Genetic diseases

Question 1

what is Achondroplasia an example of?

Answer 1

lethal alleles

Question 2

Achondroplasia

Answer 2

• due to spontaneous mutation in 80% of cases
• or can be inherited as an autosomal dominant disorder
• due to mutations in the FGFR3 gene (G380R)
• normally, FGFR3 has a negative regulatory effect on bone growth
• the mutated form of the receptor is constitutively active, resulting in severely shortened bones
• two copies of the allele are lethal

Question 3

Alzheimer’s

Answer 3

• attributed to mutations in one of three genes: those encoding APP and presenilins 1 and 2
• most cases due to sporadic mutation
• APP is critical for neuron growth, survival and post-injury repair
• an unknown enzyme in a proteolytic process causes APP to be divided into smaller fragments
• one of these fragments gives rise to fibrils of amyloid beta, which form clumps that deposit outside neurons in dense formations known as senile plaques

Question 4

what is Brachydactyly an example of?

Answer 4

lethal alleles, heterogeneity

Question 5

Brachydactyly

Answer 5

inherited dominant trait

Question 6

BRCA breast cancer

Answer 6

• due to germline mutation in the BRCA1 and BRCA2 tumour suppressor genes
• 5-10% of breast cancer cases in women are attributed to BRCA1 and BRCA2 mutations
• the cancer risk caused by the mutations is inherited in a dominant fashion, since people with the mutation are likely to acquire a second mutation, leading to the dominant expression of the cancer

Question 7

what is Charcot-Marie-Tooth disease an example of?

Answer 7

duplication

Question 8

Charcot-Marie-Tooth disease

Answer 8

• caused by mutations that cause defects in neuronal proteins, mostly affecting the myelin sheath
• 70-80% of cases due to the duplication of a large region on the short arm of chromosome 17 that includes the gene PMP22
• which produces a major component of compact myelin
• mutation arises due to misalignment at one of the repetitive elements (REP) repeat sequences due to unequal crossing over during spermatogenesis
• some mutations affect the MFN2 gene on chromosome 1, which is a mitofusin that mediates the fusion of mitochondria
• the mutated gene results in an overexpression of MFN2, which causes mitochondrial clustering and thus the degeneration of long peripheral axons
• perhaps due to defects in the axonal transport of mitochondria

Question 9

what is cystic fibrosis an example of?

Answer 9

deletion, heterogeneity

Question 10

cystic fibrosis

Answer 10

• autosomal recessive disorder
• 1/25 are carriers
• due to the mutation in CFTR, found on chromosome 7
• most common mutation is ΔF508, occurring in >90% of patients in the US
• ΔF508 creates a protein that does not fold properly and is degraded by the cell
• CFTR is involved in the production of sweat, digestive fluids and mucus
• the protein spans the cell surface membrane and acts as a channel connecting the cytoplasm to the surrounding fluid
• the most current theory suggests that defective ion transport leads to dehydration in the airway epithelia, thickening mucus

Question 11

what is Down’s syndrome an example of?

Answer 11

aneuploidy, (translocation)

Question 12

Down’s syndrome

Answer 12

• trisomy 21, caused by the failure of the 21st chromosome to separate during gamete formation
• not usually inherited
• can also be due to translocation, in which the long arm of chromosome 21 is attached to another chromosome, often 14

Question 13

what is Duchenne muscular dystrophy an example of?

Answer 13

lethal alleles, X-chromosome inactivation, deletion, translocation, aneuploidy

Question 14

Duchenne muscular dystrophy

Answer 14

• recessive, sex-linked
• can be due to:
  1. a skewed pattern of X-chromosome inactivation in female carriers of a DMD mutation
  2. X;autosome translocations that disrupt the DMD gene
  3. monosomy X, or Turner syndrome, associated with a DMD mutation in the remaining X chromosome
  4. maternal isodisomy for the X chromosome carrying a DMD mutation
• caused by a mutation in the dystrophin gene, located on the short arm of the X chromosome
• absence of dystrophin permits excess calcium to penetrate the sarcolemma
• alterations in calcium and signalling pathways causes water to enter the mitochondria, which then burst
• mitochondrial dysfunction result in the amplification of stress-induced reactive oxygen species (ROS) production
• in a complex cascading process, increased oxidative stress within the cell damages the sarcolemma and eventually results in the death of the cell
• muscle fibres undergo necrosis and are ultimately replaces by fat and fibrotic tissue (fibrosis)

Question 15

what is human deafness an example of?

Answer 15

complementation, heterogeneity

Question 16

human deafness

Answer 16

• a common disorder caused by many rare alleles; monogenic
• due to mutations in over 100 genes
• connexin 26 accounts for a majority of congenital NSHL

Question 17

what is Klinefelter’s syndrome an example of?

Answer 17

nondisjunction, aneuploidy

Question 18

Klinefelter’s syndrome

Answer 18

• XXY
• usually occurs randomly; not inherited
• due to a nondisjunction event during meiosis I or II
• X-linked recessive diseases occur less frequently in XXY males than in XY males

Question 19

what is Leber’s hereditary optic neuropathy an example of?

Answer 19

mitochondrial inheritance

Question 20

Leber’s hereditary optic neuropathy

Answer 20

• mitochondrial inheritance
• usually due to one of three pathogenic mtDNA point mutations in the subunit genes for the NADH dehydrogenase protein (complex I) of the oxidative phosphorylation chain in mitochondria

Question 21

what is Lesch-Nyhan syndrome an example of?

Answer 21

X-linked disorder

Question 22

Lesch-Nyhan syndrome

Answer 22

• rare X-linked inherited disorder
• caused by a mutation in the HPRT1 gene located on the X chromosome
• HGPRT is the ‘salvage enzyme’ for the purines: it channels hypoxanthine and guanine back into DNA synthesis
• failure of the enzyme has two results:
  1. cell breakdown product cannot be reused and are therefore degraded, giving rise to increased uric acid, a purine breakdown product
  2. the de novo pathway is stimulated due to an excess of