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 |
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Přispěvatelé: | Pathology, Plastic and Reconstructive Surgery and Hand Surgery |
Rok vydání: | 2011 |
Předmět: |
Male
Pathology medicine.medical_specialty Maxillary hypoplasia DNA Mutational Analysis Tooth eruption Nonsense mutation Down-Regulation Chromosome 9 Biology Article Cell Line Tooth Eruption Craniosynostosis Craniosynostoses Mice 03 medical and health sciences 0302 clinical medicine Genetics medicine Animals Humans Missense mutation Genetics(clinical) Supernumerary Child Genetics (clinical) 030304 developmental biology 0303 health sciences Chromosome Mapping Computational Biology Gene Expression Regulation Developmental Interleukin-11 medicine.disease Disease gene identification Pedigree Mice Inbred C57BL Tooth Supernumerary Codon Nonsense Child Preschool Female 030217 neurology & neurosurgery Signal Transduction Transcription Factors |
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 |
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