Jigsaw #2: DNA Repair Diseases

Question 1

Ataxia Ocular Motor Apraxia (AOA1):

Answer 1

Mutation: APTX; SSBR 5’ end processor.

Onset: Variable; 1-16 years.

Neurologic: difficulty coordinating movements (ataxia) and problems with side-to-side movements of the eyes (oculomotor apraxia).

Cancer: None.

Sensitivity: None.

Appearance: Involuntary movements.

Question 2

Mutation in ataxia ocular motor apraxia (AOA1) and pathway effected:

Answer 2

Mutation: aprataxin (APTX)

Pathway: SSBR 5’ end processor

Question 3

Ataxia telangiectasia (AT):

Answer 3

Mutation: ATM kinase; DSBR response.

Onset: Early childhood.

Neurologic: difficulty with coordinating movements, slurred speech, and oculomotor apraxia.

Cancer: Lymphoid.

Sensitivity: X-ray.

Appearance: Dilated blood vessels on skin & eyes.

Question 4

Mutation in ataxia telangiectasia (AT) and repair pathway effected:

Answer 4

Mutation: ATM kinase

Pathway: DSBR response

Question 5

Cockayne Syndrome:

Answer 5

Mutation: CSA or CSB; TC-NER recognition.

Onset: Normal at birth; early death.

Neurologic: Retardation, deafness/visual loss; demyelination.

Cancer: None.

Sensitivity: Sun.

Appearance: Short stature; deep set eyes; prominent ears; weakness.

Question 6

Mutation in Cockayne Syndrome and pathway effected:

Answer 6

Mutation: CSA or CSB

Pathway: TC-NER

Question 7

Werner’s Syndrome:

Answer 7

Mutation: WRN RecQ helicase; BER, SSB, DSBR.

Onset: Normal until 20s/30s. Early death.

Neurologic: None.

Cancer: Sarcomas.

Sensitivity: None.

Appearance: Premature aging; short stature.

Question 8

Werner’s Syndrome mutation and pathway affected:

Answer 8

Mutation: WRN RecQ helicase

Pathway: BER, SSBR, DSBR

Question 9

Xeroderma Pigmentosum (XP):

Answer 9

Mutation: XP proteins; XPE/C recognition; XPA/D common pathway. NER.

Onset: Early onset 1-2 years, but up to 14 years.

Neurologic: Depends; XPA/D=neuro XPE/C=none.

Cancer: Melanoma, internal cancers.

Sensitivity: Sun.

Appearance: Premature skin aging; freckles.

Question 10

Xeroderma Pigmentosum (XP) mutation and pathway effected:

Answer 10

Mutation: XP proteins

• XPE/C recognition
• XPA/D common pathway

Pathway: NER

• XPE/C GG-NER

Question 11

Lynch Syndrome:

Answer 11

Mutation: MSH2/MLH1 primarily; MMR.

Onset: Early onset cancers (<45 years).

Neurologic: None.

Cancer: Colorectal, endometrium, GI, others.

Sensitivity: None.

Appearance: N/A.

Question 12

Lynch Syndrome mutation and pathway effected:

Answer 12

Mutation: MSH2 (most prevalent), MLH1, MSH6.

Pathway: MMR

Question 13

Hallmarks of ataxia telangiectasia (AT):

Answer 13

• Immunodeficiency
• Sinus/lung infections
• telangiectasia (capillary dilation)

Question 14

Hallmarks of Cockayne Syndrome:

Answer 14

• Sun sensitivity without increased cancer risk
• Deep set eyes
• Prominent ears

Question 15

Hallmark of Werner’s Syndrome:

Answer 15

• Premature aging
• Short stature

Question 16

Hallmarks of Xeroderma Pigmentosum (XP):

Answer 16

• Sun sensitivity with increased cancer risk
  
  • melanoma
• premature aging
• freckling

Question 17

Hallmarks of Lynch Syndrome:

Answer 17

• microsatellite instability (MSI)

Question 18

Hallmarks of Ataxia Ocular Motor Apraxia (AOA1):

Answer 18

• Like AT, but no immunodeficiency or telangiectasia.
• Involuntary movements.

Question 19

Microsatellite instability (MSI):

Answer 19

• repeated sequences of DNA (1-4 bp in length)
• progressive shortening when MMR repair system is not functioning
  
  • results in the appearance of new shorter alleles compared with those represented in the normal cells.
• used as diagnostic
• detect with PCR or histology

Question 20

Microsatellites are:

Answer 20

• repetitive DNA sequence of 1–4 base nucleotides that are particularly susceptible to DNA replication errors when the MMR system is absent

Question 21

MSI PCR Image:

Answer 21

• progressive shortening when MMR repair system is not functioning, which results in the appearance of new shorter alleles compared with those represented in the normal cells.

Question 22

A microsatellite is considered unstable if:

Answer 22

• the distribution of the fragments from the tumor sample differs from that of the normal tissue.