Mutations in Multidomain Protein MEGF8 Identify a Carpenter Syndrome Subtype Associated with Defective Lateralization

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

Research output: Contribution to journalArticle

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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.

LanguageEnglish
Pages897-905
Number of pages9
JournalAmerican Journal of Human Genetics
Volume91
Issue number5
Early online date11 Oct 2012
DOIs
Publication statusPublished - 2 Nov 2012
Externally publishedYes

Fingerprint

Mutation
Epidermal Growth Factor
Dextrocardia
Situs Inversus
Syndactyly
Phenotype
Umbilical Hernia
Craniosynostoses
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Gastrulation
Transposition of Great Vessels
Cryptorchidism
Monomeric GTP-Binding Proteins
Hedgehogs
Zebrafish
Foot
Heart Diseases
Proteins
Hand
Obesity

Cite this

Twigg, Stephen R F ; Lloyd, Deborah ; Jenkins, Dagan ; Elçioglu, Nursel E. ; Cooper, Christopher D O ; Al-Sannaa, Nouriya ; Annagür, Ali ; Gillessen-Kaesbach, Gabriele ; Hüning, Irina ; Knight, Samantha J L ; Goodship, Judith A. ; Keavney, Bernard D. ; Beales, Philip L. ; Gileadi, Opher ; McGowan, Simon J. ; Wilkie, Andrew O M. / Mutations in Multidomain Protein MEGF8 Identify a Carpenter Syndrome Subtype Associated with Defective Lateralization. In: American Journal of Human Genetics. 2012 ; Vol. 91, No. 5. pp. 897-905.
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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.",
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Twigg, SRF, Lloyd, D, Jenkins, D, Elçioglu, NE, Cooper, CDO, Al-Sannaa, N, Annagür, A, Gillessen-Kaesbach, G, Hüning, I, Knight, SJL, Goodship, JA, Keavney, BD, Beales, PL, Gileadi, O, McGowan, SJ & Wilkie, AOM 2012, 'Mutations in Multidomain Protein MEGF8 Identify a Carpenter Syndrome Subtype Associated with Defective Lateralization', American Journal of Human Genetics, vol. 91, no. 5, pp. 897-905. https://doi.org/10.1016/j.ajhg.2012.08.027

Mutations in Multidomain Protein MEGF8 Identify a Carpenter Syndrome Subtype Associated with Defective Lateralization. / Twigg, Stephen R F; Lloyd, Deborah; Jenkins, Dagan; Elçioglu, Nursel E.; Cooper, Christopher D O; Al-Sannaa, Nouriya; Annagür, Ali; Gillessen-Kaesbach, Gabriele; Hüning, Irina; Knight, Samantha J L; Goodship, Judith A.; Keavney, Bernard D.; Beales, Philip L.; Gileadi, Opher; McGowan, Simon J.; Wilkie, Andrew O M.

In: American Journal of Human Genetics, Vol. 91, No. 5, 02.11.2012, p. 897-905.

Research output: Contribution to journalArticle

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T1 - Mutations in Multidomain Protein MEGF8 Identify a Carpenter Syndrome Subtype Associated with Defective Lateralization

AU - Twigg, Stephen R F

AU - Lloyd, Deborah

AU - Jenkins, Dagan

AU - Elçioglu, Nursel E.

AU - Cooper, Christopher D O

AU - Al-Sannaa, Nouriya

AU - Annagür, Ali

AU - Gillessen-Kaesbach, Gabriele

AU - Hüning, Irina

AU - Knight, Samantha J L

AU - Goodship, Judith A.

AU - Keavney, Bernard D.

AU - Beales, Philip L.

AU - Gileadi, Opher

AU - McGowan, Simon J.

AU - Wilkie, Andrew O M

PY - 2012/11/2

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N2 - 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.

AB - 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.

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