DNA Repair

Question 1

Symptoms of Ataxia Oculomotor Apraxia

Answer 1

• Autosomal recessive spinocerebellar ataxia syndrome caused by mutation in aprataxin gene (APTX, DNA end processor of SSBs with hydrolase and transferase activities
• Uncoordinated movement/gait (ataxia)
• Late axonal peripheral neuropathy
• Limited eye movement on command (oculomotor apraxia)
• Cognitive impairment
• Hypercholesterolemia
• Hypoalbuminemia
• Involuntary movements
• Cerebellar atrophy
• Resembles AT,but does not have non-neurologic features (telangiectasia or immune deficiency)
• Variable onset (1-16 years)
• Absence of increased genomic instability/cancer

Question 2

Symptoms of Ataxia Telangiectasia

Answer 2

• Autosomal recessive disorder (associated with ATM mutation)
• Hypersensitivity to ionizing radiation
• ATM normally activated by DSBs and signals to cell-cycle check-point to slow down cycle
• ATM also signals repair machinery to make DSB repairs and responds to DNA breaks during both B and T cell development/ differentiation (VDJ recombination)
• Patients have increased chromosomal abnormalities in T and B cells
• Tend to develop lymphoid cancer (30% of AT patients develop lymphoid tumors.
• Patients have variable immunodeficiencies, are susceptible to sinus and lung infections, have impaired organ maturation, and ocular/cutaneous telangiectasia (small dilated blood vessels near skin surface commonly seen on face around nose, cheeks, and chin).

Question 3

Cockayne Syndrome

Answer 3

• Hereditary disorder caused by defects in TC-NER (developmental and neurological)
• CSA and CSB mutations (impacts recognition of Stalled RNA Polymerase II)
• Growth/ mental retardation
• Neuron demyelination leads to neurological deficiencies
• Sun sensitivity, but no increase in skin cancer risk relative to XP (described below). Possibly due to the fact that transcription doesn’t resume after RNA pol II blockage or could be because affected cells undergo apoptosis.

Question 4

Werner Syndrome

Answer 4

• Autosomal Recessive disorder (mutation in RecQ-family DNA Helicase WRN, BER)
• Normal development until third decade of life
• Premature aging (onset at about age 10 to 20)
• 95% of patient have short stature (first clinical sign is lack of growth spurt as teenager)
• Subcutaneous fat deposits on trunk (stocky appearance)
• Osteoporosis of the limb bones
• Some patients may have flat feet and a high pitched voice
• Skin atrophy
• Hair loss/ graying
• Patients often develop hypogonadism (low testosterone), diabetes mellitus, cataracts, artherosclerosis
• Can be linked to predisposition to cancer, specifically sarcomas
• Median age of death between 47 and 54 years.
• Cells are sensitive to oxidative stress, exhibit shortened telomeres, chromosomal rearrangements, and telomere fusions

Question 5

Xeroderma Pigmentosum

Answer 5

• Hereditary disorder due to GG-NER defects
• Heterozygotes are asymptomatic
• Caused by mutations that affect helicase activity and damage recognition (XPC, XPE, XPD, or XPA)
• Common pathway of NER mutations (XPD/XPA) may lead to both solar sensitivity and neurodegeneration
• Extreme Solar sensitivity which leads to excessive freckling, photophobia,premature skin aging and even multiple skin cancers (benign and malignant neoplasms)
• Heightened risk of skin cancer (about 2,000 fold higher)
• 10-20 fold increase of internal cancer rates, including brain, lung, and gastric tumors
• May also exhibit progressive neuronal degeneration depending on affected XP protein
• Median age for onset of symptoms is 1-2 years, but 5% of patients have onset after 14 years
• 90% of cancers occur at sites of greatest sun exposure
• 60 to 90% develop ocular abnormalities.