Janet Berrios March 19,

 Extremely rare ~220 cases since 1975  Usually of Ashkenazi Jewish origin  Autosomal Recessive  Cancer Diagnosis at 24, Death before 30  Characteristics:  Slow Growth  Proportional Dwarfism  Beaked nose, narrow face, prominent ears  High pitched voice  Pigmentation, redness, and dilated blood vessels in skin  Mental retardation  Diabetes (Type II)  Immune Deficiency  Lung Problems  Low or no fertility  Malignancies: early onset; particularly non-Hodgkin’s lymphoma, leukemias and carcinomas of the breast, gut and skin V.A. Bohr Cell Press Review, 2008; I.D. Hickson Nature Reviews – Cancer, Molbio/MolStudents/spring2003/Baxter /BLM.gif

I.D. Hickson, Nature Reviews -- Cancer 2003

 A tumor-suppressor  Chromosome 15  Regulated by phosphorylation I.D. Hickson, Nature Reviews -- Cancer 2003

 Premature Aging  Bilateral Cataracts  Hoarseness  Skin Alterations  Thin Limbs  Premature graying, Alopecia  Short Stature  Osteoporosis  Hypogonadism  Diabetes (Type II)  Soft Tissue Calcification  Loss of Subcutaneous Fat  Malignancies: early onset; primarily sarcomas and mesenchymal tumors, some melanoma and thyroid cancers V.A. Bohr Cell Press Review, 2008; I.D. Hickson Nature Reviews – Cancer,

C.Z. Bacharati, I.D. Hickson. Chormosoma - Review (2008) Holliday Junction G-quadruplex

 First thought to be lethal  BLM deficient mice have:  Cancers of different cellular origins  But... Lack other Bloom’s syndrome characteristics  What about heterozygotes?  Haploinsufficiency?  Needed Loss of Heterozygosity?  Predisposition to cancers? BLM +/- mice did have enhanced tumor formation indicating haploinsufficiency

Two main mutation features:  Founder effects  Full range of mutation types which impairs protein expression Nature Reviews - Cancer, 2003 BLM ASH

 Highly conserved throughout evolution  Bloom’s syndrome is autosomal recessive  BLM is an ATP-dependent helicase that works in a 3’  5’ direction that affects genomic stability  BLM is active at replication sites where the replication fork has arrested  Many different mutations can occur but all impair protein expression  Biallelic mutation is only correlative to cancer