title: Mutations in Alström 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 Alström protein impairs postnatal cardiomyocyte cell cycle arrest.
authors.affiliation: 1] Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA [2].
authors.forename: Lincoln T
authors.initials: LT
authors.lastname: Shenje
authors.affiliation: 1] Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA [2].
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Marc K
authors.initials: MK
authors.lastname: Halushka
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Cecillia
authors.initials: C
authors.lastname: Lui
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Laviel
authors.initials: L
authors.lastname: Fernandez
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors.forename: Gayle B
authors.initials: GB
authors.lastname: Collin
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Nuria
authors.initials: N
authors.lastname: Amat-Alarcon
authors.affiliation: North York General Hospital, Toronto, Ontario, Canada M2K 1E1.
authors.forename: Wendy
authors.initials: W
authors.lastname: Meschino
authors.affiliation: Division of Pathology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Ernest
authors.initials: E
authors.lastname: Cutz
authors.affiliation: 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.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Raluca
authors.initials: R
authors.lastname: Yonescu
authors.affiliation: 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.
authors.forename: Denise A S
authors.initials: DA
authors.lastname: Batista
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chelko
authors.affiliation: Division of Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Crosson
authors.affiliation: Division of Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Scheel
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Vricella
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Craig
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Marosy
authors.affiliation: 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.
authors.forename: David W
authors.initials: DW
authors.lastname: Mohr
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Kurt N
authors.initials: KN
authors.lastname: Hetrick
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Romm
authors.affiliation: 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.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Scott
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: David
authors.initials: D
authors.lastname: Valle
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors.forename: Jürgen K
authors.initials: JK
authors.lastname: Naggert
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Chulan
authors.initials: C
authors.lastname: Kwon
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Doheny
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Judge
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C490729:ALMS1 protein, human; C510001:Alms1 protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011506:Proteins