The ALMS1 gene, located on chromosome 2p codes for a protein with an unknown function. Since mutations in this gene result in Alstrom syndrome - a disorder characterized by obesity, type 2 diabetes, sensorineural hearing loss cone-rod dystrophy, and cardiomyopathy - researchers have suggested that the protein may play a role in hearing, vision, insulin regulation, regulation of body weight, and normal functioning of the vital organs. Some studies point towards a lack of normal ALMS1 protein in the brain causing overeating, and a loss of normal ALMS1 in the pancreas leading to insulin resistance. These two factors together could easily lead to insulin resistance, diabetes, and obesity.
The ALMS1 protein has been shown to be ubiquitously expressed and to localize subcellularly in the centromeres. The mouse ortholog of this gene has been shown to function in ciliogenesis in inner medullary collecting duct cells, leading to the proposal that ALMS1 is involved in the functioning of centrosomes or basal bodies, and for the proper formation and/or maintenance of the primary cilia.
The ALMS1 gene is large, and spans a length of about 225 Kb with its 23 exons. ALMS1 protein is also a large protein, consists of 4,167 amino acids and has a size of about 460 KDa. The protein contains a large tandem repeat domain.
More than 80 mutations in the ALMS1 gene have been found to cause Alstrom syndrome. Most of these mutations are nonsense, with about 40% of them occurring in exon 16. The exon 16 mutations are also known to effect in a more severe phenotype. Other hotspots include exon 10 and exon 8. The most common mutation has been found to be a c.10775delC mutation, which has been observed in about 50% of reported English kindreds. Studies have also described synonymous SNPs, non-synonymous SNPs, and a deletion in exon 8. Among 67 such variants described, eight have been predicted to be disease causing.
A study by Macari et al. (1998) that involved a consanguineous family of North African origin with three affected sibs, managed to narrow down the chromosomal region linked to Alstrom syndrome to an interval of 6.1-cM from a previously established larger interval of 14.9-cM on chromosome 2p13-12.
Aldahmesh et al. (2009) reported four novel alleles in the ALMS1 gene in consanguineous families with Alström disease. They commented on the interesting observation of allelic heterogeneity for a very rare autosomal recessive disorder in a highly inbred population.
Wang et al. (2011) performed homozygosity mapping, whole-exome sequencing and direct sequencing to identify mutations affecting a collection of six consanguineous Saudi families with Leber congenital amaurosis (LCA). There were 14 affected members who had vision defects since birth or as early as two years of age. A total of five disease-causing mutations located on four genes were identified in the six families. This included a homozygous nonsense mutation (c.10945G>T, p. E3649X) in the ALMS1 gene. This novel variant was rare and absent in all 200 normal matching controls. In addition, it had not been recorded in the dbSNP 130 database and the 1,000 Genome database.
Safieh et al., (2016) described a Saudi girl with nystagmus, photophobia, mid-facial hypoplasia, bilateral enophthalmos, and diabetes. Mutation screening of candidate genes revealed a pathogenic mutation (c.8441C>A, p.S2814*) in ALMS1 gene. The authors concluded that this mutation expands the genotypic spectrum of congenital retinal dystrophies in the Saudi population.