Human molecular genetics · 2013
MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Lalani Seema R, Ware Stephanie M, Wang Xueqing, Zapata Gladys, Tian Qi, Franco Luis M, Jiang Zhengxin, Bucasas Kristine, Scott Daryl A, Campeau Philippe M, Hanchard Neil, Umaña Luis, Cast Ashley, Patel Ankita, Cheung Sau W, McBride Kim L, Bray Molly, Craig Chinault A, Boggs Barbara A, Huang Miao, Baker Mariah R, Hamilton Susan, Towbin Jeff, Jefferies John L, Fernbach Susan D, Potocki Lorraine, Belmont John W
Аннотация
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.