title: Mutations in the SBDS gene in acquired aplastic anemia.
abstract: Shwachman-Diamond syndrome (SDS; OMIM 260400), an inherited bone marrow failure syndrome, is caused by mutations in both alleles of the SBDS gene, which encodes a protein of unknown function. Here we report heterozygosity for the 258 + 2 T>C SBDS gene mutation previously identified in SDS patients in 4 of 91 patients with apparently acquired aplastic anemia (AA) but not in 276 ethnically matched controls (Fisher exact test, P < .004). Affected patients were young and had a poor outcome; they had reduced SBDS expression but no evidence of the pancreatic exocrine failure or skeletal abnormalities typical of SDS. Length of telomeres in granulocytes of SBDS heterozygous patients was short for their age, and in SDS patients with both SBDS alleles affected further analyzed, granulocytes' telomeres were even shorter, correlating in length with SBDS expression. Higher heterogeneity in telomere length also was observed in SDS patients. Telomerase activity of SBDS-deficient patients' lymphocytes was comparable with controls, and no physical interaction between SBDS protein and telomerase complex components (TERT or TERC) was established. We propose that heterozygosity for the 258 + 2 T>C SBDS mutation predisposes to AA by accelerating telomere shortening of leukocytes via a telomerase-independent mechanism.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1202, USA. calador@nhlbi.nih.gov
authors.forename: Rodrigo T
authors.initials: RT
authors.lastname: Calado
authors.forename: Solomon A
authors.initials: SA
authors.lastname: Graf
authors.forename: Keisha L
authors.initials: KL
authors.lastname: Wilkerson
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kajigaya
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Ancliff
authors.forename: Yigal
authors.initials: Y
authors.lastname: Dror
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lansdorp
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D006367:HeLa Cells; D006579:Heterozygote; D006801:Humans; D047468:Immunoprecipitation; D007668:Kidney / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D012307:Risk Factors; D012441:Saccharomyces cerevisiae; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics; D020798:Two-Hybrid System Techniques
chemical_list: D011506:Proteins; C470521:SBDS protein, human; C509186:TERT protein, human; D019098:Telomerase