Alternative titles; symbols
HGNC Approved Gene Symbol: ALMS1
SNOMEDCT: 63702009;
Cytogenetic location: 2p13.1 Genomic coordinates (GRCh38) : 2:73,385,758-73,609,919 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p13.1 | Alstrom syndrome | 203800 | Autosomal recessive | 3 |
ALMS1 localizes to the centrosome and appears to have a role in centriole structure and function (Knorz et al., 2010).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1997) cloned ALMS1, which they designated KIAA0328. The transcript contains a repetitive sequence at its 3-prime UTR. RT-PCR detected low expression in testis and little to no expression in all other tissues examined.
By linkage mapping and scrutiny of positional candidate genes, Collin et al. (2002) identified an uncharacterized transcript, KIAA0328, in which sequence variations were found to segregate with Alstrom syndrome (ALMS; 203800). By aligning KIAA0328 with overlapping transcripts from several sequence databases, they obtained a full-length cDNA sequence of 12,871 basepairs with an open reading frame of 4,169 amino acids.
Hearn et al. (2002) studied a unique patient with a familial balanced reciprocal translocation involving 2p13 in which the KIAA0328 gene was disrupted by the translocation and the other copy disrupted by an intragenic mutation to cause Alstrom syndrome. By RT-PCR with exon prediction and specific primer design, they identified an ALMS1 sequence containing an open reading frame of 12.5 kb that encodes a protein of 4,169 amino acids. The protein contains a large tandem-repeat domain comprising 34 imperfect repetitions of 47 amino acids. Hearn et al. (2002) stated that their identification of the ALMS1 gene using cloning of the breakpoint of a balanced translocation represented the first use of this strategy to identify a gene involved in a recessive disorder.
Using real-time PCR of mouse tissues, Li et al. (2007) detected highest Alms1 expression in testis. Expression was moderate in brain, eye, lung, and olfactory bulb and low in spleen, liver, and kidney. Immunohistochemical analysis localized Alms1 to the base of cilia in cultured mouse kidney cells.
Knorz et al. (2010) reported that the deduced 4,169-amino acid ALMS1 protein has an N-terminal stretch of 17 consecutive glu residues, followed by a tandem repeat domain, a putative leucine zipper, his-rich and ser-rich regions, and a C-terminal ALMS motif domain. Unlike many other centrosomal proteins, ALMS1 has limited potential to form coiled-coils. Knorz et al. (2010) also described a splice variant of ALMS1 that includes exon 2, which introduces 42 additional residues. This variant is rarely expressed in humans. High-resolution immunofluorescence microscopy of hTERT-RPE1 cells detected ALMS1 at the proximal ends of centrioles and basal bodies.
Li et al. (2007) found that depletion of Alms1 by short interfering RNA in mouse inner medullary collecting duct cells caused defective ciliogenesis. Alms1 knockdown did not affect transcription of ciliary genes, but cilia were stunted and mutant cells lacked the ability to increase calcium influx in response to mechanical stimuli. The stunted cilium phenotype was rescued by transfection of a cDNA encoding the N-terminal 1,282 amino acids of Alms1.
Using RNA interference, Knorz et al. (2010) found that knockdown of ALMS1 in human cells reduced the intensity of CNAP1 (CEP2; 609689) staining at the centrosome, increased the distance between centrioles, and caused a defect in trafficking of centriolar satellite PCM1 (600299)-positive granules.
Collin et al. (2002) and Hearn et al. (2002) identified 23 exons in the ALMS1 gene.
By radiation hybrid analysis, Nagase et al. (1997) mapped the ALMS1 gene to chromosome 2.
As a result of a linkage study in a large French Acadian kindred with Alstrom syndrome and because of evidence of founder effect, Collin et al. (1997) were able to use homozygosity mapping to identify the Alstrom disease locus. In a genomewide screen, haplotype sharing for a region on chromosome 2 was observed in all affected individuals. Two-point linkage analysis resulted in a maximum lod score of 3.84 at theta = 0.00 for marker D2S292. By testing additional markers, the disease gene was localized to a 14.9-cM region on 2p14-p13 (see Figure 3 of Collin et al., 1997). In a North African family in Algeria, Macari et al. (1998) refined the localization of the Alstrom syndrome locus to 2p13-p12, reducing the genetic interval to 6.1 cM. Collin et al. (1999) confirmed the mapping to 2p13 by performing a linkage study in 12 additional families. A maximum 2-point lod score of 7.13 (theta = 0.00) for marker D2S2110 and a maximum cumulative multipoint lod score of 9.16 for marker D2S2110 were observed. Meiotic recombination events localized the critical region containing the ALMS1 locus to a 6.1-cM interval flanked by markers D2S327 and D2S286.
Collin et al. (2002) and Hearn et al. (2002) cloned the ALMS1 gene within the critical region on 2p13 and detected mutations in ALMS1 resulting in Alstrom syndrome.
Hearn et al. (2002) detected 6 different mutations (2 nonsense and 4 frameshift causing premature stop codons) in affected members of 7 families segregating Alstrom syndrome. Collin et al. (2002) identified 6 different mutations (4 frameshift and 2 nonsense) in affected members of 6 unrelated families with Alstrom syndrome.
Collin et al. (2002) reasoned that the infantile obesity observed in individuals with Alstrom syndrome is probably caused by mutation in ALMS1, as it constitutes a relatively early (as early as 6 months) phenotype observed in all affected children. The early onset of obesity, anecdotal reports of hyperphagia, and the sensory deficits observed in individuals with Alstrom syndrome suggested to Collin et al. (2002) that the obesity is due to loss of ALMS1 function in the central nervous system. Nearly all individuals with Alstrom syndrome develop type 2 diabetes (125853), suggesting that ALMS1 may be involved in 'diabesity,' a term used by Collin et al. (2002) for combined obesity and diabetes susceptibility due to altered function of a single gene. This distinguishes it from the common forms of obesity, in which the genes that are presumably involved appear to interact with independently segregating genes that confer diabetes susceptibility, as not all obese individuals develop type 2 diabetes.
Marshall et al. (2007) identified a total of 79 mutations in the ALMS1 gene, including 55 novel mutations, among 250 individuals with a clinical diagnosis of Alstrom syndrome from 206 unrelated kindreds. There were 32 mutations in exon 16, 19 mutations in exon 10, and 17 mutations in exon 8, suggesting that these regions represent mutation hotspots. The most common allele was a 1-bp deletion (10775delC; 606844.0003), identified in 12% of mutated alleles. Common haplotypes were observed in kindreds of English descent who carried this allele, suggesting a founder effect. A genotype-phenotype correlation analysis in a subset of 58 patients found a trend for disease-causing variants in exon 16 and a more severe phenotype. These patients tended to have onset of retinal degeneration before age 1 year (p = 0.02), urologic dysfunction (p = 0.02), dilated cardiomyopathy (p = 0.03), and diabetes (p = 0.03). A significant association was found between alterations in exon 8 and absent, mild, or delayed renal disease (p = 0.0007).
In 2 cousins with Alstrom syndrome from a consanguineous Turkish pedigree, Taskesen et al. (2012) identified homozygosity for insertion of a novel 333-bp Alu Ya5 SINE retrotransposon into exon 16 of the ALMS1 gene (606844.0008). The severely affected male proband died at 14 years of age of multiple organ failure after an episode of acute gastroenteritis; his 6-year-old female cousin developed vision loss and obesity in early childhood and had hypertriglyceridemia but otherwise normal hepatic, pulmonary, cardiac, and renal function and normal hearing.
See 606844.0009 for a possible association between Leber congenital amaurosis (LCA; see 204000) and mutation in the ALMS1 gene.
Collin et al. (2005) generated a mouse model of Alstrom syndrome using an Alms1 gene-trapped ES cell line. Alms1 -/- mice developed features similar to human patients with ALMS, including obesity, hypogonadism, hyperinsulinemia, retinal dysfunction, and late-onset hearing loss. Insulin resistance and increased body weight were apparent at 8 to 12 weeks of age, with hyperglycemia manifesting at 16 weeks of age. Alms1 -/- mice displayed abnormal auditory brainstem responses after 8 months of age. Diminished cone ERG b-wave response was observed early, followed by the degeneration of photoreceptor cells. Electron microscopy revealed accumulation of intracellular vesicles in the inner segments of photoreceptors, whereas immunohistochemical analysis showed mislocalization of rhodopsin (RHO; 180380) to the outer nuclear layer. Collin et al. (2005) suggested that ALMS1 may play a role in intracellular trafficking.
Li et al. (2007) studied a mouse model of Alstrom syndrome in which the Alms1 protein was prematurely terminated at 2,130 amino acids. Primary fibroblasts and kidney cells from homozygous mutant mice expressed both mutant mRNA and protein, and they showed normal primary cilia and normal localization of the mutant protein. Homozygous mutant mice increased in weight faster than wildtype mice due to increased fat mass, and they had abnormal blood lipid chemistry, defective sperm formation, and defective rhodopsin transport in the retina. By 6 months of age, homozygous mutant mice developed multiple dilated cortical tubules, and older animals showed loss of cilia from kidney proximal tubules, which was associated with foci of apoptosis or proliferation.
In the large consanguineous Acadian kindred with Alstrom syndrome (ALMS; 203800) studied by Collin et al. (1997) and Marshall et al. (1997), Collin et al. (2002) identified an insertion of 19 bp in exon 16 of the ALMS1 gene, causing a frameshift resulting in early termination at codon 3530. All 5 affected subjects from the extended pedigree were homozygous with respect to the insertion. Transmission of the insertion allele in unaffected carriers was consistent with previously reported haplotypes (Collin et al., 1997).
In a consanguineous Italian family with Alstrom syndrome (ALMS; 203800), Collin et al. (2002) observed an 8383C-T transition in the ALMS1 gene in homozygous state, causing a nonsense change, glu2795 to ter (G2795X).
In 2 unrelated young adults with Alstrom syndrome (ALMS; 203800), Collin et al. (2002) found a 10775delC mutation in the ALMS1 gene. One subject was a 19-year-old male of British ancestry and the other a 21-year-old male who traced his ancestry to Britain 2 centuries earlier. Both presented with infantile cardiomyopathy within the first 2 months of life and subsequently developed short stature, scoliosis, type 2 diabetes, and renal insufficiency. However, they differed in the course of their disease presentation. The first experienced a sudden recurrence of dilated cardiomyopathy at age 18 and had no evidence of hepatic dysfunction, whereas the second presented with severe hepatic failure at age 20 and had not had a recurrence of cardiomyopathy. This difference in disease progression in individuals carrying the same mutation suggested that the phenotypic variability observed in many individuals with Alstrom syndrome may be the result of genetic or environmental modifiers interacting with the ALMS1 locus.
In 2 sibs with Alstrom syndrome, Hearn et al. (2002) found compound heterozygosity for the 10775delC mutation and a trp3664-to-ter mutation in the ALMS1 gene (W3664X; 606844.0006); the former was inherited from the father and the latter presumably from the mother. The W3664X mutation was caused by a G-to-A transition at nucleotide 10992. Hearn et al. (2002) found the 10775delC mutation in 3 additional families not known to be related to the original family in which this mutation was identified.
Marshall et al. (2007) identified the 10775delC mutation in 12% of mutated alleles from a large study of 250 patients with ALMS. Common haplotypes were observed in kindreds of English descent who carried this allele, suggesting a founder effect.
Hearn et al. (2002) described a patient with Alstrom syndrome (ALMS; 203800) who was compound heterozygous for mutations involving the ALMS1 gene. The ALMS1 gene on the maternal chromosome 2 was disrupted by the translocation break; the ALMS1 gene on the paternal chromosome carried a deletion of 2 bp in exon 8 (2141delCT) that was predicted to cause premature termination 5 codons downstream of the deletion.
For discussion of the trp3664-to-ter (W3664X) mutation in the ALMS1 gene that was found in compound heterozygous state in patients with Alstrom syndrome (ALMS; 203800) by Hearn et al. (2002), see 606844.0003.
In 3 Turkish sisters with Alstrom syndrome (ALMS; 203800), Ozgul et al. (2007) identified a homozygous 8164C-T transition in the ALMS1 gene, resulting in an arg2722-to-ter (R2722X) substitution. The girls had been followed for 20 years and showed typical clinical features of the disorder with some additional unusual findings such as pes planus, tooth enamel discoloration, and structural renal anomalies.
In 2 cousins with Alstrom syndrome (ALMS; 203800) from a consanguineous Turkish pedigree, Taskesen et al. (2012) identified homozygosity for insertion of a 333-bp Alu Ya5 element in exon 16 of the ALMS1 gene, predicted to cause a frameshift resulting in a premature termination codon. PCR genotyping for the presence of the Alu allele revealed that the wildtype allele produces a 313-bp PCR product, whereas the Alu allele produces a 646-bp PCR product. Taskesen et al. (2012) did not detect a 100% identical sequence anywhere in the human genome assembly, indicating a previously unknown polymorphism of active Alu Ya5 elements. The authors suggested that the truncation of 34 nucleotides at the 5-prime end of the ALMS1(Alu) allele, possibly due to incomplete reverse transcription during transposition, made it likely that this particular element would no longer be transcription- or retroposition-competent. The ALMS1(Alu) allele was detected in 2 (6.9%) of 29 unaffected individuals from the same Turkish village as the affected pedigree, but was not found in 50 unrelated Turkish controls. The severely affected male proband died at 14 years of age of multiple organ failure after an episode of acute gastroenteritis; his 6-year-old female cousin developed vision loss and obesity in early childhood and had hypertriglyceridemia but otherwise normal hepatic, pulmonary, cardiac, and renal function and normal hearing.
In a study of 250 patients with Alstrom syndrome (ALMS; 203800), Marshall et al. (2007) identified 2 alleles carrying a 10945G-T transversion in exon 16 of the ALMS1 gene, resulting in a glu3649-to-ter (E3649X) substitution.
Associations Pending Confirmation
In members of a large consanguineous Saudi Arabian family who had been diagnosed with Leber congenital amaurosis (LCA; see 204000), Wang et al. (2011) identified homozygosity for the E3649X mutation in the ALMS1 gene. The authors stated that no other syndromic features such as hearing loss or obesity had been reported in the Saudi Arabian patients.
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., Naggert, J. K. Alms1-disrupted mice recapitulate human Alstrom syndrome. Hum. Molec. Genet. 14: 2323-2333, 2005. [PubMed: 16000322] [Full Text: https://doi.org/10.1093/hmg/ddi235]
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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., Naggert, J. K. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alstrom syndrome. Nature Genet. 31: 74-78, 2002. [PubMed: 11941369] [Full Text: https://doi.org/10.1038/ng867]
Hearn, T., Renforth, G. L., Spalluto, C., Hanley, N. A., Piper, K., Brickwood, S., White, C., Connolly, V., Taylor, J. F. N., Russell-Eggitt, I., Bonneau, D., Walker, M., Wilson, D. I. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alstrom syndrome. Nature Genet. 31: 79-83, 2002. [PubMed: 11941370] [Full Text: https://doi.org/10.1038/ng874]
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Li, G., Vega, R., Nelms, K., Gekakis, N., Goodnow, C., McNamara, P., Wu, H., Hong, N. A., Glynne, R. A role for Alstrom syndrome protein, Alms1, in kidney ciliogenesis and cellular quiescence. PLoS Genet. 3: e8, 2007. Note: Electronic Article. [PubMed: 17206865] [Full Text: https://doi.org/10.1371/journal.pgen.0030008]
Macari, F., Lautier, C., Girardet, A., Dadoun, F., Darmon, P., Dutour, A., Renard, E., Bouvagnet, P., Claustres, M., Oliver, C., Grigorescu, F. Refinement of genetic localization of the Alstrom syndrome on chromosome 2p12-13 by linkage analysis in a North African family. Hum. Genet. 103: 658-661, 1998. [PubMed: 9921899] [Full Text: https://doi.org/10.1007/s004390050887]
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Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 4: 141-150, 1997. [PubMed: 9205841] [Full Text: https://doi.org/10.1093/dnares/4.2.141]
Ozgul, R. K., Satman, I., Collin, G. B., Hinman, E. G., Marshall, J. D., Kocaman, O., Tutuncu, Y., Yilmaz, T., Naggert, J. K. Molecular analysis and long-term clinical evaluation of three siblings with Alstrom syndrome. Clin. Genet. 72: 351-356, 2007. [PubMed: 17850632] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00848.x]
Taskesen, M., Collin, G. B., Evsikov, A. V., Guzel, A., Ozgul, R. K., Marshall, J. D., Naggert, J. K. Novel Alu retrotransposon insertion leading to Alstrom syndrome. Hum. Genet. 131: 407-413, 2012. [PubMed: 21877133] [Full Text: https://doi.org/10.1007/s00439-011-1083-9]
Wang, X., Wang, H., Cao, M., Li, Z., Chen, X., Patenia, C., Gore, A., Abboud, E. B., Al-Rajhi, A. A., Lewis, R. A., Lupski, J. R., Mardon, G., Zhang, K., Muzny, D., Gibbs, R. A., Chen, R. Whole-exome sequencing identifies ALMS1, IQCB1, CNGA3, and MYO7A mutations in patients with Leber congenital amaurosis. Hum. Mutat. 32: 1450-1459, 2011. [PubMed: 21901789] [Full Text: https://doi.org/10.1002/humu.21587]