Mutations in multidomain protein MEGF8 identify a Carpenter syndrome subtype associated with defective lateralization.
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.
Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Stephen R F
SR
Twigg
Deborah
D
Lloyd
Dagan
D
Jenkins
Nursel E
NE
Elçioglu
Christopher D O
CD
Cooper
Nouriya
N
Al-Sannaa
Ali
A
Annagür
Gabriele
G
Gillessen-Kaesbach
Irina
I
Hüning
Samantha J L
SJ
Knight
Judith A
JA
Goodship
Bernard D
BD
Keavney
Philip L
PL
Beales
Opher
O
Gileadi
Simon J
SJ
McGowan
Andrew O M
AO
Wilkie
D000168:Acrocephalosyndactylia / Q000175:diagnosis / Q000235:genetics*; D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D002648:Child; D002675:Child, Preschool; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D015027:Zebrafish / Q000235:genetics
C577333:MEGF8 protein, human; D008565:Membrane Proteins