Abstract
Background: Alström syndrome (AS) is an extremely rare, autosomal recessive disorder characterised by multi-organ features that typically manifest within the first two decades of life. AS is caused by mutations in the Alström syndrome 1 (ALMS1) gene located at 2p13.1.
Methods: In the current study, two brothers from a first-cousin consanguineous family presented with a complex phenotype and were suspected of having AS.
Results: Both brothers were found to be homozygous for a novel nonsense c.7310C>A (p.S2437X) mutation in exon-8 of ALMS1 gene. The consanguineous parents were sequenced and both were heterozygous for the same mutation.
Conclusions: This particular mutation has never been reported before and confirmed the diagnosis of AS in the patients. Our work identifies a novel mutation in ALMS1 gene responsible for the complex phenotype of AS in these patients.
Acknowledgments
We are indebted to the patients and their families for participating in our studies.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organisation(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Alstrom CH, Hallgren B, Nilsson LB, Asander H. Retinal degeneration combined with obesity, diabetes mellitus and neurogenous deafness: a specific syndrome (not hitherto described) distinct from the Laurence-Moon-Bardet-Biedl syndrome: a clinical, endocrinological and genetic examination based on a large pedigree. Acta Psychiatr Neurol Scand Suppl 1959;129:1–35.Search in Google Scholar
2. Marshall JD, Bronson RT, Collin GB, Nordstrom AD, Maffei P, et al. New Alstrom syndrome phenotypes based on the evaluation of 182 cases. Arch Intern Med 2005;165:675–83.10.1001/archinte.165.6.675Search in Google Scholar PubMed
3. Collin GB, Marshall JD, Ikeda A, So WV, Russell-Eggitt I, et al. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alstrom syndrome. Nat Genet 2002;31:74–8.10.1038/ng867Search in Google Scholar PubMed
4. Marshall JD, Maffei P, Collin GB, Naggert JK. Alstrom syndrome: genetics and clinical overview. Curr Genomics 2011;12:225–35.10.2174/138920211795677912Search in Google Scholar PubMed PubMed Central
5. Collin GB, Marshall JD, Cardon LR, Nishina PM. Homozygosity mapping at Alstrom syndrome to chromosome 2p. Hum Mol Genet 1997;6:213–9.10.1093/hmg/6.2.213Search in Google Scholar PubMed
6. Nagase T, Ishikawa K, Nakajima D, Ohira M, Seki N, et al. 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 1997;4:141–50.10.1093/dnares/4.2.141Search in Google Scholar PubMed
7. Hearn T, Renforth GL, Spalluto C, Hanley NA, Piper K, et al. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alstrom syndrome. Nat Genet 2002;31:79–83.10.1038/ng874Search in Google Scholar PubMed
8. Marshall JD, Hinman EG, Collin GB, Beck S, Cerqueira R, et al. Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alstrom syndrome. Hum Mutat 2007;28:1114–23.10.1002/humu.20577Search in Google Scholar PubMed
9. Pereiro I, Hoskins BE, Marshall JD, Collin GB, Naggert JK, et al. Arrayed primer extension technology simplifies mutation detection in Bardet-Biedl and Alstrom syndrome. Eur J Hum Genet 2011;19:485–8.10.1038/ejhg.2010.207Search in Google Scholar PubMed PubMed Central
10. Marshall JD, Muller J, Collin GB, Milan G, Kingsmore SF, et al. Alstrom syndrome: mutation spectrum of ALMS1. Hum Mutat 2015;36:660–8.10.1002/humu.22796Search in Google Scholar PubMed PubMed Central
11. Ozanturk A, Marshall JD, Collin GB, Duzenli S, Marshall RP, et al. The phenotypic and molecular genetic spectrum of Alstrom syndrome in 44 Turkish kindreds and a literature review of Alstrom syndrome in Turkey. J Hum Genet 2015;60:1–9.10.1038/jhg.2014.85Search in Google Scholar PubMed PubMed Central
12. Li G, Vega R, Nelms K, Gekakis N, Goodnow C, et al. A role for Alstrom syndrome protein, alms1, in kidney ciliogenesis and cellular quiescence. PLoS Genet 20075;3:e8.10.1371/journal.pgen.0030008Search in Google Scholar PubMed PubMed Central
13. Han YG, Spassky N, Romaguera-Ros M, Garcia-Verdugo JM, Aguilar A, et al. Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat Neurosci 2008;11:277–84.10.1038/nn2059Search in Google Scholar PubMed
14. Andersen JS, Wilkinson CJ, Mayor T, Mortensen P, Nigg EA, et al. Proteomic characterization of the human centrosome by protein correlation profiling. Nature 2003;426:570–4.10.1038/nature02166Search in Google Scholar PubMed
15. Collin GB, Cyr E, Bronson R, Marshall JD, Gifford EJ, et al. Alms1-disrupted mice recapitulate human Alstrom syndrome. Hum Molec Genet 2005;14:2323–33.10.1093/hmg/ddi235Search in Google Scholar PubMed PubMed Central
16. Hearn T, Spalluto C, Phillips VJ, Renforth GL, Copin N, et al. Subcellular localization of ALMS1 supports involvement of centrosome and basal body dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. Diabetes 2005;54:1581–7.10.2337/diabetes.54.5.1581Search in Google Scholar PubMed
17. Kousta E, Hadjiathanasiou CG, Tolis G, Papathanasiou A. Pleiotropic genetic syndromes with developmental abnormalities associated with obesity. J Pediatr Endocrinol Metab 2009;22:581–92.10.1515/JPEM.2009.22.7.581Search in Google Scholar PubMed
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