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ALMS1
ALMS1 centrosome and basal body associated protein
The ALMS1 gene provides instructions for a protein involved in various cellular processes, with mutations linked to Alström syndrome, a rare inherited disorder. The ALMS1 gene encodes a large protein whose precise function is still under investigation, but it is believed to play a critical role in cellular structures such as centrosomes and cilia.
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 is responsible for producing the ALMS1 protein, which is thought to be integral to several fundamental cellular activities. Although its full functional scope is not yet entirely understood, evidence suggests it influences hearing, vision, and the regulation of body weight, as well as the healthy function of organs including the heart, kidney, lungs, and liver. The protein may also have a role in the pancreas's regulation of insulin, which is crucial for managing blood glucose levels.
The ALMS1 protein is found broadly across the body's tissues, typically in low concentrations. Its presence in specific cellular components underscores its potential importance in cell maintenance and signalling.
What the gene does
Within cells, the ALMS1 protein localises to centrosomes, which are key organisers of cell division and are involved in the assembly of microtubules. Microtubules are protein structures that facilitate intracellular transport and help cells maintain their shape. The ALMS1 protein is also observed at the base of cilia, which are small, finger-like projections found on the surface of most cells during their lifecycle.
Cilia are essential for cell movement and participate in numerous chemical signalling pathways. Based on its cellular localisation, research indicates that the ALMS1 protein may contribute to the organisation of microtubules, the transport of various cellular materials, and the normal functioning of cilia. Disruptions to this protein's function, particularly due to genetic variants, can lead to widespread systemic issues.
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Chromosome location
The ALMS1 gene is situated on the short arm of chromosome 2, specifically at position 2p13.1. This genomic location places the gene in a region of the chromosome that can be precisely identified by cytogenetic banding techniques.
Protein structure
The ALMS1 protein is a substantial protein comprising 4168 amino acids. Its structural organisation includes several distinct domains. An initial Disordered region is found at amino acids 1-69. Further into the protein, a large section from amino acids 539-2200 is characterised as a 34 X 47 AA approximate tandem repeat Region, which includes multiple smaller Repeat domains. Specifically, Repeat 1 is located at amino acids 539-585, Repeat 2 at 586-632, Repeat 3 at 633-679, Repeat 4 at 680-726, Repeat 5 at 727-774, Repeat 6 at 775-821, Repeat 7 at 822-871, and Repeat 8 at 872-918. Several Disordered regions are interspersed within these repeats, such as at 558-579, 606-625, 699-718, 735-769, and 841-865.
Key variants
The ALMS1 gene can undergo various types of genetic changes, known as variants. Over 80 different variants in the ALMS1 gene have been identified in individuals with associated health conditions. Most of these variants lead to the production of an ALMS1 protein that is abnormally short and consequently non-functional. The specific impact of these variants can vary depending on their 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.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
Variants in the ALMS1 gene are predominantly linked to Alström syndrome. This condition is inherited in an autosomal recessive manner and can affect multiple body systems, leading to a wide range of symptoms. Research suggests that a lack of functional ALMS1 protein may contribute to features such as overeating due to brain dysfunction and insulin resistance if the pancreas is affected. The ALMS1 gene has also been mentioned in relation to Leber congenital amaurosis.
UK clinical status
The ALMS1 gene is recognised within the NHS Genomic Medicine Service due to its association with several conditions. It is listed as 'green' on multiple PanelApp panels, indicating strong evidence for its clinical utility in diagnosing inherited disorders. These include panels for Alstrom syndrome (R106), DDG2P, Diabetes with additional phenotypes suggestive of a monogenic aetiology, Foetal anomalies (R21), Insulin resistance (including lipodystrophy), Intellectual disability, Monogenic hearing loss (R67), Ophthalmological ciliopathies, Paediatric or syndromic cardiomyopathy (R135), Rare multisystem ciliopathy disorders, Renal ciliopathies, Retinal disorders (R32), Severe early-onset obesity (R149), 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 the primary condition associated with the ALMS1 gene?
The primary condition linked to variants in the ALMS1 gene is Alström syndrome, a rare inherited disorder affecting multiple body systems, including vision, hearing, and metabolic functions.
Where is the ALMS1 protein found in cells?
The ALMS1 protein is primarily found in cellular structures called centrosomes and at the base of cilia. These locations suggest its involvement in cell division, microtubule organisation, and various cellular signalling pathways.
What is the inheritance pattern for Alström syndrome?
Alström syndrome is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of a pathogenic ALMS1 variant, one from each parent, to develop the condition.
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