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

Am J Hum Genet. 2012 Nov 2;91(5):897-905. doi: 10.1016/j.ajhg.2012.08.027. Epub 2012 Oct 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • MEGF8 protein, human
  • Membrane Proteins

Supplementary concepts

  • Acrocephalopolysyndactyly Type II