Article

Mutations in Alström Protein Impair Terminal Differentiation of Cardiomyocytes

Nature Communications (Impact Factor: 10.74). 03/2014; 5:3416. DOI: 10.1038/ncomms4416
Source: PubMed

ABSTRACT Cardiomyocyte cell division and replication in mammals proceed through embryonic development and abruptly decline soon after birth. The process governing cardiomyocyte cell cycle arrest is poorly understood. Here we carry out whole-exome sequencing in an infant with evidence of persistent postnatal cardiomyocyte replication to determine the genetic risk factors. We identify compound heterozygous ALMS1 mutations in the proband, and confirm their presence in her affected sibling, one copy inherited from each heterozygous parent. Next, we recognize homozygous or compound heterozygous truncating mutations in ALMS1 in four other children with high levels of postnatal cardiomyocyte proliferation. Alms1 mRNA knockdown increases multiple markers of proliferation in cardiomyocytes, the percentage of cardiomyocytes in G2/M phases, and the number of cardiomyocytes by 10% in cultured cells. Homozygous Alms1-mutant mice have increased cardiomyocyte proliferation at 2 weeks postnatal compared with wild-type littermates. We conclude that deficiency of Alström protein impairs postnatal cardiomyocyte cell cycle arrest.

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Available from: Janet Scheel, Mar 13, 2015
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    • "Furthermore, deficiency of the Alström protein in postnatal mice decreases postnatal cardiomyocyte cell cycle arrest. Phenotypically, the heart/body ratio was increased in mutant mice compared to wild-type [Shenje et al., 2014]. "
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    ABSTRACT: Background: Two siblings from consanguineous parents of Turkish descent presented with isolated dilated cardiomyopathy, leading to early death in infancy. The diagnosis of mitogenic cardiomyopathy was made histologically. Methods and results: Linkage analysis combined with exome sequencing identified a homozygous deleterious mutation in the ALMS1 gene as the cause of this phenotype. Conclusions: Alstrom syndrome is characterized by a typically transient dilating cardiomyopathy in infancy, suggesting that mitogenic cardiomyopathy represents the extreme phenotype, resulting in demise before the other clinical symptoms become evident. This observation further illustrates the role of ALMS1 and cell cycle regulation. (C) 2014 Published by Elsevier Masson SAS.
    European Journal of Medical Genetics 06/2014; 57(9). DOI:10.1016/j.ejmg.2014.06.004 · 1.49 Impact Factor
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