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

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

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

Stephen R F Twigg et al. Am J Hum Genet..

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.

Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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Figures

Figure 1
Figure 1
Clinical Features of Individuals withMEGF8 Mutations (A–G) Subject 1 showing facial features at the age of 4.5 years (A), chest and side view at the age of 9 years (B), a chest radiograph at the age of 9 years (C), clinical appearance of hands at the age of 4.5 years (D) and feet at the age of 9 years (E), and radiographs of hands and feet at the age of 10 years (F and G). Note the tongue-like projections at the base of the proximal phalanges (F and G, arrowheads); these are frequently noted in Carpenter syndrome. (H and I) Facial features of subject 2 at the age of 6.4 years.
Figure 2
Figure 2
Structure ofMEGF8, Domain Organization of the Encoded Protein, and Position of Mutations Identified in Carpenter Syndrome (A) Cartoon shows organization of the 41 exonMEGF8. The reference sequence omits the alternatively spliced exon 12A (red box). (B) Domain organization of encoded protein shows motifs identified by SMART analysis.
Figure 3
Figure 3
Functional Analysis of MEGF8 Missense Substitutions in Zebrafish Embryos (A) In situ hybridization ofntl at 10 hpf for labeling the notochord and blastoderm margin, shown in dorsal view. Embryos injected with 6 ng ofmegf8 moE2 exhibited severe epiboly defects (right), characterized by the shortening and widening of the notochord, discontinuous staining (indicated by the arrow), and an open blastopore (asterisk). Embryos injected with control morpholino (MO) are shown on the left. (B) Quantification of epiboly defects and genetic rescue. Shown are the proportions of embryos injected with the indicated dose ofmegf8 morpholino and different versions ofMEGF8 RNA (wild-type [WT] or missense mutant forms [c.595G>C (p.Gly199Arg), c.4496G>A (p.Arg1499His), or c.7099A>G (p.Ser2367Gly)]) either in combination or alone. p values correspond to statistical differences compared to uninjected embryos according to a Fisher’s exact test (two-tailed).megf8 MOs and standard control MOs were purchased from Gene Tools. A full-length (41 exon)MEGF8 cDNA clone was obtained from Origene, and mutant versions encoding each missense mutation were generated with the QuikChange Site-Directed Mutagenesis Kit (Stratagene) (see Table S2 for oligonucleotides). All clones were sequence verified and subcloned into pcDNA3-DEST53 with Gateway cloning (Invitrogen). Capped RNA was synthesized with the mMESSAGE mMACHINE kit (Ambion). Wild-type zebrafish (Danio rerio) embryos were raised at 28.5°C, and microinjections (∼1 nl) were performed at the 1-cell stage. In situ hybridization was performed with RNA probes labeled with digoxigenin (Roche) and detected with BCIP/NBT (5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium) (Sigma).
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References

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