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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.

Original publication

DOI

10.1016/j.ajhg.2011.05.024

Type

Journal article

Journal

Am J Hum Genet

Publication Date

15/07/2011

Volume

89

Pages

67 - 81

Keywords

Animals, Cell Line, Child, Child, Preschool, Chromosome Mapping, Codon, Nonsense, Computational Biology, Craniosynostoses, DNA Mutational Analysis, Down-Regulation, Female, Gene Expression Regulation, Developmental, Humans, Interleukin-11, Male, Mice, Mice, Inbred C57BL, Pedigree, Signal Transduction, Tooth Eruption, Tooth, Supernumerary, Transcription Factors