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OBSL1
obscurin like cytoskeletal adaptor 1
The OBSL1 gene provides instructions for a protein that helps regulate cellular protein breakdown and is involved in the body's response to growth hormones. OBSL1 encodes obscurin like cytoskeletal adaptor 1, a protein critical for maintaining proper cellular function through its role in the ubiquitin-proteasome system.
OBSL1 is located on the long (q) arm of chromosome 2, at band 2q35. Arm ratio per GRCh38 - banding schematic.
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Overview
The OBSL1 gene, also known as obscurin like cytoskeletal adaptor 1, is crucial for cellular health. It provides the blueprint for a protein that influences the breakdown of other proteins within cells. This process is vital for quality control and regulating key cellular activities, including growth and division.
Changes in the OBSL1 gene can disrupt these fundamental cellular processes, leading to specific health conditions. Understanding OBSL1's role offers insights into the genetic basis of certain developmental disorders.
What the gene does
The OBSL1 gene directs the production of a protein that is believed to help maintain appropriate levels of cullin-7, another protein. Cullin-7 is a component of the ubiquitin-proteasome system, which is the cellular machinery responsible for breaking down surplus or damaged proteins. Within this system, cullin-7 assists in assembling an E3 ubiquitin ligase complex. This complex attaches ubiquitin molecules to target proteins, marking them for degradation by proteasomes.
This ubiquitin-proteasome system is vital for cellular quality control, ensuring that damaged, misshapen, or excess proteins are removed. It also plays a role in regulating proteins involved in essential cellular processes such as cell division timing and growth. Specifically, the OBSL1 protein and cullin-7 are thought to contribute to regulating proteins involved in the body's response to growth hormones, although their precise mechanisms in this context are still under investigation.
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Chromosome location
The OBSL1 gene is located on chromosome 2, specifically at position 2q35. This chromosomal address indicates its precise position on the long arm (q) of chromosome 2, within region 3, band 5.
Protein structure
The OBSL1 protein, comprising 1896 amino acids, features a complex arrangement of domains. It contains multiple immunoglobulin-like (Ig-like) domains, including Ig-like 1 (amino acids 12-100), Ig-like 2 (amino acids 128-225), Ig-like 3 (amino acids 243-330), Ig-like 4 (amino acids 339-425), Ig-like 5 (amino acids 714-800), Ig-like 6 (amino acids 804-893), Ig-like 7 (amino acids 902-982), Ig-like 8 (amino acids 986-1075), Ig-like 9 (amino acids 1078-1172), Ig-like 10 (amino acids 1174-1261), and Ig-like 11 (amino acids 1265-1343). Additionally, the protein includes a Fibronectin type-III domain (amino acids 517-615). Regions involved in interaction with the TTN protein are located at amino acids 17-19 and 85-94. A disordered region is also noted between amino acids 106-127.
Key variants
Variants in the OBSL1 gene can include changes that alter single amino acids, or lead to abnormally shortened and non-functional proteins. These genetic changes can disrupt the gene's ability to produce a functional protein, impacting its role in cellular protein degradation and growth regulation. Such alterations are typically associated with an autosomal recessive inheritance pattern.
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.1230C>G | p.Tyr410Ter | Pathogenic | ★★☆☆ | not provided |
c.1260dup | p.Val421fs | Pathogenic | ★★☆☆ | 3M syndrome 2 |
c.1273dup | p.Thr425fs | Pathogenic | ★★☆☆ | OBSL1-related disorder |
c.1406del | p.Pro469fs | Pathogenic | ★★☆☆ | not provided |
c.2032C>T | p.Gln678Ter | Pathogenic | ★★☆☆ | 3M syndrome 2 |
c.2164del | p.Asp722fs | Pathogenic | ★★☆☆ | 3M syndrome 2 |
c.259del | p.Arg87fs | Pathogenic/Likely pathogenic | ★★☆☆ | OBSL1-related disorder |
c.35dup | p.Cys13fs | Pathogenic/Likely pathogenic | ★★☆☆ | OBSL1-related disorder |
c.427dup | p.Ala143fs | Pathogenic/Likely pathogenic | ★★☆☆ | 3M syndrome 2 |
c.458dup | p.Leu154fs | Pathogenic | ★★☆☆ | 3M syndrome 2 |
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 OBSL1 gene are primarily associated with 3-M syndrome. This is an inherited disorder characterised by skeletal abnormalities, including short stature, and distinctive facial features. The genetic changes in OBSL1 disrupt its normal function, contributing to the clinical presentation of this syndrome.
Inheritance pattern
Conditions caused by pathogenic OBSL1 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
OBSL1 is recognised within the UK's NHS Genomic Medicine Service pathways. It is listed with a 'green' status on several NHS England Genomic Clinical Interpretation Partnership (GeCIP) domains, indicating strong evidence for its gene-disease association. This includes its presence on panels for DDG2P, Foetal anomalies (R21), IUGR and IGF abnormalities, Monogenic short stature (R453), and Skeletal dysplasia (R104).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the OBSL1 gene?
The OBSL1 gene produces a protein that helps regulate the levels of another protein called cullin-7. This partnership is crucial for the ubiquitin-proteasome system, which is responsible for breaking down unwanted or damaged proteins within cells, thereby maintaining cellular quality control.
How is OBSL1 related to 3-M syndrome?
Pathogenic variants in the OBSL1 gene are a known genetic cause of 3-M syndrome. These variants disrupt the normal function of the OBSL1 protein, leading to the characteristic features of the syndrome, such as short stature and specific skeletal and facial abnormalities.
What does 'autosomal recessive inheritance' mean for OBSL1-related conditions?
Autosomal recessive inheritance means that an individual must inherit two copies of a pathogenic variant in the OBSL1 gene (one from each parent) to develop a condition like 3-M syndrome. If someone inherits only one pathogenic variant, they are typically a carrier and do not show symptoms of the condition.
References
- Clayton PE, Hanson D, Magee L. Exploring the spectrum of 3-M syndrome, a primordial short stature disorder of disrupted ubiquitination. Clinical endocrinology. 2012. PMID: 22624670
- Hanson D, Murray PG, Coulson T. Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling. Journal of molecular endocrinology. 2012. PMID: 23018678
- Hanson D, Murray PG, Black GC. The genetics of 3-M syndrome: unravelling a potential new regulatory growth pathway. Hormone research in paediatrics. 2011. PMID: 22156540
- Huber C, Fradin M, Edouard T. OBSL1 mutations in 3-M syndrome are associated with a modulation of IGFBP2 and IGFBP5 expression levels. Human mutation. 2010. PMID: 19877176
- Hanson D, Murray PG, Sud A. The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1. American journal of human genetics. 2009. PMID: 19481195
- Adam MP, Bick S, Mirzaa GM. 3-M Syndrome. 1993. PMID: 20301654