Diseases

Question 1

Xeroderma Pigmentosum

Answer 1

Autosomal recessive trait caused by loss of function of XPA-XPA gene responsible for NER –> cannot repair mutations from UV light exposure

Symptoms: skin and eye sensitivity to light, skin freckling and discoloration, dry skin, skin cancer by age 10, neurological abnormalities, 30-37 yr life span.

Question 2

Colorectal cancer (MBD4 deficiency)

Answer 2

MBD4 is enzyme that recognizes deamination linked to cancer. Cannot fix C –> T via BER. Should act as glycosylase in first step.

Question 3

Diphtheria

Answer 3

C. diphtheriae produces and secretes diphtheria toxin encoded by the tox gene. Bacteria requires iron, so when iron levels are low it releases toxin to kill cells and lyse iron into blood. Iron represses transcription.

Symptoms: thick, gray membrane in throat and tonsils; sore throat, swollen lymph nodes, fever, chills, nasal discharge

Question 4

Rett Syndrome

Answer 4

X-linked dominant mutation in the MECP2 methyl-CpG-binding protein –> no HDACs recruited –> chromatin stays in euchromatic form and is expressed when it shouldn’t be, mostly in neural genes

Symptoms: slow development, loss of mobility in hands, seizures, wide gait

Question 5

Colorectal and Gastric Cancers

Answer 5

LOF in GATA4 TF that differentiates stem cells due to hypermethylated CpG islands in promoter –> stem cells do not differentiate into normal colorectal and gastric cells

Question 6

Fragile X Syndrome

Answer 6

X-linked dominant CGG repeat in 5’ UTR of FMR1 gene promoter –> aberrant methylation silences translation of mRNAs important for neuronal function

Symptoms: autism, long face, prominent jaw, large ears, macroorchidism

Question 7

Friedrich Ataxia

Answer 7

Autosomal recessive GAA repeat in promoter / intron of FXN gene coding frataxin –> aberrant methylation –> silencing impairs mitochondrial function –> neurodegenration, cardiomyopathy

Symptoms: damages spinal cord and nerves controlling arms and legs, scoliosis, muscle weakness, difficulty walking

Question 8

Angelman Syndrome

Answer 8

Maternal deletion on Chromosome 15 during egg formation that causes loss of UBE3A gene –> inability to encode ubiquitin protein ligase E3A to target proteins for degradation; paternal copy epigenetically imprinted (silenced)

Symptoms: intellectual disability, excessive laughter, seizures

Question 9

Prader-Willi

Answer 9

Parental deletion on Chromosome 15 during sperm formation that causes loss of snoRNA SNORD116 –> loss of ability to regulate mRNA stability and alternative splicing; maternal copy epigenetically imprinted (silenced)

Symptoms: hyperphagia, obesity, intellectual impairment

Question 10

Dilated Cardiomyopathy

Answer 10

Mutations in LMNA gene encoding lamina causes aberrant splicing of mRNA in structural nuclear proteins that doesn’t splice intron 3, gets included in intron 4. Caused by A incorrectly substituted for G –> 9 extra nucleotides.

Symptoms: muscle fibers unnaturally stretched, ventricles bigger than they should be

Question 11

Spinal Muscular Atrophy

Answer 11

Autosomal recessive mutation in SMN1 gene. Healthy individuals also have non-functional SMN2 gene that incorrectly splices out exon 7.

Symptoms: death of spinal neurons –> progressive muscle wasting, mobility and respiratory impairments

Question 12

Duchenne Muscular Dystrophy

Answer 12

X-linked recessive trait caused by deletion in DMD gene that deletes part of intron 49 and exon 50 causing a frameshift mutation in 51 – premature stop codon, no dystrophin production.

Symptoms: muscle weakness in arms, hips, thighs w/ rapid progression and need for respiratory assistance

Question 13

Sickle Cell Anemia

Answer 13

Autosomal recessive missense mutation in beta-globin gene HBB where position 6 is Glu –> Val (charged –> hydrophobic) causing hemoglobin to distort and aggregate, blocking flow of blood (and oxygen).

Question 14

Familial Adenomatous Polyposis

Answer 14

Heritable form of colorectal cancer due to nonsense mutation in exon 15 of APC gene coding for FAP –> truncated protein

Question 15

Cystic Fibrosis

Answer 15

Autosomal recessive in-frame deletion of F508 in CFTR gene –> misfolding of chloride channel protein

Symptoms: thick, viscous mucus in airways; pancreatic dysfunction and diabetes

Question 16

Huntington Disease

Answer 16

Autosomal dominant in-frame CAG repeat of HTT gene –> aggregation of misfolded protein entangling other molecules needed by neurons

Symptoms: progressive neurological disorder with uncontrolled movements, decline in cognition and changes in personality

Question 17

Breast Cancer (BRAC2)

Answer 17

BRAC2 functions to repair dsDNA breaks, can be truncated by deletion of T causing frameshift mutation at 6174

Common in Ashkenazi Jewish decent

Question 18

Breast Cancer (BRAC1)

Answer 18

BRAC1 is tumor suppressor gene that is mutated / LOF in breast cancer. miRNA 182 gene that negatively regulates BRAC1 can be overexpressed due to hypomethylation of CpG islands in gene encoding miR-182.

Question 19

Hereditary transthyretin amyloidosis (hATTR)

Answer 19

Autosomal dominant mutation in TTR gene that encodes transthyretin. Tetramer secreted by liver is destabilized into dissociating monomers that misfold and aggregate into amyloid fibrils and deposit in the nerves, heart and GI tract causing peripheral neuropathy that progresses over time.

Can be treated with siRNA by knocking down bad copy. Make siRNA that only targets common Val30Met or Val122Ile mutations.

Question 20

Acute Hepatic Porphyrias

Answer 20

Deficiencies in enzymes that synthesize heme cause buildup of neurotoxic precursors. Heme negatively regulates this process.

Can be treated with siRNA knocking out the first enzyme, prevents accumulation of any steps after it. Would require supplemental heme to turn off accumulation of first precursor due to loss of negative feedback loop.

Question 21

Scurvy

Answer 21

Deficiency in Vitamin C causes weakness in tropocollagen triple helix by preventing hdroxylation of proline and lysine –> no hydrogen bonding with bridging water molecules

Question 22

Osteogenesis Imperfecta

Answer 22

Autosomal dominant mutations in COL1A1 or COL1A2 genes coding for type 1 collagen where Gly is substituted with Cys or Ser (larger R group) –> impaired protein maturation

Type 1: Most common and mildest; bone fragility, blue sclera, hearing loss, imperfect teeth

Type 2: Lethal at birth

Type 3: Severe; shorter stature, larger head, scoliosis, difficulty breathing and swallowing, rib fractures

Type 4: Very uncommon, varies in severity but decreases after puberty and has average life expectancy

Question 23

Ehlers-Danlos Syndromes

Answer 23

Classical EDS = mutation in type 5 collagen causing skin hyper elasticity, joint hyper mobility, easy bruising

Vascular EDS = mutation in type 3 collagen causing arterial rupture, GI perforation, uterine rupture during pregnancy etc.

Question 24

Menkes

Answer 24

X-linked recessive disorder of copper metabolism due to mutation in ATP7A gene encoding transmembrane protein needed for copper absorption –> impairs function of lysyl oxidase

Symptoms: Build up of copper in kidneys, kinky / brittle hair, effects in bones and skin, neurological deficits.

Question 25

Marfan Syndrome

Answer 25

Autosomal dominant mutation in FBN1 gene coding for fibrillin –> glycoprotein required for formation of elastic fibers

Symptoms: tall and thin, flexible joints, scoliosis, aortic rupture

Question 26

Alpha-thalassemias

Answer 26

Decreased alpha globin production due to mutations in HBA1 and HBA2 –> excess beta chains for unstable tetramers leading to anemia

Question 27

Beta-thalassemias

Answer 27

Reduced or absent beta globin production due to mutations in HBB –> excess alpha chains –> anemia

Question 28

Neurofibromatosis type 1

Answer 28

Results from overproduction of TGF-alpha proto-oncogene.

Symptoms: cafe au lait spots, learning disabilities, optic nerve glioma, brain tumors, osseous lesions

Question 29

Burkitt’s Lymphoma

Answer 29

Chromosome translocation between 14 and 8 –> recombination leads to myc gene from chromosome 8 being under control of chromosome 14 –> overexpression of proto oncogene that turns