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.

Transcriptome analysis of IL-10-stimulated (M2c) macrophages by next-generation sequencing

“…Genes otherwise associated with wound healing and inflammatory resolution include MMP8 , CD163 , and FPR1 (Philippidis et al, 2004; Gutiérrez-Fernández et al, 2007; Liu et al, 2014). The other identified M2c markers include MCTP2 , which is involved in intracellular trafficking (Lalani et al, 2013); GXYLT2 , which is a xylotransferase (Sethi et al, 2010); LIN7A , which is involved in epithelial and neuronal junction organization (Perego et al, 1999); and SH3PXD2B , which is involved in podosome formation (Lányi et al, 2011). Gene expression trends were further confirmed using qRTPCR for MMP8, MARCO, CD163 , and VCAN (Supplementary Fig.…”

Sorting nexin 27 (SNX27) variants associated with seizures, developmental delay, behavioral disturbance, and subcortical brain abnormalities

“…Relevant known interaction partners, and their known (solid lines) or proposed (dashed lines) downstream interaction partners, physiologic consequences or phenotypic outcomes are shown. Interaction partners include several neuroreceptors (5‐HT 4, AMPA, NMDA and mGluR5), ATP7a, GLUT1, ADAM22, NLGN2, MCTP2, and CFTR . Possible downstream mediators include MAM domain‐containing glycosylphosphatidylinositol anchor protein 1 (MDGA1) or Notch .…”

“…If cardiac septal defects appear in further case reports, further experiments should determine whether these effects could be mediated by multiple C2 and transmembrane domain‐containing protein 2 ( MCTP2 ). MCTP2 is enriched in the interactome with SNX27 and has been previously implicated, in a dose‐sensitive manner, in cardiogenesis in humans . One patient with a maternally mosaic 2.2 Mb deletion encompassing MCTP2 demonstrated coarctition of the aorta (CoA), developmental delay and facial dysmorphology.…”

Cytogenomic Aberrations in Congenital Cardiovascular Malformations

“…NR2F2 plays an important role in angiogenesis, atrial malformations, and lymphatic development in animal models [Aranguren et al, 2011;Pereira et al, 1999]. While NR2F2 has been implicated in AVSD in some families [Al Turki et al, 2014], MCTP2 has been shown to be important for left-sided outflow tract development [Lalani et al, 2013b]. It is plausible that there are other dosage-sensitive genes important for human cardiac morphogenesis within this 15q26 interval.…”