genetics post midterm

Question 1

Philadelphia chromosome

Answer 1

t (9;22) -> activation of abl proto-oncogene in hematopoietic cells, results in chronic myelogenous leukemia

Question 2

Burkitt’s lymphoma

Answer 2

t (8;14)

Question 3

Wolf-Hirschhorn syndrome

Answer 3

Del 4p - large deletion. Facial anomalies (widely-spaced eyes), prominent nose, abnormal iris, cardiac anomalies, mental and developmental delay

Question 4

Cri-du-chat

Answer 4

Del 5p. 46, XX, del(5p) or 46 XY del(5p).

High-pitched, cat-like cry. Mental retardation, speech problems. Microcephaly

Dx with FISH, CGH, karyotype banding studies

Question 5

Velocardiofacial syndrome (DiGeorge syndrome)

Answer 5

Microdeletion in chromosome 22q. Congenital heart defects, absence of thymus (thymic aplasia), cleft lip and palate, facial anomalies (narrow palpebral fissures, prominent nasal root), learning disability.

Dx with FISH

Question 6

Angelman and Prader Willi syndromes

Answer 6

Angelman syndrome - deletion of maternal chromosome 15

Prader Willi syndrome - deletion of paternal chromosome 15

Question 7

WAGR syndrome

Answer 7

Wilms’ tumor, aniridia, genitourinary malformations, and retardation of growth and development. Del(11p13). LOF of WT1 gene on chromosome 11 -> encodes TF important in control of cell growth and differentiation

Dx with FISH - shows failure of PAX6 locus specific probe

Question 8

Yellow agouti (Ay) mutation

Answer 8

Interferes with a-MSH binding to melanocortin receptor, which is involved in food intake regulation

Question 9

obese (ob) mutation

Answer 9

Defect in leptin protein (satiation signal)

Question 10

diabetes (db) mutation

Answer 10

Defect in leptin protein receptor

Question 11

fat mutation

Answer 11

Defect in fat transport across membranes

Question 12

tubby mutation

Answer 12

Defect in upstream signaling molecules (transcription factor

Question 13

MC4R mutation

Answer 13

Defect in melanocortin 4 receptor, a member of the rhodopsin family of G-protein receptors. Autosomal dominant

Question 14

Chronic myeloid leukemia

Answer 14

Philadelphia translocation (9;22) (p210;p160)-> hybrid Bcl-Abl protein

Question 15

Imatinib mesylate (ST1571)

Answer 15

Powerful tyrosine kinase inhibitor specific for a few TKs including ABL -> very effective against BCR/ABL fusion gene (against Ph+ chronic myeloid leukemia). ABL is stuck in its activated form -> imatinib binds to the tyrosine kinase active site and prevents its activity

Question 16

Bloom syndrome

Answer 16

Autosomal recessive. Defect in BLM gene (15q26.1) = RecQL3 DNA helicase required for replication repair, recombination. Chromosomal instability resulting in many chromosomal breaks and sister chromatid exchanges. High incidence of cancer of a broad range of types

Smaller than average, narrow chin, prominent nose and ears, facial rash (pigment and dilated blood vessels) upon exposure to sun; often get diabetes and have neurological, lung, and immune system deficiencies

Question 17

Ataxia telangiectasia

Answer 17

Autosomal recessive cancer

Question 18

Xeroderma pigmentosum

Answer 18

Autosomal recessive, mutations in 9 NER (nucleotide excision repair) genes. Clinical sun sensitivity - sunburn, blistering, freckled with hyperpigmented skin lesions. Ocular involvement - conjunctivitis, ocular tumors. 1000-fold increase in skin cancer including melanomas. DNA dmg is cumulative and irreversible

Question 19

Fanconi anemia

Answer 19

Autosomal recessive cancer

Question 20

Dysplastic nevus syndrome

Answer 20

Precursor to malignant melanoma. Inherited mutation in p16 (INK4A) CDK inhibitor

Question 21

Li-Fraumeni

Answer 21

Inherited mutation in p53-> increased risk for breast, bone, brain cancers, adrenocortical tumors, soft-tissue carcinomas. Cancer appears at young age

Question 22

Familial adenomatous polyposis

Answer 22

Mutations in the APC (adenomatous polyposis coli, “gatekeeper”) gene on chromosome 5 (5q21). Multiple (>100) adenomatous polyps develop in distal colon that SLOWLY progress to cancer. APC is normally tumor suppressor that phosphorylates B-catenin in absence of WNT -> ubiquitination and B-catenin degradation.

Mutation in B-catenin (unable to be phosphorylated) gives similar results -> no WNT needed to trigger growth

Question 23

Hereditary non-polyposis colon cancer (HNPCC)/Lynch syndrome

Answer 23

Mutation in DNA MMR (“caretaker”, like RAS, p53) genes -> accumulate mutations RAPIDLY, tumors have microsatellite instability

Question 24

Breast/ovarian cancer

Answer 24

Mutation in BRCA1 - breast, BRCA2 - ovarian. Pancreatic and other cancers also more common. BRCA1 and 2 involved in DNA repair or apoptosis when DNA can’t be repaired.

Question 25

HER-2

Answer 25

Overexpressed in sporadic breast cancer. Is gene for growth factor rec -> get double minute chromosomes

Tx: Herceptin drug (Ab) -> binds to HER2 and prevents binding of EGF to HER2. Very effective for HER2+ tumors, useless for HER2- tumors

Question 26

Alzheimers dz

Answer 26

Evidence for DNA fragmentation int he brain cells of AD pts. Proapoptotic Bak and Bad protein levels increased (antiapoptotic proteins Bcl-2 and Bcl-xL also increased, perhaps compensatory response in surviving neurons). APP, PS1, and PS2 proteins are cleaved by caspase-3. Neuronal caspase-3 immunoreactivity increased