Twigg, Stephen R.F., Lloyd, Deborah, Jenkins, Dagan, Elçioglu, Nursel E., Cooper, Christopher D.O., Al-Sannaa, Nouriya, Annagür, Ali, Gillessen-Kaesbach, Gabriele, Hüning, Irina, Knight, Samantha J.L., Goodship, Judith A., Keavney, Bernard D., Beales, Philip L., Gileadi, Opher, McGowan, Simon J. and Wilkie, Andrew O.M. (2012) Mutations in multidomain protein MEGF8 identify a Carpenter syndrome subtype associated with defective lateralization. American Journal of Human Genetics, 91 (5). pp. 897-905. ISSN 1537-6605

Carpenter syndrome is an autosomal-recessive multiple-congenital-malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet; many other clinical features occur, and the most frequent include obesity, umbilical hernia, cryptorchidism, and congenital heart disease. Mutations of RAB23, encoding a small GTPase that regulates vesicular transport, are present in the majority of cases. Here, we describe a disorder caused by mutations in multiple epidermal-growth-factor-like-domains 8 (MEGF8), which exhibits substantial clinical overlap with Carpenter syndrome but is frequently associated with abnormal left-right patterning. We describe five affected individuals with similar dysmorphic facies, and three of them had either complete situs inversus, dextrocardia, or transposition of the great arteries; similar cardiac abnormalities were previously identified in a mouse mutant for the orthologous Megf8. The mutant alleles comprise one nonsense, three missense, and two splice-site mutations; we demonstrate in zebrafish that, in contrast to the wild-type protein, the proteins containing all three missense alterations provide only weak rescue of an early gastrulation phenotype induced by Megf8 knockdown. We conclude that mutations in MEGF8 cause a Carpenter syndrome subtype frequently associated with defective left-right patterning, probably through perturbation of signaling by hedgehog and nodal family members. We did not observe any subject with biallelic loss-of function mutations, suggesting that some residual MEGF8 function might be necessary for survival and might influence the phenotypes observed.

Mutations in Multidomain Protein MEGF8 Identify a Carpenter Syndrome Subtype Associated with Defective Lateralization.pdf - Published Version
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