@article{cd340b5b4ad14d0890544fc6568c14b1,
title = "Mutations in Alstr{\"o}m protein impair terminal differentiation of cardiomyocytes",
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 Alstr{\"o}m protein impairs postnatal cardiomyocyte cell cycle arrest.",
author = "Shenje, {Lincoln T.} and Peter Andersen and Halushka, {Marc K.} and Cecillia Lui and Laviel Fernandez and Collin, {Gayle B.} and Nuria Amat-Alarcon and Wendy Meschino and Ernest Cutz and Kenneth Chang and Raluca Yonescu and Batista, {Denise A.S.} and Yan Chen and Stephen Chelko and Crosson, {Jane E.} and Janet Scheel and Luca Vricella and Craig, {Brian D.} and Marosy, {Beth A.} and Mohr, {David W.} and Hetrick, {Kurt N.} and Romm, {Jane M.} and Scott, {Alan F.} and David Valle and Naggert, {J{\"u}rgen K.} and Chulan Kwon and Doheny, {Kimberly F.} and Judge, {Daniel P.}",
note = "Funding Information: We thank the families presented in this report for their participation. We thank Dr Peter Rainer for assistance with analysis of myocyte sizes, Dr Kenneth Boheler for providing mouse embryonic stem cells with the Ncx-puromycin transgene, and Dr Deepak Srivastava for providing aMHC-GFP transgenic mice. We also thank Drs Loren Field, Charles Steenbergen, and E. Rene Rodriguez for their helpful advice and guidance. Supported by funding from the JHU Friends in Red, the Zegar Family Foundation, The Michel Mirowski, MD Discovery Fund (to D.P.J.), Mrs Seena Lubcher (to D.P.J.), R01HL111198 and 4R00HL09223 (NIH/National Heart Lung & Blood Institute) (to C.K.), Maryland Stem Cell Research Fund (to C.K.), Magic That Matters Fund (to C.K.), the Lundbeck Foundation (to P.A.) and HD036878 (NIH) (to J.K.N. and G.B.C.). The JHU Center for Inherited Disease Research is supported by funding from NIH contract HHSN268200782096C. The authors acknowledge contributions by the Baylor-Hopkins Center for Mendelian Genomics, supported by a grant from the NIH/National Human Genome Research Institute (5U54HG006542).",
year = "2014",
month = mar,
day = "4",
doi = "10.1038/ncomms4416",
language = "English (US)",
volume = "5",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}