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BLM
BLM RecQ like helicase
The BLM gene encodes a helicase enzyme vital for maintaining genomic integrity and DNA repair, with pathogenic variants linked to Bloom syndrome. The BLM gene provides instructions for creating the BLM protein, which functions as a RecQ helicase.
BLM is located on the long (q) arm of chromosome 15, at band 15q26.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The BLM gene, or BLM RecQ like helicase, is a crucial component of the human genome responsible for maintaining DNA stability. It is classified within the RecQ helicase family, a group of enzymes known for their role as "caretakers of the genome" [PMID:17986790]. The protein product of the BLM gene helps ensure the integrity of genetic material during vital cellular processes like DNA replication and repair.
Pathogenic variants within the BLM gene are primarily associated with Bloom syndrome, an autosomal recessive inherited disorder. This condition is characterised by features such as short stature, a distinctive skin rash, and a significantly elevated lifetime risk of various cancers [PMID:15622085]. Understanding the BLM gene is therefore important for comprehending genetic predisposition to certain conditions.
What the gene does
The BLM gene directs the synthesis of the BLM protein, which acts as a DNA helicase. Helicases are enzymes that bind to DNA and unwind its double helical structure. This unwinding is a fundamental step required for DNA replication, which occurs before cell division, and for the efficient repair of damaged DNA segments [PMID:15622085]. By unwinding DNA, the BLM protein facilitates access for other enzymes involved in these processes.
One significant function of the BLM protein involves preventing excessive sister chromatid exchanges. During cell division, chromosomes are duplicated, forming two identical sister chromatids. These chromatids can sometimes exchange segments of DNA. While some exchange is normal, the BLM protein helps to regulate this process, ensuring genomic stability. Its involvement in these DNA repair and maintenance pathways underscores its importance in preventing mutations and chromosomal abnormalities, which can lead to disease [PMID:17986790].
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Chromosome location
The BLM gene is situated on chromosome 15, specifically at position 15q26.1. This location refers to the long arm (q) of chromosome 15, within region 26, band 1. The precise positioning of the gene helps in understanding its genetic context and how variants within it might be inherited.
Protein structure
The BLM protein is composed of 1417 amino acids and features several distinct functional regions and domains. The protein includes multiple disordered regions, found at amino acids 1-21, 203-227, and 250-291. A region from amino acids 301-600 is necessary for interaction with SPIDR, while amino acids 362-414 are crucial for dimerization and homooligomerization. Key functional domains include the Helicase ATP-binding domain (amino acids 676-851), which contains a DEAH box motif (amino acids 795-798). Additionally, the protein has a Helicase C-terminal domain (amino acids 877-1024) and several regions involved in 3' overhang DNA-binding, located at amino acids 870-873, 897-899, 1000-1003, 1110-1112, 1121-1125, and 1160-1166. A DNA Holliday junction binding region is present between amino acids 1094-1139.
Key variants
Variants within the BLM gene can impact the structure and function of the BLM protein, potentially affecting its ability to maintain DNA integrity. Many different types of genetic changes have been identified, including deletions, insertions, and single nucleotide changes. These variants may be classified based on their predicted impact on protein function, ranging from benign to pathogenic.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1025dup | p.Leu342fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bloom syndrome |
c.1366dup | p.Ser456fs | Pathogenic | ★★☆☆ | Bloom syndrome |
c.1545del | p.Asn515fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bloom syndrome |
c.1784C>A | p.Ser595Ter | Pathogenic | ★★☆☆ | Bloom syndrome |
c.2116del | p.Ser706fs | Pathogenic | ★★☆☆ | Bloom syndrome |
c.2456del | p.Gln819fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bloom syndrome |
c.253del | p.Arg85fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bloom syndrome |
c.2608_2630dup | p.Asp877fs | Pathogenic | ★★☆☆ | Bloom syndrome |
c.3427G>T | p.Glu1143Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Bloom syndrome |
c.3664del | p.Thr1223fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bloom syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the BLM gene are associated with Bloom syndrome. This is an autosomal recessive inherited condition, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to develop the disorder. Bloom syndrome is characterised by distinctive physical features and a significantly increased risk of developing various cancers at an early age.
Inheritance pattern
Conditions caused by pathogenic BLM variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The BLM gene is recognised in the UK National Health Service (NHS) Genomic Medicine Service as relevant for several conditions. It is listed on PanelApp UK for indications such as 'Childhood solid tumours', 'Childhood solid tumours cancer susceptibility', 'COVID-19 research', 'DDG2P', 'Fanconi anaemia or Bloom syndrome', 'Foetal anomalies', 'Haematological malignancies cancer susceptibility', 'Haematological malignancies for rare disease', 'Insulin resistance (including lipodystrophy)', 'Intellectual disability', 'IUGR and IGF abnormalities', 'Monogenic short stature', 'Pigmentary skin disorders', 'Primary immunodeficiency or monogenic inflammatory bowel disease', 'Severe insulin resistance and lipodystrophy syndromes', and 'Severe microcephaly'.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the BLM gene?
The BLM gene produces the BLM protein, a DNA helicase responsible for unwinding DNA. This process is essential for DNA replication and the repair of damaged DNA, helping to maintain genomic stability.
Which condition is primarily associated with pathogenic BLM gene variants?
Pathogenic variants in the BLM gene are primarily associated with Bloom syndrome, an inherited disorder characterised by short stature, a skin rash, and a significantly increased risk of developing various cancers.
How is Bloom syndrome inherited?
Bloom syndrome is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of a pathogenic BLM gene variant, one from each parent, to develop the condition.
References
- Arora H, Chacon AH, Choudhary S. Bloom syndrome. International journal of dermatology. 2014. PMID: 24602044
- Singh DK, Ahn B, Bohr VA. Roles of RECQ helicases in recombination based DNA repair, genomic stability and aging. Biogerontology. 2009. PMID: 19083132
- Ouyang KJ, Woo LL, Ellis NA. Homologous recombination and maintenance of genome integrity: cancer and aging through the prism of human RecQ helicases. Mechanisms of ageing and development. 2008. PMID: 18430459
- Amor-Guéret M, Dubois-d'Enghien C, Laugé A. Three new BLM gene mutations associated with Bloom syndrome. Genetic testing. 2008. PMID: 18471088
- Liu Y, West SC. More complexity to the Bloom's syndrome complex. Genes & development. 2008. PMID: 18923071
- Wu L. Role of the BLM helicase in replication fork management. DNA repair. 2007. PMID: 17363339
- German J, Sanz MM, Ciocci S. Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry. Human mutation. 2007. PMID: 17407155
- Guo RB, Rigolet P, Ren H. Structural and functional analyses of disease-causing missense mutations in Bloom syndrome protein. Nucleic acids research. 2007. PMID: 17878217
- Bugreev DV, Yu X, Egelman EH. Novel pro- and anti-recombination activities of the Bloom's syndrome helicase. Genes & development. 2007. PMID: 18003860
- Amor-Guéret M. Bloom syndrome, genomic instability and cancer: the SOS-like hypothesis. Cancer letters. 2006. PMID: 15950375
- Cheok CF, Bachrati CZ, Chan KL. Roles of the Bloom's syndrome helicase in the maintenance of genome stability. Biochemical Society transactions. 2005. PMID: 16246145
- Adam MP, Bick S, Mirzaa GM. Bloom Syndrome. 1993. PMID: 20301572