FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a protein containing a large tandem-repeat domain as well as additional low complexity regions. The encoded protein functions in microtubule organization, particularly in the formation and maintanance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. [provided by RefSeq, Apr 2014] PHENOTYPE: Homozygous null mice display obesity starting after puberty, hypogonadism, hyperinsulinemia, male-specific hyperglycemia, retinal dysfunction, and late-onset hearing loss. [provided by MGI curators]
Figure 1.Earthquakemice exhibited increased body weights compared to wild-type littermates. Scaled body weights are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.
The earthquake phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R6260, some of which showed increased body weights compared to wild-type littermates (Figure 1).
Nature of Mutation
Figure 2.Linkage mapping of the increased body weight phenotype using a recessive model of inheritance. Manhattan plot shows -log10 P values (Y-axis) plotted against the chromosome positions of 80 mutations (X-axis) identified in the G1 male of pedigree R6260. Weight data are shown for single locus linkage analysis without consideration of G2 dam identity. Horizontal pink and red lines represent thresholds of P = 0.05, and the threshold for P = 0.05 after applying Bonferroni correction, respectively.
Whole exome HiSeq sequencing of the G1 grandsire identified 80 mutations. The increased body weight phenotype was linked to mutations in two genes on chromosome 6: Fbxo41 and Alms1. The mutation in Alms1 was presumed causative as the body weight phenotype observed in earthquake mice mimics that of other Alms1 mutant mice (see aresand MGI). The mutation in Alms1 is an A to T transversion at base pair 85,628,735 (v38) on chromosome 6, or base pair 41,237 in the GenBank genomic region NC_000072 encoding Alms1. Linkage was found with a recessive model of inheritance, wherein five variant homozygotes departed phenotypically from 19 homozygous reference mice and 26 heterozygous mice with a P value of 3.84 x 10-5 (Figure 2).
The mutation corresponds to residue 6,074 in the mRNA sequence NM_145223 within exon 10 of 23 total exons.
The mutated nucleotide is indicated in red. The mutation results in substitution of lysine 1,987 for a premature stop codon (K1987*) in the ALMS1 protein.
Figure 3. Domain organization of ALMS1. See the text for more details. The earthquake mutation results in a lysine to stop codon substitution at position 1987. This image is interactive; click to view additional mutations in Alms1.
Alms1 encodes Alström Syndrome 1 (ALMS1), which has a glutamine-rich segment (amino acids 2-80), a proline-rich segment (amino acids 90-113), a putative leucine zipper (amino acids), a large tandem repeat domain (TRD) comprised of 34 imperfect repeats of a 45-50-amino acid sequence (amino acids 440−1362), a histidine-rich region (amino acids 2582-2618), two putative nuclear localization signals, a serine-rich region, and an ALMS motif (amino acids 3124-3251) [Figure 3; (1-4)]. The functional significance of the domains of ALMS1 is unknown.
The earthquake mutation results in substitution of lysine 1,987 for a premature stop codon (K1987*) in the ALMS1 protein; Lys1987 is within the TRD.
Please see the record for ares for more information about Alms1.
ALMS1 has putative roles in cell cycle regulation, cell migration, apoptosis, extracellular matrix production, ciliary assembly and/or function, adipogenesis, cytoplasmic microtubular organization, endosomal transport, and regulation of the transport of proteins between the cytoplasm and the ciliary axoneme (4-8). ALMS1 is proposed to be involved in intracellular trafficking of one or more uncharacterized receptors to the primary cilium membrane. ALMS1 may be involved in vesicle transport from the Golgi to the cilium and/or in intraflagellar transport. When ALMS1 is present, signals from the transported receptor regulate cellular homeostasis, neurogenesis, or organ function. In the absence of ALMS1, the receptor(s) are not transported within the cilia, resulting in defective signaling. In the absence of ALMS1 there is obesity, neurosensory deficit, and organ failure.
Homozygous or compound heterozygous mutations in ALMS1 that typically result in coding of a premature stop codon and coding of a truncated protein are linked to Alström syndrome (OMIM: #203800; (2;9)]. Alström syndrome has variable symptoms including childhood obesity due to an excess accumulation of subcutaneous adipose tissue, hyperinsulinemia, acanthosis nigricans (a marker of severe insulin resistance), type 2 diabetes mellitus, hypertriglyceridemia that can lead to acute pancreatitis, hypothyroidsism, growth hormone deficiency, sensorineural hearing loss, and progressive rod-cone dystrophy leading to blindness [(10); reviewed in (11;12)].
Several Alms1 mutant mouse models (fat aussie (foz), Alms1L2131X, and Alms1-/-) have been characterized (13-15). All of the mouse models exhibited rapid weight gain due to an increase in body fat and increased eating at weaning. In addition, all of the mutant Alms1 alleles also resulted in hyperinsulinemia, increased cholesterol levels (total and HDL), moderate late-onset (after ~16 weeks) diabetes only in the male mice, steatosis of the liver, hyperplastic pancreatic islets, and hypogonadism leading to infertility in the male mice. The phenotype of the earthquake mice indicate loss of ALMS1-associated function.