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IGHMBP2
immunoglobulin mu DNA binding protein 2
The IGHMBP2 gene provides instructions for creating a protein involved in DNA unwinding and replication, crucial for proper cellular function throughout the body. IGHMBP2 encodes the immunoglobulin mu DNA binding protein 2, an enzyme essential for various cellular processes, including DNA replication and repair.
IGHMBP2 is located on the long (q) arm of chromosome 11, at band 11q13.3. Arm ratio per GRCh38 - banding schematic.
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Clinical tests that include this
Overview
The IGHMBP2 gene, formally known as immunoglobulin mu DNA binding protein 2, directs the production of an enzyme vital for maintaining cellular integrity. This enzyme acts as a helicase, a type of protein that unwinds the double-stranded DNA molecule.
Its function is critical during cell division for DNA replication, ensuring that each new cell receives a complete and accurate set of chromosomes. Additionally, the IGHMBP2 protein contributes to gene expression by supporting the production of RNA and its subsequent translation into proteins.
What the gene does
The IGHMBP2 protein primarily functions as a helicase, temporarily separating the two strands of DNA. This unwinding is fundamental for DNA replication, a process where the cell duplicates its genetic material before dividing. Without proper unwinding, DNA cannot be accurately copied, which can lead to cellular dysfunction.
Beyond replication, the IGHMBP2 protein is also thought to be involved in the synthesis of RNA from a DNA template. Furthermore, it is implicated in the process of translation, where genetic information carried by messenger RNA is used to construct proteins. The IGHMBP2 protein is produced widely across tissues and organs in the body.
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Chromosome location
The IGHMBP2 gene is situated on chromosome 11, specifically at position 11q13.3. This precise location specifies where the gene can be found within the human genome, residing on the long arm (q) of chromosome 11.
Protein structure
The IGHMBP2 protein consists of 993 amino acids. Its structure includes several key domains and regions that facilitate its functions. It features a UPF1-type SF1B helicase ATP-binding domain spanning amino acids 191-438, followed by a UPF1-type SF1B helicase C-terminal domain from amino acids 439-649. A single-stranded DNA-binding region is located between amino acids 638-785. Disordered regions are present at amino acids 651-723, 782-828, and 841-879. The protein also contains an R3H domain (amino acids 723-786), a nuclear localization signal motif (amino acids 864-868), and an AN1-type zinc finger at amino acids 891-940.
Key variants
Variants within the IGHMBP2 gene can alter the structure and function of the resulting protein. These genetic changes can impair the protein's ability to unwind DNA, interfere with DNA replication, or disrupt other essential cellular processes. The clinical impact of a variant depends on its specific nature and location within the gene.
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.1061-2A>G | - | Pathogenic | ★★☆☆ | Autosomal recessive distal spinal muscular atrophy 1 |
c.1126G>A | p.Glu376Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive distal spinal muscular atrophy 1 |
c.1241_1254dup | p.Ser419fs | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease axonal type 2S |
c.1398del | p.Val467fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive distal spinal muscular atrophy 1 |
c.1730T>G | p.Leu577Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive distal spinal muscular atrophy 1 |
c.2356del | p.Ala786fs | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease axonal type 2S |
c.2429del | p.Pro810fs | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease axonal type 2S |
c.2540del | p.Gln847fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive distal spinal muscular atrophy 1 |
c.2796del | p.Cys932fs | Pathogenic | ★★☆☆ | Autosomal recessive distal spinal muscular atrophy 1 |
c.408_409del | p.Leu137fs | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease axonal type 2S |
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
Variants in the IGHMBP2 gene are associated with several inherited conditions, primarily affecting the nervous system and muscle function. One such condition is Spinal muscular atrophy with respiratory distress (AR), which can lead to muscle weakness and breathing difficulties. Another condition linked to IGHMBP2 variants is Charcot-Marie-Tooth disease.
UK clinical status
The IGHMBP2 gene is included in several NHS Genomic Medicine Service national test panels. These include panels for DDG2P, Foetal anomalies (R21), Hereditary neuropathy, Hereditary neuropathy or pain disorder (R78), and Paediatric motor neuronopathies, indicating its recognised clinical significance in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the IGHMBP2 gene?
The IGHMBP2 gene provides instructions for making an enzyme that acts as a helicase, unwinding DNA strands. This is crucial for processes like DNA replication, RNA production, and protein synthesis within cells.
What health conditions are associated with variants in IGHMBP2?
Variants in the IGHMBP2 gene are primarily associated with inherited neurological conditions such as Spinal muscular atrophy with respiratory distress (AR) and Charcot-Marie-Tooth disease.
How does IGHMBP2 contribute to DNA replication?
IGHMBP2 functions as a helicase, which means it temporarily unwinds the double helix structure of DNA. This unwinding is a necessary step for DNA to be copied accurately during cell division, ensuring each new cell receives a complete set of chromosomes.
References
- Guenther UP, Handoko L, Varon R. Clinical variability in distal spinal muscular atrophy type 1 (DSMA1): determination of steady-state IGHMBP2 protein levels in five patients with infantile and juvenile disease. Journal of molecular medicine (Berlin, Germany). 2009. PMID: 18802676
- Guenther UP, Handoko L, Laggerbauer B. IGHMBP2 is a ribosome-associated helicase inactive in the neuromuscular disorder distal SMA type 1 (DSMA1). Human molecular genetics. 2009. PMID: 19158098
- de Planell-Saguer M, Schroeder DG, Rodicio MC. Biochemical and genetic evidence for a role of IGHMBP2 in the translational machinery. Human molecular genetics. 2009. PMID: 19299493
- Kaindl AM, Guenther UP, Rudnik-Schöneborn S. Spinal muscular atrophy with respiratory distress type 1 (SMARD1). Journal of child neurology. 2008. PMID: 18263757
- Guenther UP, Varon R, Schlicke M. Clinical and mutational profile in spinal muscular atrophy with respiratory distress (SMARD): defining novel phenotypes through hierarchical cluster analysis. Human mutation. 2007. PMID: 17431882