Mutations in Alström protein impair terminal differentiation of cardiomyocytes

Lincoln T. Shenje, Peter Andersen, Marc K. Halushka, Cecillia Lui, Laviel Fernandez, Gayle B. Collin, Nuria Amat-Alarcon, Wendy Meschino, Ernest Cutz, Kenneth Chang, Raluca Yonescu, Denise A. S. Batista, Yan Chen, Stephen Chelko, Jane E. Crosson, Janet Scheel, Luca Vricella, Brian D. Craig, Beth A. Marosy, David W. Mohr, Kurt N. Hetrick, Jane M. Romm, Alan F. Scott, David Valle, Jürgen K. Naggert, Chulan Kwon, Kimberly F. Doheny and Daniel P. Judge ()
Additional contact information
Lincoln T. Shenje: Johns Hopkins University School of Medicine
Peter Andersen: Johns Hopkins University School of Medicine
Marc K. Halushka: Johns Hopkins University School of Medicine
Cecillia Lui: Johns Hopkins University School of Medicine
Laviel Fernandez: Johns Hopkins University School of Medicine
Gayle B. Collin: The Jackson Laboratory
Nuria Amat-Alarcon: Johns Hopkins University School of Medicine
Wendy Meschino: North York General Hospital
Ernest Cutz: The Hospital for Sick Children
Kenneth Chang: The Hospital for Sick Children
Raluca Yonescu: Johns Hopkins University School of Medicine
Denise A. S. Batista: Johns Hopkins University School of Medicine
Yan Chen: Johns Hopkins University School of Medicine
Stephen Chelko: Johns Hopkins University School of Medicine
Jane E. Crosson: Johns Hopkins University School of Medicine
Janet Scheel: Johns Hopkins University School of Medicine
Luca Vricella: Johns Hopkins University School of Medicine
Brian D. Craig: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Beth A. Marosy: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
David W. Mohr: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Kurt N. Hetrick: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Jane M. Romm: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Alan F. Scott: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
David Valle: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Jürgen K. Naggert: The Jackson Laboratory
Chulan Kwon: Johns Hopkins University School of Medicine
Kimberly F. Doheny: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Daniel P. Judge: Johns Hopkins University School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4416

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