Mutations in Multidomain Protein MEGF8 Identify a Carpenter Syndrome Subtype Associated with Defective Lateralization
- Authors
- Twigg, S.R., Lloyd, D., Jenkins, D., Elcioglu, N.E., Cooper, C.D., Al-Sannaa, N., Annagur, A., Gillessen-Kaesbach, G., Huning, I., Knight, S.J., Goodship, J.A., Keavney, B.D., Beales, P.L., Gileadi, O., McGowan, S.J., and Wilkie, A.O.
- ID
- ZDB-PUB-121019-24
- Date
- 2012
- Source
- American journal of human genetics 91(5): 897-905 (Journal)
- Registered Authors
- Keywords
- none
- 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
- PubMed
- 23063620 Full text @ Am. J. Hum. Genet.
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.