Abstract
Alström syndrome is a homogeneous autosomal recessive disorder that is characterized by childhood obesity associated with hyperinsulinemia, chronic hyperglycemia and neurosensory deficits1,2. The gene involved in Alström syndrome probably interacts with genetic modifiers, as subsets of affected individuals present with additional features such as dilated cardiomyopathy3, hepatic dysfunction4, hypothyroidism5, male hypogonadism, short stature and mild to moderate developmental delay, and with secondary complications normally associated with type 2 diabetes, such as hyperlipidemia and atherosclerosis. Our detection of an uncharacterized transcript, KIAA0328, led us to identify the gene ALMS1, which contains sequence variations, including four frameshift mutations and two nonsense mutations, that segregate with Alström syndrome in six unrelated families. ALMS1 is ubiquitously expressed at low levels and does not share significant sequence homology with other genes reported so far. The identification of ALMS1 provides an entry point into a new pathway leading toward the understanding of both Alström syndrome and the common diseases that characterize it.
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Acknowledgements
We are greatly indebted to the individuals with Alström syndrome and their families for their participation in this study. We thank the laboratory of D.I. Wilson for sharing 5′ cDNA sequence information; Alström Syndrome International; the Center for Human Genetics, Bar Harbor, Maine; A.V. Levin; R. Weksburg and M.D. Ludman for referral of patients and D. McMinimy, J.H. Kim, J. Hurd and T. Radcliffe for technical assistance. We also thank E. Leiter and S. Ackerman for critical review of this manuscript. This study was supported by grants from the National Institutes of Health and the American Diabetes Association (to P.M.N.). Institutional shared services were supported by a National Cancer Institute Support grant (to P.M.N. and J.K.N.). Support of the clinical assessment of Kindred 57 was provided by a grant from M.I.U.R. (to N.S.).
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Collin, G., Marshall, J., Ikeda, A. et al. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome. Nat Genet 31, 74–78 (2002). https://doi.org/10.1038/ng867
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DOI: https://doi.org/10.1038/ng867
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