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Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alström syndrome

Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alström syndrome
Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alström syndrome
Alstrom syndrome is a monogenic recessive disorder featuring an array of clinical manifestations, with systemic fibrosis and multiple organ involvement, including retinal degeneration, hearing loss, childhood obesity, diabetes mellitus, dilated cardiomyopathy (DCM), urological dysfunction, and pulmonary, hepatic, and renal failure. We evaluated a large cohort of patients with Alstrom syndrome for mutations in the ALMS1 gene. In total, 79 disease-causing variants were identified, of which 55 are novel mutations. The variants are primarily clustered in exons 8, 10, and 16, although we also identified novel mutations in exons 12 and 18. Most alleles were identified only once (45/79), but several were found recurrently. Founder effects are likely in families of English and Turkish descent. We also identified 66 SNPs and assessed the functional significance of these variants based on the conserved identity of the protein and the severity of the resulting amino acid substitution. A genotype-phenotype association study examining 18 phenotypic parameters in a subset of 58 patients found suggestive associations between disease-causing variants in exon 16 and the onset of retinal degeneration before the age of 1 year (P = 0.02), the occurrence of urological dysfunction (P = 0.02), of DCM (P = 0.03), and of diabetes (P = 0.03). A significant association was found between alterations in exon 8 and absent, mild, or delayed renal disease (P = 0.0007). This data may have implications for the understanding of the molecular mechanisms of ALMS1 and provides the basis for further investigation of how alternative splicing of ALMS1 contributes to the severity of the disease
Alström syndrome, ALMS1, genotype-phenotype correlation, SNPs, renal disease
1059-7794
1114-1123
Marshall, Jan D.
b3e0463f-5cb5-4c3b-a667-b09ea5aad0f6
Hinman, Elizabeth G.
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Collin, Gayle B.
1363ff94-ef41-4119-b355-ec4bf6f177fc
Beck, Sebastian
7847c6c2-672f-4826-b412-c733e618da93
Cerqueira, Rita
90195b72-3895-46fd-92b7-d12755459015
Maffei, Pietro
f25ec63c-1148-45de-937e-9acb1287cc3f
Milan, Gabriella
4ec03f6c-9050-4aa9-849d-63403eb70fdd
Zhang, Weidong
642dd5e5-4aa3-4c4a-94f8-ad4b2d5c7184
Wilson, David I.
1500fca1-7082-4271-95f4-691f1d1252a2
Hearn, Tom
2665cc10-6632-47cb-9460-bd0ea745380e
Tavares, Purificação
b8504f34-138d-497d-97fc-e5b3488380eb
Vettor, Roberto
3832c44a-a6b5-415b-8e37-c8b4e0009335
Veronese, Caterina
201f890f-ce11-4a72-9342-f01e578667c2
Martin, Mitchell
1ac1e02d-bece-4d3f-a6ae-16232407d29a
So, W. Venus
6de57f1f-1e75-43a5-8f74-883a1560a375
Nishina, Patsy M.
98cd88ee-3fbf-4e7c-9059-cd491b6d58dc
Naggert, Jürgen K.
d4d00cbe-b209-4f30-bb08-4336bf10c8af
Marshall, Jan D.
b3e0463f-5cb5-4c3b-a667-b09ea5aad0f6
Hinman, Elizabeth G.
b47c3bad-9adc-4124-903b-b96c8e9b083e
Collin, Gayle B.
1363ff94-ef41-4119-b355-ec4bf6f177fc
Beck, Sebastian
7847c6c2-672f-4826-b412-c733e618da93
Cerqueira, Rita
90195b72-3895-46fd-92b7-d12755459015
Maffei, Pietro
f25ec63c-1148-45de-937e-9acb1287cc3f
Milan, Gabriella
4ec03f6c-9050-4aa9-849d-63403eb70fdd
Zhang, Weidong
642dd5e5-4aa3-4c4a-94f8-ad4b2d5c7184
Wilson, David I.
1500fca1-7082-4271-95f4-691f1d1252a2
Hearn, Tom
2665cc10-6632-47cb-9460-bd0ea745380e
Tavares, Purificação
b8504f34-138d-497d-97fc-e5b3488380eb
Vettor, Roberto
3832c44a-a6b5-415b-8e37-c8b4e0009335
Veronese, Caterina
201f890f-ce11-4a72-9342-f01e578667c2
Martin, Mitchell
1ac1e02d-bece-4d3f-a6ae-16232407d29a
So, W. Venus
6de57f1f-1e75-43a5-8f74-883a1560a375
Nishina, Patsy M.
98cd88ee-3fbf-4e7c-9059-cd491b6d58dc
Naggert, Jürgen K.
d4d00cbe-b209-4f30-bb08-4336bf10c8af

Marshall, Jan D., Hinman, Elizabeth G., Collin, Gayle B., Beck, Sebastian, Cerqueira, Rita, Maffei, Pietro, Milan, Gabriella, Zhang, Weidong, Wilson, David I., Hearn, Tom, Tavares, Purificação, Vettor, Roberto, Veronese, Caterina, Martin, Mitchell, So, W. Venus, Nishina, Patsy M. and Naggert, Jürgen K. (2007) Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alström syndrome. Human Mutation, 28 (11), 1114-1123. (doi:10.1002/humu.20577).

Record type: Article

Abstract

Alstrom syndrome is a monogenic recessive disorder featuring an array of clinical manifestations, with systemic fibrosis and multiple organ involvement, including retinal degeneration, hearing loss, childhood obesity, diabetes mellitus, dilated cardiomyopathy (DCM), urological dysfunction, and pulmonary, hepatic, and renal failure. We evaluated a large cohort of patients with Alstrom syndrome for mutations in the ALMS1 gene. In total, 79 disease-causing variants were identified, of which 55 are novel mutations. The variants are primarily clustered in exons 8, 10, and 16, although we also identified novel mutations in exons 12 and 18. Most alleles were identified only once (45/79), but several were found recurrently. Founder effects are likely in families of English and Turkish descent. We also identified 66 SNPs and assessed the functional significance of these variants based on the conserved identity of the protein and the severity of the resulting amino acid substitution. A genotype-phenotype association study examining 18 phenotypic parameters in a subset of 58 patients found suggestive associations between disease-causing variants in exon 16 and the onset of retinal degeneration before the age of 1 year (P = 0.02), the occurrence of urological dysfunction (P = 0.02), of DCM (P = 0.03), and of diabetes (P = 0.03). A significant association was found between alterations in exon 8 and absent, mild, or delayed renal disease (P = 0.0007). This data may have implications for the understanding of the molecular mechanisms of ALMS1 and provides the basis for further investigation of how alternative splicing of ALMS1 contributes to the severity of the disease

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More information

Published date: 26 June 2007
Keywords: Alström syndrome, ALMS1, genotype-phenotype correlation, SNPs, renal disease

Identifiers

Local EPrints ID: 60029
URI: http://eprints.soton.ac.uk/id/eprint/60029
ISSN: 1059-7794
PURE UUID: f2a08c3a-8577-42b4-8ec4-cd0e108b3db2

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Date deposited: 08 Sep 2008
Last modified: 15 Mar 2024 11:18

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Contributors

Author: Jan D. Marshall
Author: Elizabeth G. Hinman
Author: Gayle B. Collin
Author: Sebastian Beck
Author: Rita Cerqueira
Author: Pietro Maffei
Author: Gabriella Milan
Author: Weidong Zhang
Author: David I. Wilson
Author: Tom Hearn
Author: Purificação Tavares
Author: Roberto Vettor
Author: Caterina Veronese
Author: Mitchell Martin
Author: W. Venus So
Author: Patsy M. Nishina
Author: Jürgen K. Naggert

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