title: MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development.
abstract: Coarctation of the aorta (CoA) and hypoplastic left heart syndrome (HLHS) have been reported in rare individuals with large terminal deletions of chromosome 15q26. However, no single gene important for left ventricular outflow tract (LVOT) development has been identified in this region. Using array-comparative genomic hybridization, we identified two half-siblings with CoA with a 2.2 Mb deletion on 15q26.2, inherited from their mother, who was mosaic for this deletion. This interval contains an evolutionary conserved, protein-coding gene, MCTP2 (multiple C2-domains with two transmembrane regions 2). Using gene-specific array screening in 146 individuals with non-syndromic LVOT obstructive defects, another individual with HLHS and CoA was found to have a de novo 41 kb intragenic duplication within MCTP2, predicted to result in premature truncation, p.F697X. Alteration of Mctp2 gene expression in Xenopus laevis embryos by morpholino knockdown and mRNA overexpression resulted in the failure of proper OT development, confirming the functional importance of this dosage-sensitive gene for cardiogenesis. Our results identify MCTP2 as a novel genetic cause of CoA and related cardiac malformations.
authors.affiliation: Department of Molecular and Human Genetics.
authors.forename: Seema R
authors.initials: SR
authors.lastname: Lalani
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Ware
authors.forename: Xueqing
authors.initials: X
authors.lastname: Wang
authors.forename: Gladys
authors.initials: G
authors.lastname: Zapata
authors.forename: Qi
authors.initials: Q
authors.lastname: Tian
authors.forename: Luis M
authors.initials: LM
authors.lastname: Franco
authors.forename: Zhengxin
authors.initials: Z
authors.lastname: Jiang
authors.forename: Kristine
authors.initials: K
authors.lastname: Bucasas
authors.forename: Daryl A
authors.initials: DA
authors.lastname: Scott
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Campeau
authors.forename: Neil
authors.initials: N
authors.lastname: Hanchard
authors.forename: Luis
authors.initials: L
authors.lastname: Umaña
authors.forename: Ashley
authors.initials: A
authors.lastname: Cast
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.forename: Sau W
authors.initials: SW
authors.lastname: Cheung
authors.forename: Kim L
authors.initials: KL
authors.lastname: McBride
authors.forename: Molly
authors.initials: M
authors.lastname: Bray
authors.forename: A
authors.initials: A
authors.lastname: Craig Chinault
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Boggs
authors.forename: Miao
authors.initials: M
authors.lastname: Huang
authors.forename: Mariah R
authors.initials: MR
authors.lastname: Baker
authors.forename: Susan
authors.initials: S
authors.lastname: Hamilton
authors.forename: Jeff
authors.initials: J
authors.lastname: Towbin
authors.forename: John L
authors.initials: JL
authors.lastname: Jefferies
authors.forename: Susan D
authors.initials: SD
authors.lastname: Fernbach
authors.forename: Lorraine
authors.initials: L
authors.lastname: Potocki
authors.forename: John W
authors.initials: JW
authors.lastname: Belmont
mesh_terms: D000818:Animals; D001017:Aortic Coarctation / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D005260:Female; D018628:Gene Dosage; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006352:Heart Ventricles / Q000254:growth & development*; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D023421:Models, Animal; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000254:growth & development
chemical_list: C496711:MCTP2 protein, human; D008565:Membrane Proteins