Alternative titles; symbols
HGNC Approved Gene Symbol: BLM
SNOMEDCT: 4434006;
Cytogenetic location: 15q26.1 Genomic coordinates (GRCh38) : 15:90,717,346-90,816,166 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q26.1 | Bloom syndrome | 210900 | Autosomal recessive | 3 |
The RecQ gene family is named after the E. coli gene. RecQ is an E. coli gene that is a member of the RecF recombination pathway, a pathway of genes in which mutations abolish the conjugational recombination proficiency and ultraviolet resistance of a mutant strain. RECQL (600537) is a human gene isolated from HeLa cells, the product of which possesses DNA-dependent ATPase, DNA helicase, and 3-prime-to-5-prime single-stranded DNA translocation activities.
The hypermutability of Bloom syndrome (BLM; 210900) cells includes hyperrecombinability. Ellis et al. (1995) noted that although cells from all persons with Bloom syndrome exhibit the diagnostic high sister chromatid exchange (SCE) rate, in some persons a minor population of low SCE lymphocytes exist in the blood. Lymphoblastoid cell lines (LCLs) with low SCE rates can be developed from these low SCE lymphocytes. In multiple low SCE LCLs examined from 11 patients with BS, polymorphic loci distal to BLM on 15q had become homozygous in LCLs from 5 persons, whereas polymorphic loci proximal to the BLM locus remained heterozygous in all low SCE LCLs. These observations supported the hypothesis that low SCE lymphocytes arose through recombination within the BLM locus in persons with BS who had inherited paternally and maternally derived BLM alleles mutated at different sites. Such a recombination event in a precursor stem cell in these compound heterozygotes thus gave rise to a cell whose progeny had a functionally wildtype gene and phenotypically a low SCE rate (Ellis et al., 1995). Ellis et al. (1995) used the low SCE LCLs in which reduction to homozygosity had occurred for localizing BLM by an approach referred to as somatic crossover point (SCP) mapping. The precise map position of BLM was determined by comparing the genotypes of the recombinant low SCE LCLs from the 5 persons mentioned above with their constitutional genotypes at loci in the region around BLM. The strategy was to identify the most proximal polymorphic locus possible that was constitutionally heterozygous and that had been reduced to homozygosity in the low SCE LCLs, and to identify the most distal polymorphic locus possible that had remained constitutionally heterozygous in them. The BLM gene would have to be in the short interval defined by the reduced (distal) and the unreduced (proximal) heterozygous markers. The power of this approach was limited only by the density of polymorphic loci available in the immediate vicinity of BLM. A candidate for BLM was identified by direct selection of a cDNA derived from a 250-kb segment of the genome in 15q26.1 to which BLM had been assigned by SCP mapping. cDNA analysis of the candidate gene identified a 4,437-bp cDNA that encoded a 1,417-amino acid peptide with homology to the RecQ helicases, a subfamily of DExH box-containing DNA and RNA helicases.
The RECQL3 gene maps to chromosome 15q26.1 (Ellis et al., 1995).
Ellis and German (1996) reported that the BLM protein has similarity to 2 other proteins that are members of the RecQ family of helicases, namely the gene product encoded by RECQL2 (604611), also called WRN, and the product of the yeast gene Sgs1. Sgs1 was identified by a mutation that suppressed the slow-growth phenotype of mutations in the topoisomerase gene (see 126420). These proteins have 42 to 44% amino acid identity across the conserved helicase motifs. In addition, the proteins are of similar length and contain highly negatively charged N-terminal regions and highly positively charged C-terminal regions. Ellis and German (1996) noted that these similarities in overall structure have raised the possibility that the proteins play similar roles in metabolism. Since the Sgs1 gene product is known to interact with the products of the yeast topoisomerase genes, they predicted that the BLM and WRN genes interact with human topoisomerases.
Ellis et al. (1999) described the effects on the abnormal cellular phenotype of BS, namely an excessive rate of SCE, when normal BLM cDNA was stably transfected into 2 types of BS cells, SV40-transformed fibroblasts and Epstein-Barr virus-transformed lymphoblastoid cells. The experiments proved that BLM cDNA encodes a functional protein capable of restoring to or toward normal the uniquely characteristic high-SCE phenotype of BS cells.
In an immunocytologic study of mouse spermatocytes, Walpita et al. (1999) showed that the BLM protein is first evident as discrete foci along the synaptonemal complexes of homologously synapsed autosomal bivalents in late zygonema of meiotic prophase. BLM foci progressively dissociated from the synapsed autosomal axes during early pachynema and were no longer seen in mid-pachynema. BLM colocalized with the single-stranded DNA-binding replication protein A (see 179835), which had been shown to be involved in meiotic synapsis. However, there was a temporary delay in the appearance of BLM protein along the synaptonemal complexes relative to replication protein A, suggesting that BLM is required for a late step in processing of a subset of genomic DNA involved in establishment of interhomolog interactions in early meiotic prophase. In late pachynema and into diplonema, BLM is more dispersed in the nucleoplasm, especially over the chromatin most intimately associated with the synaptonemal complexes, suggesting a possible involvement of BLM in resolution of interlocks in preparation for homologous chromosome disjunction during anaphase I.
Yankiwski et al. (2000) found that the BLM protein is located in the nucleus of normal human cells in the nuclear domain 10 (ND10; see 604587) or promyelocytic leukemia nuclear bodies. These structures are punctate deposits of proteins disrupted upon viral infection and in certain human malignancies. BLM was found primarily in ND10 except during S phase, when it colocalized with the WRN gene product, in the nucleolus. BLM colocalized with a select subset of telomeres in normal cells and with large telomeric clusters seen in simian virus 40-transformed normal fibroblasts. During S phase, Bloom syndrome cells expel micronuclei containing sites of DNA synthesis. The BLM protein is likely to be part of a DNA surveillance mechanism operating during S phase.
Von Kobbe et al. (2002) confirmed interaction between BLM and WRN in immunoprecipitates of soluble nuclear extracts of HeLa cells. Immunolocalization of endogenous BLM and exogenously expressed WRN in several human cell lines showed colocalization of the 2 helicases in some nuclear foci and not in others, suggesting that their interaction is dynamic. Using pull-down assays with several truncation mutants, von Kobbe et al. (2002) determined that the BLM-binding regions of WRN include the N-terminal exonuclease domain and the RQC-containing regions. They mapped the WRN-binding region of BLM to the middle of the molecule. Von Kobbe et al. (2002) showed that BLM, by binding the exonuclease domain of WRN, inhibited WRN exonuclease activity. BLM had no effect on WRN helicase activity.
Bloom syndrome cells show marked genomic instability; in particular, hyperrecombination between sister chromatids and homologous chromosomes. Karow et al. (2000) investigated the mechanism by which the BLM protein normally suppresses hyperrecombination. They showed that in vitro BLM selectively binds Holliday junctions formed during genetic recombination and acts on recombination intermediates containing a Holliday junction to promote ATP-dependent branch migration. They presented a model in which BLM disrupts potentially recombinogenic molecules that arise at sites of stalled replication forks. They suggested that their results have implications for the role of BLM as an antirecombinase in the suppression of tumorigenesis.
Using various truncations of the BLM protein attached to green fluorescent protein, Kaneko et al. (1997) found that only the BLM protein truncated at amino acid 1357, containing an intact helicase domain and 2 arms, was transported to the nucleus, indicating that BLM protein translocates into the nucleus and that the distal arm of the bipartite basic residues in the C terminus of the BLM protein is essential for targeting the nucleus.
Wang et al. (2000) used immunoprecipitation and mass spectrometry analyses to identify BRCA1 (113705)-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM (607585), BLM, MSH2 (609309), MSH6 (600678), MLH1 (120436), the RAD50 (604040)-MRE11 (600814)-NBS1 (602667) complex, and the RFC1 (102579)-RFC2 (600404)-RFC4 (102577) complex. Confocal microscopy demonstrated that BRCA1, BLM, and the RAD50-MRE11-NBS1 complex colocalize to large nuclear foci. Wang et al. (2000) suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process.
By coimmunoprecipitation and in vitro pull-down assays, Beamish et al. (2002) verified direct interaction between ATM and BLM. By mutation analysis, they mapped the BLM-binding domain of ATM to residues 82 through 89. The ATM-binding region of BLM mapped to residues 636 to 1,074. Beamish et al. (2002) determined that the mitosis-associated hyperphosphorylation of BLM was partially dependent upon ATM phosphorylating thr99 and thr122 in the N-terminal region of BLM. Radiation-induced phosphorylation of BLM at thr99 was dose-dependent in normal cells and was defective in AT cells. BS lymphoblasts showed radiosensitivity that could be corrected by transfection of wildtype BLM but not by transfection of a thr99 phosphorylation-minus mutant. This phosphorylation-minus mutant did not alter SCE frequency, indicating that radiosensitivity and increased SCE are mediated by separate BLM domains.
Wu et al. (2000) determined that BLM and topoisomerase III-alpha (TOP3A; 601243) colocalized in the nucleus of human cells and coimmunoprecipitated from cell extracts. By in vitro binding assays with truncated BLM mutants, the authors identified 2 independent domains that mediate the interaction with TOP3A. One domain resides between residues 143 and 212 in the N-terminal domain of BLM, and the other resides between residues 1266 and 1417 in the C-terminal domain.
Dutertre et al. (2002) noted that BLM is phosphorylated and is excluded from the nuclear matrix during mitosis. BLM immunopurified from mitosis-arrested HeLa cells was phosphorylated and showed 3-prime-to-5-prime DNA helicase activity. Coimmunoprecipitation experiments revealed that phosphorylated BLM interacted with TOP3A. BLM was dephosphorylated in response to ionizing radiation and by inhibition of CDC2 (116940)/cyclin B (123836). Upon dephosphorylation, BLM relocalized to an insoluble subcellular compartment.
Mohaghegh and Hickson (2001) reviewed the DNA helicase deficiencies associated with cancer predisposition and premature aging disorders.
Opresko et al. (2002) found that, in vitro, TRF2 (602027) showed high affinity for BLM and for WRN, and that TRF2 interaction with either helicase resulted in stimulation of its activity. WRN or BLM, partnered with replication protein A (RPA; see 179835), actively unwound long telomeric duplex regions that were pre-bound by TRF2.
Telomerase-negative immortalized human cells maintain telomeres by alternative lengthening of telomeres (ALT) pathway(s), which may involve homologous recombination. Stavropoulos et al. (2002) found that endogenous BLM protein colocalized with telomeric foci in ALT human cells but not telomerase-positive immortal cell lines or primary cells. BLM interacted in vivo with the telomeric protein TRF2 in ALT cells, as detected by FRET and coimmunoprecipitation. Transient overexpression of GFP-BLM resulted in marked, ALT cell-specific increases in telomeric DNA. The association of BLM with telomeres and its effect on telomere DNA synthesis required a functional helicase domain. The authors suggested that BLM may facilitate recombination-driven amplification of telomeres in ALT cells.
Franchitto and Pichierri (2002) reviewed the roles of RECQL2 and RECQL3 in resolution of a stall in DNA replication, as well as their possible interaction with the MRE11-RAD50-NBS1 complex. Components of this complex are mutated in 2 genetic instability syndromes, Nijmegen breakage syndrome (251260) and ataxia telangiectasia-like disorder (604391).
Imamura and Campbell (2003) showed that the human BLM gene can suppress both the temperature-sensitive growth defect and the DNA damage sensitivity of the yeast DNA replication mutant Dna2-1. This yeast mutant is defective in a helicase/nuclease that is required either to coordinate with the crucial Fen1 nuclease of the yeast in Okazaki fragment maturation or to compensate for yeast Fen1 when its activity is impaired. Using coimmunoprecipitation from yeast extracts, Imamura and Campbell (2003) showed that human BLM interacts with both Dna2 and Fen1 of S. cerevisiae, suggesting that it participates in the same steps of DNA replication or repair as these 2 yeast proteins.
Wu and Hickson (2003) demonstrated that BLM and TOP3A together effect the resolution of a recombination intermediate containing a double Holliday junction. The mechanism, which they termed double-junction dissolution, is distinct from classical Holliday junction resolution and prevents exchange of flanking sequences. Loss of such an activity explains many of the cellular phenotypes of Bloom syndrome. Wu and Hickson (2003) proposed that double Holliday junctions are formed during the homologous recombination-dependent repair of daughter strand gaps that arise during replication, and that the dissolution of these double Holliday junctions by BLM prevents the diagnostically high sister chromatid exchange frequency seen in Bloom syndrome cells. Furthermore, BLM-catalyzed double-junction dissolution may act to suppress tumorigenesis by preventing loss of heterozygosity, a feature associated with BLM deficiency in mice, through the suppression of ectopic recombination and crossing-over between homologous chromosomes.
By coimmunoprecipitation of HeLa cell nuclear extracts, Meetei et al. (2003) identified 3 distinct multiprotein complexes associated with BLM, all of which were different from the BASC complex reported by Wang et al. (2000). One of the complexes, designated BRAFT, contained the Fanconi anemia core complementation group proteins FANCA (607139), FANCG (602956), FANCC (613899), FANCE (613976), and FANCF (613897), as well as Topo III-alpha and RPA. BLM complexes isolated from an FA cell line had a lower molecular mass, likely due to loss of FANCA and other FA components. BLM- and FANCA-associated complexes had DNA unwinding activity, and BLM was required for this activity.
Lillard-Wetherell et al. (2004) reported that BLM colocalized and complexed with TERF2 (602027) in cells that employ ALT. BLM colocalized with TERF2 in foci actively synthesizing DNA during late S and G2/M; colocalization increased in late S and G2/M when ALT is thought to occur. TERF1 (600951) and TERF2 interacted directly with BLM and regulated its unwinding activity in vitro. Whereas TERF2 stimulated BLM unwinding of telomeric and nontelomeric substrates, TERF1 inhibited its unwinding of telomeric substrates only. TERF2 stimulated BLM unwinding with equimolar concentrations of TERF1 but not when TRF1 was added in molar excess. Lillard-Wetherell et al. (2004) proposed a function for BLM in recombination-mediated telomere lengthening and a model for the coordinated regulation of BLM activity at telomeres by TERF1 and TERF2.
Eladad et al. (2005) showed that BLM is a substrate for SUMO1 (601912) modification, with lys317, lys331, lys334, and lys347 being preferred sites of modification. Unlike normal BLM, a double-mutant BLM protein with lysine-to-arginine substitutions at residues 317 and 331 was not modified by SUMO1, and it failed to localize efficiently to the PML nuclear bodies. Rather, double-mutant BLM protein induced the formation of DNA damage-induced foci (DDI) that contained BRCA1 (113705) protein and phosphorylated histone H2AX (601772). Double-mutant BLM only partially complemented the genomic instability phenotypes of Bloom syndrome cells as assessed by sister-chromatid exchange and micronuclei formation assays. Eladad et al. (2005) hypothesized that BLM is a DNA damage sensor that signals the formation of DDI, for which SUMO1 modification is a negative regulator of BLM signaling function.
Mimitou and Symington (2008) demonstrated that yeast Exo1 nuclease (606063) and Sgs1 helicase functioned in alternative pathways for double-strand break (DSB) processing. Novel, partially resected intermediates, whose initial generation depended on Sae2 (see 604124), accumulated in yeast lacking both Exo1 and Sgs1 and were poor substrates for homologous recombination. When Sae2 was absent, in addition to Exo1 and Sgs1, homology-dependent repair failed and unprocessed DSBs accumulated. Mimitou and Symington (2008) concluded that there is a 2-step mechanism for DSB processing during homologous recombination, with the Mre11 complex and Sae2 removing a small oligonucleotide from DNA ends to form an early intermediate, followed by processing of this intermediate by Exo1 and/or Sgs1 to generate extensive tracts of single-stranded DNA that serve as a substrate for Rad51 (179617). Since BLM is the human homolog of Sgs1, the results suggested that some of the defects observed in Bloom syndrome could be due to altered DSB processing.
Killen et al. (2009) used physical analysis of the highly repeated, self-similar ribosomal RNA gene clusters as sentinel biomarkers for dysregulated homologous recombination to demonstrate that loss of BLM protein function caused a striking increase in spontaneous molecular-level genomic restructuring. Analysis of single cell-derived subclonal populations from wildtype human cell lines showed that gene cluster architecture is ordinarily faithfully preserved under mitosis, but was so unstable in cell lines derived from BLMs as to make gene cluster architecture in different subclonal populations unrecognizable one from another. Cells defective in a different RecQ helicase, the WRN (RECQL2; 604611) protein, did not exhibit the gene cluster instability (GCI) phenotype, indicating that the BLM protein specifically, rather than RecQ helicases generally, held back this recombination-mediated genomic instability. An ATM (607585)-defective cell line also showed elevated rDNA GCI, although not to the extent of BLM-defective cells. Killen et al. (2009) hypothesized that genomic restructuring mediated by dysregulated recombination between the abundant low-copy repeats in the human genome may be an important additional mechanism of genomic instability driving the initiation and progression of human cancer.
Wechsler et al. (2011) used Bloom syndrome cells, in which the BLM gene is inactive, to analyze human cells compromised for the known Holliday junction dissolution/resolution pathways. Wechsler et al. (2011) showed that depletion of MUS81 (606591) and GEN1 (612449), or SLX4 (613278) and GEN1, from Bloom syndrome cells results in severe chromosome abnormalities, such that sister chromatids remain interlinked in a side-by-side arrangement and the chromosomes are elongated and segmented. Wechsler et al. (2011) concluded that normally replicating human cells require Holliday junction processing activities to prevent sister chromatid entanglements and thereby ensure accurate chromosome condensation. This phenotype was not apparent when both MUS81 and SLX4 were depleted from Bloom syndrome cells, suggesting that GEN1 can compensate for their absence. Additionally, Wechsler et al. (2011) showed that depletion of MUS81 or SLX4 reduces the high frequency of sister chromatid exchanges in Bloom syndrome cells, indicating that MUS81 and SLX4 promote sister chromatid exchange formation, in events that may ultimately drive the chromosome instabilities that underpin early-onset cancers associated with Bloom syndrome.
Using protein interaction assays with human cell lines and expression constructs, Wan et al. (2013) showed that BLM interacted with endogenous SPIDR (615384), a nuclear scaffolding protein. Both proteins colocalized to nuclear foci following DNA damage in HeLa cells. Knockdown of SPIDR or BLM via small interfering RNA resulted in increased frequency of sister chromatid exchange following DNA damage and impaired RAD51 focus formation. Coimmunoprecipitation experiments showed that BLM interacted in a ternary complex with SPIDR and RAD51. Knockdown of SPIDR in HeLa cells reduced the association of BLM with RAD51 and increased the number of chromosomal aberrations and cell sensitivity to DNA damage. Wan et al. (2013) concluded that SPIDR provides a link between BLM and the homologous recombination machinery.
Hu et al. (2013) delineated 2 pathways that spontaneously fuse inverted repeats to generate unstable chromosomal rearrangements in wildtype mouse embryonic stem cells. Gamma radiation induced a RECQL3-regulated pathway that selectively fused identical, but not mismatched, repeats. By contrast, ultraviolet light induced a RAD18 (605256)-dependent pathway that efficiently fused mismatched repeats. In addition, TREX2 (300370), a 3-prime-to-5-prime exonuclease, suppressed identical repeat fusion but enhanced mismatched repeat fusion, clearly separating these pathways. TREX2 associated with UBC13 (603679) and enhanced PCNA (176740) ubiquitination in response to ultraviolet light, consistent with its being a novel member of error-free postreplication repair. RAD18 and TREX2 also suppressed replication fork stalling in response to nucleotide depletion. Replication fork stalling induced fusion for identical and mismatched repeats, implicating faulty replication as a causal mechanism for both pathways.
In patients with Bloom syndrome, Ellis et al. (1995) identified chain-terminating mutations in the BLM gene. Mutation analysis in the first 13 unrelated persons with BS examined permitted the identification of 7 unique mutations in 10 of them. The fact that 4 of the 7 mutations resulted in premature termination of translation indicated that the cause of most Bloom syndrome is the loss of enzymatic activity of the BLM gene product. Identification of loss-of-function mutations in BLM is consistent with the autosomal recessive transmission, and the homology of BLM and RecQ suggested that BLM has enzymatic activity. Ellis et al. (1995) suggested that the absence of the BLM gene product probably destabilizes other enzymes that participate in DNA replication and repair, perhaps through direct interaction and through more general responses to DNA damage. In 4 persons of Jewish ancestry, they detected a homozygous deletion/insertion mutation (604610.0001) in the BLM gene. Homozygosity was predictable because linkage disequilibrium had been detected in Ashkenazi Jews with Bloom syndrome between BLM, D15S127, and FES (Ellis et al., 1994). Thus a person who carried this deletion/insertion mutation was a founder of Ashkenazi Jewish population and nearly all Ashkenazi Jews with Bloom syndrome inherited the mutation identical by descent from this common ancestor.
In a patient with Bloom syndrome and both high- and low-SCE cell lines, Foucault et al. (1997) identified compound heterozygosity for a cys1036-to-phe (C1036F; 604610.0004) substitution in the C-terminal region of the peptide and an unidentified mutation affecting expression of the RECQL3 gene. Foucault et al. (1997) concluded that somatic intragenic recombination resulted in cells that had an untranscribed allele carrying the 2 parental RECQL3 mutations and a wildtype allele which allowed reversion to the low SCE phenotype. Topoisomerase II-alpha (126430) mRNA and protein levels were decreased in the high SCE cells, whereas they were normal in the corresponding low SCE cells. Foucault et al. (1997) proposed that in addition to its putative helicase activity, RECQL3 might be involved in transcription regulation.
German et al. (2007) identified 64 different mutations in 125 of 134 individuals with Bloom syndrome from a patient registry. There were 54 mutations resulting in premature termination and 10 missense mutations. Several recurrent and founder mutations were identified.
In their Table I, Lindor et al. (2000) provided a comparison of the 5 human RECQ helicases identified to that time. The RECQL3 gene is deficient in Bloom syndrome. The RECQL2 gene is deficient in Werner syndrome (277700), and the RECQL4 gene (603780) is deficient in Rothmund-Thomson syndrome (268400). No disorder had been related to RECQ1 (RECQL) or RECQL5 (603781).
Chester et al. (1998) found that mouse embryos homozygous for a targeted mutation in the murine Bloom syndrome gene are developmentally delayed and die by embryonic day 13.5. They determined that the interrupted gene is the homolog of the human BLM gene by its homologous sequence, its chromosomal location, and the demonstration of high numbers of sister chromatid exchanges in cultured murine Blm -/- fibroblasts. The proportional dwarfism seen in the human is consistent with the small size and developmental delay (12 to 24 hours) seen during midgestation in murine Blm -/- embryos. The growth retardation in mutant embryos can be accounted for by a wave of increased apoptosis in the epiblast restricted to early postimplantation embryogenesis. Mutant embryos do not survive past day 13.5, and at this time exhibit severe anemia. Red blood cells and their precursors from Blm -/- embryos are heterogeneous in appearance and have increased numbers of macrocytes and micronuclei. Both the apoptotic wave and the appearance of micronuclei in red blood cells are likely cellular consequences of damaged DNA caused by effects on replicating or segregating chromosomes.
Kusano et al. (2001) demonstrated that Drosophila Dmblm is identical to mus309, a locus originally identified in a mutagen-sensitivity screen. One mus309 allele, which carries a stop codon between 2 of the helicase motifs, causes partial male sterility and complete female sterility. Mutant males produce an excess of XY sperm and nullo sperm, consistent with a high frequency of nondisjunction and/or chromosome loss. These phenotypes of mus309 suggest that Dmblm functions in DNA double-strand break repair. The mutant Dmblm phenotypes were partially rescued by an extra copy of the DNA repair gene Ku70 (152690), indicating that the 2 genes functionally interact in vivo.
Goss et al. (2002) used homologous recombination to disrupt the mouse Blm gene to simulate BLM(Ash), a frameshift mutation in the BLM gene present in 1% of Ashkenazi Jews. Mice heterozygous for this mutation developed lymphoma earlier than wildtype littermates in response to challenge with murine leukemia virus at birth and twice the number of intestinal tumors when crossed with mice carrying mutation in the APC gene (611731). Goss et al. (2002) concluded that Blm is a modifier of tumor formation in the mouse and that Blm haploinsufficiency is associated with tumor predisposition.
Adams et al. (2003) studied the Drosophila BLM ortholog MUS309 and demonstrated that mutants are severely impaired in their ability to carry out repair DNA synthesis during synthesis-dependent strand annealing. Consequently, repair in the mutants is completed by error-prone pathways that create large deletions. Adams et al. (2003) concluded that their results suggested a model in which BLM maintains genomic stability by promoting efficient repair DNA synthesis and thereby prevents double-strand break repair by less precise pathways.
Guo et al. (2004) exploited the high rate of mitotic recombination in Bloom syndrome protein (Blm)-deficient embryonic stem cells to generate a genomewide library of homozygous mutant cells from heterozygous mutations induced with a revertible gene trap retrovirus. Guo et al. (2004) screened this library for cells with defects in DNA mismatch repair (MMR), a system that detects and repairs base-base mismatches. They demonstrated the recovery of cells with homozygous mutations in known and novel mismatch repair genes. Guo et al. (2004) identified DNMT1 (126375) as a novel MMR gene and confirmed that Dnmt1-deficient embryonic stem cells exhibit microsatellite instability, providing a mechanistic explanation for the role of DNMT1 in cancer.
Yusa et al. (2004) used a tetracycline-regulated Blm allele, Blm(tet), to introduce biallelic mutations across the genome in mouse embryonic stem cells. Transient loss of Blm expression induced homologous recombination not only between sister chromatids but also between homologous chromosomes. Yusa et al. (2004) considered that the phenotype of embryonic stem cells bearing biallelic mutations would be maintained after withdrawal of the tetracycline analog doxycycline. Indeed, a combination of N-ethyl-N-nitrosourea mutagenesis and transient loss of Blm expression enabled them to generate an embryonic stem cell library with genomewide biallelic mutations. The library was evaluated by screening for mutants of glycosylphosphatidylinositol-anchor biosynthesis, which involves at least 23 genes distributed throughout the genome. Mutants derived from 12 different genes were obtained and 2 unknown mutants were simultaneously isolated. Yusa et al. (2004) concluded that their results indicated that phenotype-based genetic screening with Blm(tet) is very efficient and raises possibilities for identifying gene functions in embryonic stem cells.
Babbe et al. (2009) found that specific inactivation of Blm in mouse B cells in vivo drastically reduced both developing B cells in bone marrow and mature B cells in the periphery, particularly the B1a subset. Serum concentrations of all Ig subtypes were low, even after immunization. Blm -/- B cells had reduced antibody class switch capacity in vitro, but Blm was not critical for class switch recombination. Mice with Blm -/- B cells that also lacked p53 (TP53; 191170) had increased propensity to develop B-cell lymphoma due to high rates of chromosomal structural abnormalities and impaired cell cycle progression. Babbe et al. (2009) concluded that BLM ensures proper development and function of the various B-cell subsets and also counteracts lymphomagenesis.
In 4 ostensibly unrelated persons of Jewish ancestry with Bloom syndrome (BLM; 210900), Ellis et al. (1995) found homozygosity for a 6-bp deletion/7-bp insertion at nucleotide 2281 of the BLM cDNA. Deletion of ATCTGA and insertion of TAGATTC caused the insertion of the novel codons for LDSR after amino acid 736, and after these codons there was a stop codon. Ellis et al. (1995) concluded that a person carrying this deletion/insertion mutation was a founder of the Ashkenazi-Jewish population, and that nearly all Ashkenazi Jews with Bloom syndrome inherited the mutation identical by descent from this common ancestor. Identification of the mutation by a PCR test was now possible for screening for carriers among Ashkenazim.
Straughen et al. (1998) described a rapid method for detecting the 6-bp deletion/7-bp insertion, a predominant Ashkenazi Jewish mutation in Bloom syndrome. They commented that in the Bloom syndrome registry, one or both parents of 52 of the 168 registered persons are Ashkenazi Jews.
Using a convenient PCR assay, Ellis et al. (1998) found the 6-bp del/7-bp ins mutation, blm(Ash), on 58 of 60 chromosomes transmitted by Ashkenazi parents to persons with Bloom syndrome. In contrast, in 91 unrelated non-Ashkenazic persons with BS whom they examined, blm(Ash) was identified in only 5, these coming from Spanish-speaking Christian families from the southwestern United States, Mexico, or El Salvador. These data, along with haplotype analyses, showed that blm(Ash) was independently established through a founder effect in Ashkenazi Jews and in immigrants to formerly Spanish colonies. This striking observation underscored the complexity of Jewish history and demonstrated the importance of migration and genetic drift in the formation of human populations.
In a study of the frequency of the BLM 6-bp del/7-bp ins mutation in a group of Ashkenazi Jews, unselected for personal or family history of Bloom syndrome, Oddoux et al. (1999) found the mutation in 5 of 1,155 individuals, yielding a frequency of 1/231 (95% CI, 1/123-1/1,848). The low frequency is consistent with an absence of heterozygote advantage for carriers of 1 copy of the mutant allele. The frequency of heterozygotes for other autosomal recessive conditions within their panel had been validated in other studies, suggesting that the test panel was representative of the Ashkenazi Jewish population. Those frequencies were Tay-Sachs disease, 1/28; cystic fibrosis, 1/25; Gaucher disease, 1/15; BRCA2, 6174delT, 1/106; Canavan disease, 1/41; and Fanconi anemia complementation group C, 1/116.
To determine whether carriers of BLM mutations are at increased risk of colorectal cancer, Gruber et al. (2002) genotyped 1,244 cases of colorectal cancer and 1,839 controls, both of Ashkenazi Jewish ancestry, to estimate the relative risk of colorectal cancer among carriers of the BLM(Ash) founder mutation. Ashkenazi Jews with colorectal cancer were more than twice as likely to carry the BLM(Ash) mutation than Ashkenazi Jewish controls without colorectal cancer (odds ratio = 2.45, 95% CI 1.3 to 4.8; P = 0.0065). Gruber et al. (2002) verified that the APC I1307K mutation (611731.0029) did not confound their results.
In a Japanese patient with Bloom syndrome (BLM; 210900), Ellis et al. (1995) found homozygosity for a deletion of CAA at nucleotide position 631-633 in the BLM gene, resulting in a stop codon at amino acid position 186.
In an Italian patient (BSR92) with Bloom syndrome (BLM; 210900), German et al. (2007) identified homozygosity for a large deletion in exons 11 and 12 in the RECQL3 gene (2308-953_2555+4719del6126), causing a frameshift (Ile770fs). (German and Ellis (2001) noted that the mutation in patient BSR92 was assigned incorrectly by Ellis et al. (1995). Ellis et al. (1995) had reported the patient to be homozygous for a 2596T-C transition resulting in an ile841-to-thr substitution. Table 1 in their article had erroneously stated that the change occurred at position 843.)
In a patient with Bloom syndrome (BLM; 210900), Foucault et al. (1997) identified compound heterozygosity for a 3181G-T transversion in the RECQL3 gene, resulting in a cys1036-to-phe (C1036F) substitution in the C-terminal region of the peptide, and an unidentified mutation affecting expression of the RECQL3 gene. The patient was initially believed to be homozygous for the C1036F mutation, but SSCP analysis, direct sequencing of RT-PCR products, and EcoRI digestion using a restriction site created by the mutation showed that the mutation was not present in low SCE cells from the patient. No EcoRI digestion was observed on paternal PCR products. Partial EcoRI digestion was seen with PCR products from maternal and patient DNA and from high- and low-SCE cells from the patient, and direct sequencing confirmed the presence of both a wildtype and mutated sequence at nucleotide 3181 in the high- and low-SCE cell lines, indicating heterozygosity for the mutation. Foucault et al. (1997) concluded that somatic intragenic recombination resulted in cells that had an untranscribed allele carrying the 2 parental RECQL3 mutations and a wildtype allele which allowed reversion to the low-SCE phenotype.
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