Inactivation of IL11 Signaling Causes Craniosynostosis, Delayed Tooth Eruption, and Supernumerary Teeth

Autor: Steven A. Wall, Irene M.J. Mathijssen, Irma Thesleff, Eamonn R. Maher, Satu Parmanen, Neil V. Morgan, Aimee L. Fenwick, Louise Brueton, Lotta Veistinen, Marja L. Mikkola, Sirpa Arte, Andrew O.M. Wilkie, Peter J. van der Spek, Louise M. Judd, Sven Kreiborg, Pekka Nieminen, Andrew S. Giraud
Přispěvatelé: Pathology, Plastic and Reconstructive Surgery and Hand Surgery
Rok vydání: 2011
Předmět:
Zdroj: American Journal of Human Genetics, 89(1), 67-81. Cell Press
ISSN: 0002-9297
Popis: Craniosynostosis and supernumerary teeth most often occur as isolated developmental anomalies, but they are also separately manifested in several malformation syndromes. Here, we describe a human syndrome featuring craniosynostosis, maxillary hypoplasia, delayed tooth eruption, and supernumerary teeth.We performed homozygosity mapping in three unrelated consanguineous Pakistani families and localized the syndrome to a region in chromosome 9. Mutational analysis of candidate genes in the region revealed that all affected children harbored homozygous missense mutations (c.662C>G [p.Pro221Arg], c.734C>G [p.Ser245Cys], or c.886C>T [p.Arg296Trp]) in IL11RA (encoding interleukin 11 receptor, alpha) on chromosome 9p13.3. In addition, a homozygous nonsense mutation, c.475C>T (p.Gln159X), and a homozygous duplication, c.916-924dup (p.Thr306-Ser308dup), were observed in two north European families. In cell-transfection experiments, the p.Arg296Trp mutation rendered the receptor unable to mediate the IL11 signal, indicating that the mutation causes loss of IL11RA function. We also observed disturbed cranial growth and suture activity in the Il11ra null mutant mice, in which reduced size and remodeling of limb bones has been previously described. We conclude that IL11 signaling is essential for the normal development of craniofacial bones and teeth and that its function is to restrict suture fusion and tooth number. The results open up the possibility of modulation of IL11 signaling for the treatment of craniosynostosis. © 2011 by The American Society of Human Genetics. All rights reserved.
Databáze: OpenAIRE