Mutations in Alström protein impair terminal differentiation of cardiomyocytes.
Document Type
Article
Publication Date
3-4-2014
JAX Source
Nat Commun 2014 Mar 4; 5:3416.
Volume
5
First Page
3416
Last Page
3416
ISSN
2041-1723
PMID
24595103
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. Nat Commun 2014 Mar 4; 5:3416.
Recommended Citation
Shenje L,
Andersen P,
Halushka M,
Lui C,
Fernandez L,
Collin GB,
Amat-Alarcon N,
Meschino W,
Cutz E,
Chang K,
Yonescu R,
Batista D,
Chen Y,
Chelko S,
Crosson J,
Scheel J,
Vricella L,
Craig B,
Marosy B,
Mohr D,
Hetrick K,
Romm J,
Scott A,
Valle D,
Naggert JK,
Kwon C,
Doheny K,
Judge D.
Mutations in Alström protein impair terminal differentiation of cardiomyocytes. Nat Commun 2014 Mar 4; 5:3416.