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: Seema R Lalani, Stephanie M Ware, Xueqing Wang, Gladys Zapata, Qi Tian, Luis M Franco, Zhengxin Jiang, Kristine Bucasas, Daryl A Scott, Philippe M Campeau, Neil Hanchard, Luis Umaña, Ashley Cast, Ankita Patel, Sau W Cheung, Kim L McBride, Molly Bray, A Craig Chinault, Barbara A Boggs, Miao Huang, Mariah R Baker, Susan Hamilton, Jeff Towbin, John L Jefferies, Susan D Fernbach, Lorraine Potocki, John W Belmont
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 22 Issue 21 Pg. 4339-48 (Nov 01 2013) ISSN: 1460-2083 [Electronic] England
• PMID: 23773997 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• MCTP2 protein, human
• Membrane Proteins

Topics

• Animals
• Aortic Coarctation (genetics)
• Comparative Genomic Hybridization
• Female
• Gene Dosage
• Gene Knockdown Techniques
• Genetic Predisposition to Disease
• Genetic Variation
• Heart Ventricles (growth & development)
• Humans
• Hypoplastic Left Heart Syndrome (ethnology, genetics)
• Male
• Membrane Proteins (genetics)
• Models, Animal
• Sequence Analysis, DNA
• Sequence Deletion
• Xenopus laevis (embryology, genetics, growth & development)