Mutations in Multidomain Protein MEGF8 Identify a Carpenter Syndrome Subtype Associated with Defective Lateralization
Yükleniyor...
Dosyalar
Tarih
2012
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Cell Press
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
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.
Açıklama
Anahtar Kelimeler
Kaynak
American Journal of Human Genetics
WoS Q Değeri
Q1
Scopus Q Değeri
Q1
Cilt
91
Sayı
5
Künye
Twigg, S. R. F., Lloyd, D., Jenkins, D., Elçioğlu, N. E., Cooper, C. D. O., Al-Sannaa, N., Annağur, A., Gillessen-Kaesbach, G., Hüning, I., J.L. Knight, S., Goodship, J. A., Keavney, B. D., Beales, P. L., Gileadi, O., McGowan, S. J., Wilkie, A. O.M., (2012). Mutations in Multidomain Protein MEGF8 Identify a Carpenter Syndrome Subtype Associated with Defective Lateralization. American Journal of Human Genetics, 91(5), 897-905.
http://dx.doi.org/10.1016/j.ajhg.2012.08.027
