Long‐term study of the immunodeficiency of Bloom's syndrome

Abstract

Bloom's syndrome (BS) is an autosomal recessive disease, caused by mutations in the BLM gene. This gene codes for BLM protein, which is a helicase involved in DNA repair. DNA repair is especially important for the development and maturation of the T and B cells. Since BLM is involved in DNA repair, we aimed to study if BLM deficiency affects T and B cell development and especially somatic hypermutation (SHM) and class switch recombination (CSR) processes. Clinical data of six BS patients was collected , and immunoglobulin serum levels were measured at different time points. In addition, we performed immune pheno-typing of the B and T cells and analyzed the SHM and CSR in detail by analyzing IGHA and IGHG transcripts using next-generation sequencing. The serum immunoglobulin levels were relatively low, and patients had an increased number of infections. The absolute number of T, B, and NK cells were low but still in the normal range. Remarkably, all BS patients studied had a high percentage (20-80%) of CD4+ and CD8+ effector memory T cells. The process of SHM seems normal; however, the Ig subclass distribution was not normal, since the BS patients had more IGHG1 and IGHG3 transcripts. In conclusion , BS patients have low number of lymphocytes, but the immunodeficiency seems relatively mild since they have no severe or opportunistic infections. Most changes in the B cell development were seen in the CSR process; however, further studies are necessary to elucidate the exact role of BLM in CSR.

Molecular genetics of RecQ helicase disorders

“…Blm m3/m3 mice in the C57BL/ 6129S5 genetic background did not show the expected small body size. Because human BS patients often show immune deficiency and a reduced level of IgM [81], the Blm m3/m3 were analysed for immune deficiency and were found to express a reduced amount of IgM. Blm m3/m3 mice showed a higher level of tumour formation than wild-type controls.…”

A Conserved G4 DNA Binding Domain in RecQ Family Helicases

“…3,28 A distinguishing biochemical property of some RecQ family helicases is the ability to unwind G4 DNA. [29][30][31] In G4 DNA, interactions among four DNA strands are stabilized by Hoogsteen base-pairing to form quartets of guanine bases.…”

A human nuclease specific for G4 DNA

“…(ii) The transcription of the switch regions that must precede recombination could promote G-quartet formation by denaturing S regions in switching B cells in vivo. (iii) BLM helicase preferentially unwinds G4 DNA substrates (12), and this helicase is missing in Bloom's syndrome, a genetic disease associated with immunodeficiency because of impaired switch recombination (35)(36)(37). (iv) The factor LR1, which is induced in switching B cells and binds tightly to duplex S region sequences, is composed of two polypeptides with very high affinity for DNA containing G quartets, nucleolin and hnRNP D (9,10,(38)(39)(40).…”