Mutations in multidomain protein MEGF8 identify a Carpenter syndrome subtype associated with defective lateralization.

Abstract

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.

• Authors: Stephen R F Twigg, Deborah Lloyd, Dagan Jenkins, Nursel E Elçioglu, Christopher D O Cooper, Nouriya Al-Sannaa, Ali Annagür, Gabriele Gillessen-Kaesbach, Irina Hüning, Samantha J L Knight, Judith A Goodship, Bernard D Keavney, Philip L Beales, Opher Gileadi, Simon J McGowan, Andrew O M Wilkie
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 91 Issue 5 Pg. 897-905 (Nov 02 2012) ISSN: 1537-6605 [Electronic] United States
• PMID: 23063620 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• MEGF8 protein, human
• Membrane Proteins

Topics

• Acrocephalosyndactylia (diagnosis, genetics)
• Alleles
• Animals
• Animals, Genetically Modified
• Child
• Child, Preschool
• Facies
• Female
• Genetic Association Studies
• Genotype
• Humans
• Male
• Membrane Proteins (chemistry, genetics)
• Mutation
• Zebrafish (genetics)