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ALMS1
ALMS1 centrosome and basal body associated protein
The ALMS1 gene provides instructions for a protein believed to be important for hearing, vision, and the function of various organs, with variants linked to Alström syndrome. The ALMS1 gene codes for a large protein implicated in diverse cellular processes, including ciliary function and microtubule organisation.
ALMS1 is located on the short (p) arm of chromosome 2, at band 2p13.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The ALMS1 gene, full name ALMS1 centrosome and basal body associated protein, is crucial for producing a protein whose precise functions are still being investigated. This protein is thought to play a role in maintaining the health and function of various organs, including the heart, kidneys, lungs, liver, and pancreas, and is also linked to hearing and vision. Located in specific cellular structures, the ALMS1 protein is fundamental for cellular organisation and signalling pathways, particularly those involving cilia.
What the gene does
The ALMS1 protein is found in most body tissues, typically at low concentrations. Within cells, it localises to centrosomes, which are vital for cell division and for assembling microtubules-proteins that facilitate intracellular transport and maintain cell shape. The ALMS1 protein is also present at the base of cilia, which are finger-like projections involved in cell movement and various chemical signalling pathways. Researchers suggest that, based on its cellular location, the ALMS1 protein likely contributes to the organisation of microtubules, the transport of materials within cells, and the normal functioning of cilia. While its exact role is still being elucidated, evidence indicates its involvement in processes affecting hearing, vision, and the regulation of body weight, as well as the function of the heart, kidney, lungs, and liver. It may also influence pancreatic insulin regulation.
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Chromosome location
The ALMS1 gene is situated on the short arm of chromosome 2, specifically at position 2p13.1. This gene provides instructions for synthesising a protein composed of 4168 amino acids.
Protein structure
The ALMS1 protein is a large molecule with a complex domain architecture. It features several disordered regions, including an N-terminal Disordered region (amino acids 1-69) and additional Disordered regions throughout its length, such as those at amino acids 558-579, 606-625, 699-718, 735-769, and 841-865. A prominent feature is the extensive 34 X 47 AA approximate tandem repeat region spanning amino acids 539-2200, which includes multiple specific repeats like Repeat 1 (amino acids 539-585), Repeat 2 (amino acids 586-632), Repeat 3 (amino acids 633-679), Repeat 4 (amino acids 680-726), Repeat 5 (amino acids 727-774), Repeat 6 (amino acids 775-821), Repeat 7 (amino acids 822-871), and Repeat 8 (amino acids 872-918).
Key variants
Variants in the ALMS1 gene can impact the structure and function of the encoded protein. Many identified variants lead to the production of an unusually short and non-functional protein. Such changes can disrupt cellular processes where the ALMS1 protein is involved, contributing to the development of associated genetic conditions.
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.10120dup | p.Ser3374fs | Pathogenic/Likely pathogenic | ★★☆☆ | Alstrom syndrome |
c.10532G>A | p.Trp3511Ter | Pathogenic | ★★☆☆ | Alstrom syndrome |
c.1208C>A | p.Ser403Ter | Pathogenic | ★★☆☆ | Alstrom syndrome |
c.2697del | p.Ile900fs | Pathogenic/Likely pathogenic | ★★☆☆ | Alstrom syndrome |
c.5026C>T | p.Gln1676Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Alstrom syndrome |
c.5870_5873del | p.Asp1957fs | Pathogenic | ★★☆☆ | Alstrom syndrome |
c.6457C>T | p.Gln2153Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Alstrom syndrome |
c.647-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Alstrom syndrome |
c.6544C>T | p.Gln2182Ter | Pathogenic | ★★☆☆ | Alstrom syndrome |
c.8096dup | p.Ser2700fs | Pathogenic | ★★☆☆ | Alstrom 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 within the ALMS1 gene are primarily associated with Alström syndrome, a rare inherited disorder. This condition is characterised by a broad range of symptoms affecting multiple body systems. Additionally, some variants in ALMS1 have been linked to Leber congenital amaurosis, a severe form of inherited vision loss.
UK clinical status
The ALMS1 gene is part of several "green" panels within the NHS Genomic Medicine Service PanelApp, indicating strong evidence for its association with specific conditions. These include panels for Alstrom syndrome (R106), Monogenic hearing loss (R67), Ophthalmological ciliopathies, Retinal disorders (R32), Paediatric or syndromic cardiomyopathy (R135), and Severe early-onset obesity (R149). It is also included in panels for Diabetes with additional phenotypes suggestive of a monogenic aetiology, Foetal anomalies (R21), Intellectual disability, Insulin resistance (including lipodystrophy), Rare multisystem ciliopathy disorders, Renal ciliopathies, and Severe insulin resistance and lipodystrophy syndromes (R158).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is Alström syndrome?
Alström syndrome is a rare inherited condition caused by pathogenic variants in the ALMS1 gene. It affects multiple organ systems, leading to symptoms such as vision and hearing impairment, obesity, type 2 diabetes, and heart problems.
Where is the ALMS1 protein located in cells?
The ALMS1 protein is found in structures called centrosomes, which are important for cell division, and at the base of cilia, which are finger-like projections involved in cell movement and signalling pathways.
How does the ALMS1 gene relate to insulin regulation?
Research suggests that the ALMS1 protein may influence how the pancreas regulates insulin, a hormone vital for controlling blood glucose levels. Disruption of this function due to ALMS1 variants can contribute to conditions like type 2 diabetes.
References
- Li G, Vega R, Nelms K. A role for Alström syndrome protein, alms1, in kidney ciliogenesis and cellular quiescence. PLoS genetics. 2007. PMID: 17206865
- Marshall JD, Hinman EG, Collin GB. Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alström syndrome. Human mutation. 2007. PMID: 17594715
- Joy T, Cao H, Black G. Alstrom syndrome (OMIM 203800): a case report and literature review. Orphanet journal of rare diseases. 2007. PMID: 18154657
- Minton JA, Owen KR, Ricketts CJ. Syndromic obesity and diabetes: changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alstrom syndrome. The Journal of clinical endocrinology and metabolism. 2006. PMID: 16720663
- Marshall JD, Bronson RT, Collin GB. New Alström syndrome phenotypes based on the evaluation of 182 cases. Archives of internal medicine. 2005. PMID: 15795345
- Hearn T, Spalluto C, Phillips VJ. Subcellular localization of ALMS1 supports involvement of centrosome and basal body dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. Diabetes. 2005. PMID: 15855349
- Collin GB, Marshall JD, Ikeda A. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome. Nature genetics. 2002. PMID: 11941369
- Hearn T, Renforth GL, Spalluto C. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alström syndrome. Nature genetics. 2002. PMID: 11941370
- Adam MP, Bick S, Mirzaa GM. Alström Syndrome. 1993. PMID: 20301444