene of myotonic dystrophy type 2?

Answer 28

CCTG repeat in intron 1 of the ZNF9 gene on chromosome 3

Question 29

What are the major differences between myotonic dystrophy type 1 and type 2?

Answer 29

Type 1 presents by late teens, while type 2 presents in adulthood; clinical features are more severe in type 1 than type 2; anticipation occurs in type 1 but not in type 2

Question 30

What is the mechanism of myotonic dystrophy?

Answer 30

No direct affect on muscle cell function; CTG expansions in non-coding regions of the affected gene recruit RNA binding proteins that affect mRNA metabolism in myoblasts, myocytes and neurons

Question 31

What downstream proteins are affected in myotonic dystrophy?

Answer 31

MBNL, splicing factor, depletion causes loss of splicing function; CUGBP1, mRNA degradation factor, upregulated by CUG binding

Question 32

What is the treatment for myotonic dystrophy?

Answer 32

No cure; therapeutic options include medications and implantable defibrillators to prevent sudden cardiac death, regular MRIs to monitor cardiac and skeletal muscle wasting