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.

The role of telomere biology in bone marrow failure and other disorders

“…In a study of 91 patients with apparently acquired AA, four were found to be heterozygous for the 258+2 T-C SBDS gene mutation (Calado et al 2007). These patients did not have clinical evidence of pancreatic exocrine failure or other anomalies associated with SDS.…”

Telomere length in inherited bone marrow failure syndromes

“…8 Short telomeres were previously reported in FA, DBA and SDS, using a variety of different cell types, and methods that are less sensitive than flow-FISH (Table 1). [10][11][12][13][14][15][16][17][18][19][20] Most studies indicated that average values for each group of patients were less than the average for age-matched controls. Telomeres are long DNA repeats and a protein complex at chromosome ends that are essential for genome integrity.…”

Mutation of SBDS and SH2D1A is not associated with aplastic anemia in Japanese children

“…A recent study showed a heterozygous mutation of SBDS, 258+2T>C, in 4 out of 91 patients with apparently acquired AA. 7 In addition, a mutation of SH2D1A causes X-linked lymphoproliferative syndrome which is associated with fatal Epstein-Barr virus (EBV) infection and AA. 8 Given that a small population of patients with primary EBV infection develops AA, SH2D1A is also a candidate for association with AA.…”