|Coordinate||85,619,712 bp (GRCm38)|
|Base Change||T ⇒ C (forward strand)|
|Gene Name||ALMS1, centrosome and basal body associated|
|Chromosomal Location||85,587,531-85,702,753 bp (+)|
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]
|Amino Acid Change||Serine changed to Proline|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000071904] [ENSMUSP00000148796]|
AA Change: S507P
|Predicted Effect||probably benign
PolyPhen 2 Score 0.004 (Sensitivity: 0.98; Specificity: 0.59)
|Predicted Effect||probably benign
PolyPhen 2 Score 0.001 (Sensitivity: 0.99; Specificity: 0.15)
|Meta Mutation Damage Score||0.126|
|Is this an essential gene?||Non Essential (E-score: 0.000)|
|Candidate Explorer Status||CE: excellent candidate; human score: 2; ML prob: 1|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Last Updated||2019-05-22 12:33 PM by Diantha La Vine|
|Record Created||2018-11-09 2:04 PM by Bruce Beutler|
The portly phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized female G3 mice of the pedigree R5947, some of which showed increased body weights compared to wild-type sex-matched littermates (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 61 mutations. The body weight phenotype was linked to a mutation in Alms1: a T to C transition at base pair 85,619,712 (v38) on chromosome 6, or base pair 32,214 in the GenBank genomic region NC_000072 encoding Alms1. Linkage was found with a recessive model of inheritance, wherein two variant homozygotes departed phenotypically from nine homozygous reference mice and five heterozygous mice with a P value of 2.223 x 10-5 (Figure 2).
The mutation corresponds to residue 1,634 in the NM_145223 mRNA sequence in exon 8 of 23 total exons.
The mutated nucleotide is indicated in red. The mutation results in a serine to proline substitution at amino acid 507 (S507P) in the ALMS1 protein, and is strongly predicted by Polyphen-2 to be benign (score = 0.004).
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 portly mutation results in a serine to proline substitution at amino acid 507 (S507P); residue 507 is within the TRD.
For more information about Alms1, please see the record for ares.
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 portly mice indicate loss of ALMS1-associated function.
portly(F):5'- AGATTCGGAAAGTGTCACCTG -3'
portly(R):5'- GAGGACGCTGTTAGAATGTCAG -3'
portly_seq(F):5'- GAAAGTGTCACCTGCTCTTAGGAC -3'
portly_seq(R):5'- AGCCTTCTTGTGAGCAGATCCAG -3'
1. Knorz, V. J., Spalluto, C., Lessard, M., Purvis, T. L., Adigun, F. F., Collin, G. B., Hanley, N. A., Wilson, D. I., and Hearn, T. (2010) Centriolar Association of ALMS1 and Likely Centrosomal Functions of the ALMS Motif-Containing Proteins C10orf90 and KIAA1731. Mol Biol Cell. 21, 3617-3629.
2. Collin, G. B., Marshall, J. D., Ikeda, A., So, W. V., Russell-Eggitt, I., Maffei, P., Beck, S., Boerkoel, C. F., Sicolo, N., Martin, M., Nishina, P. M., and Naggert, J. K. (2002) Mutations in ALMS1 Cause Obesity, Type 2 Diabetes and Neurosensory Degeneration in Alstrom Syndrome. Nat Genet. 31, 74-78.
3. Hearn, T., Renforth, G. L., Spalluto, C., Hanley, N. A., Piper, K., Brickwood, S., White, C., Connolly, V., Taylor, J. F., Russell-Eggitt, I., Bonneau, D., Walker, M., and Wilson, D. I. (2002) Mutation of ALMS1, a Large Gene with a Tandem Repeat Encoding 47 Amino Acids, Causes Alstrom Syndrome. Nat Genet. 31, 79-83.
4. Hearn, T., Spalluto, C., Phillips, V. J., Renforth, G. L., Copin, N., Hanley, N. A., and Wilson, D. I. (2005) Subcellular Localization of ALMS1 Supports Involvement of Centrosome and Basal Body Dysfunction in the Pathogenesis of Obesity, Insulin Resistance, and Type 2 Diabetes. Diabetes. 54, 1581-1587.
5. Jagger, D., Collin, G., Kelly, J., Towers, E., Nevill, G., Longo-Guess, C., Benson, J., Halsey, K., Dolan, D., Marshall, J., Naggert, J., and Forge, A. (2011) Alstrom Syndrome Protein ALMS1 Localizes to Basal Bodies of Cochlear Hair Cells and Regulates Cilium-Dependent Planar Cell Polarity. Hum Mol Genet. 20, 466-481.
6. Collin, G. B., Cyr, E., Bronson, R., Marshall, J. D., Gifford, E. J., Hicks, W., Murray, S. A., Zheng, Q. Y., Smith, R. S., Nishina, P. M., and Naggert, J. K. (2005) Alms1-Disrupted Mice Recapitulate Human Alstrom Syndrome. Hum Mol Genet. 14, 2323-2333.
7. Andersen, J. S., Wilkinson, C. J., Mayor, T., Mortensen, P., Nigg, E. A., and Mann, M. (2003) Proteomic Characterization of the Human Centrosome by Protein Correlation Profiling. Nature. 426, 570-574.
8. Li, G., Vega, R., Nelms, K., Gekakis, N., Goodnow, C., McNamara, P., Wu, H., Hong, N. A., and Glynne, R. (2007) A Role for Alstrom Syndrome Protein, alms1, in Kidney Ciliogenesis and Cellular Quiescence. PLoS Genet. 3, e8.
9. Joy, T., Cao, H., Black, G., Malik, R., Charlton-Menys, V., Hegele, R. A., and Durrington, P. N. (2007) Alstrom Syndrome (OMIM 203800): A Case Report and Literature Review. Orphanet J Rare Dis. 2, 49.
10. Marshall, J. D., Bronson, R. T., Collin, G. B., Nordstrom, A. D., Maffei, P., Paisey, R. B., Carey, C., Macdermott, S., Russell-Eggitt, I., Shea, S. E., Davis, J., Beck, S., Shatirishvili, G., Mihai, C. M., Hoeltzenbein, M., Pozzan, G. B., Hopkinson, I., Sicolo, N., Naggert, J. K., and Nishina, P. M. (2005) New Alstrom Syndrome Phenotypes Based on the Evaluation of 182 Cases. Arch Intern Med. 165, 675-683.
11. Marshall, J. D., Beck, S., Maffei, P., and Naggert, J. K. (2007) Alstrom Syndrome. Eur J Hum Genet. 15, 1193-1202.
12. Girard, D., and Petrovsky, N. (2011) Alstrom Syndrome: Insights into the Pathogenesis of Metabolic Disorders. Nat Rev Endocrinol. 7, 77-88.
13. Arsov, T., Silva, D. G., O'Bryan, M. K., Sainsbury, A., Lee, N. J., Kennedy, C., Manji, S. S., Nelms, K., Liu, C., Vinuesa, C. G., de Kretser, D. M., Goodnow, C. C., and Petrovsky, N. (2006) Fat Aussie--a New Alstrom Syndrome Mouse Showing a Critical Role for ALMS1 in Obesity, Diabetes, and Spermatogenesis. Mol Endocrinol. 20, 1610-1622.
14. Favaretto, F., Milan, G., Collin, G. B., Marshall, J. D., Stasi, F., Maffei, P., Vettor, R., and Naggert, J. K. (2014) GLUT4 Defects in Adipose Tissue are Early Signs of Metabolic Alterations in Alms1GT/GT, a Mouse Model for Obesity and Insulin Resistance. PLoS One. 9, e109540.
|Science Writers||Anne Murray|
|Authors||Zhao Zhang and Bruce Beutler|