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Nat Commun. 2014 Mar 4;5:3416. doi: 10.1038/ncomms4416.

Mutations in Alström protein impair terminal differentiation of cardiomyocytes.

Author information

1
1] Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA [2].
2
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
3
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
4
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
5
North York General Hospital, Toronto, Ontario, Canada M2K 1E1.
6
Division of Pathology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
7
1] Division of Pathology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8 [2] KK Women's and Children's Hospital and Duke-NUS Graduate Medical School, Singapore 229899, Singapore.
8
1] Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA [2] McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
9
Division of Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
10
Division of Cardiothoracic Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
11
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
12
1] McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA [2] High Throughput Sequencing Facility, Genetic Resources Core Facility, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.

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.

PMID:
24595103
PMCID:
PMC3992616
DOI:
10.1038/ncomms4416
[Indexed for MEDLINE]
Free PMC Article

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