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 Batista, Yan Chen, Stephen Chelko, Jane Crosson, Janet Scheel, Luca Vricella, Brian D. Craig, Beth A. Marosy, David W. MohrKurt N. Hetrick, Jane M. Romm, Alan F Scott, David Valle, Jürgen K. Naggert, Chulan Kwon, Kimberly Doheny, Daniel P. Judge

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number3416
JournalNature Communications
Volume5
DOIs
StatePublished - Mar 4 2014

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mutations
Cardiac Myocytes
Cells
proteins
cell division
Mutation
mammals
cycles
sequencing
cultured cells
markers
mice
Proteins
Mammals
Cell Cycle Checkpoints
Cell Division
Messenger RNA
Exome
Protein Deficiency
G2 Phase

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Mutations in Alström protein impair terminal differentiation of cardiomyocytes. / Shenje, Lincoln T.; Andersen, Peter; Halushka, Marc K; Lui, Cecillia; Fernandez, Laviel; Collin, Gayle B.; Amat-Alarcon, Nuria; Meschino, Wendy; Cutz, Ernest; Chang, Kenneth; Yonescu, Raluca; Batista, Denise; Chen, Yan; Chelko, Stephen; Crosson, Jane; Scheel, Janet; Vricella, Luca; Craig, Brian D.; Marosy, Beth A.; Mohr, David W.; Hetrick, Kurt N.; Romm, Jane M.; Scott, Alan F; Valle, David; Naggert, Jürgen K.; Kwon, Chulan; Doheny, Kimberly; Judge, Daniel P.

In: Nature Communications, Vol. 5, 3416, 04.03.2014.

Research output: Contribution to journalArticle

Shenje, LT, Andersen, P, Halushka, MK, 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, BD, Marosy, BA, Mohr, DW, Hetrick, KN, Romm, JM, Scott, AF, Valle, D, Naggert, JK, Kwon, C, Doheny, K & Judge, DP 2014, 'Mutations in Alström protein impair terminal differentiation of cardiomyocytes', Nature Communications, vol. 5, 3416. https://doi.org/10.1038/ncomms4416
Shenje, Lincoln T. ; Andersen, Peter ; Halushka, Marc K ; Lui, Cecillia ; Fernandez, Laviel ; Collin, Gayle B. ; Amat-Alarcon, Nuria ; Meschino, Wendy ; Cutz, Ernest ; Chang, Kenneth ; Yonescu, Raluca ; Batista, Denise ; Chen, Yan ; Chelko, Stephen ; Crosson, Jane ; Scheel, Janet ; Vricella, Luca ; Craig, Brian D. ; Marosy, Beth A. ; Mohr, David W. ; Hetrick, Kurt N. ; Romm, Jane M. ; Scott, Alan F ; Valle, David ; Naggert, Jürgen K. ; Kwon, Chulan ; Doheny, Kimberly ; Judge, Daniel P. / Mutations in Alström protein impair terminal differentiation of cardiomyocytes. In: Nature Communications. 2014 ; Vol. 5.
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AU - Valle, David

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