Candidate Gene Analysis of Tooth Agenesis Identifies Novel Mutations in Six Genes and Suggests Significant Role for WNT and EDA Signaling and Allele Combinations

Peer reviewe

Panoramic radiographs of dentitions with tooth agenesis.

<p>Congenitally missing teeth are denoted with asterisks (*), and peg-shaped maxillary lateral incisors with arrows. All radiographs show many retained deciduous teeth. A. Dentition of a 15-year-old girl (family 219) with a heterozygous frameshift mutation K237SfsX2 in <i>MSX1</i>. All second premolars and third molars, maxillary first premolars and mandibular central incisors are missing. Maxillary lateral incisors are peg-shaped. <b>B</b>. 11-year-old girl (family 283) with a heterozygous missense mutation p. R47P in <i>PAX9</i> lacks all third molars, two maxillary second molars, three second premolars and mandibular central incisors. Left maxillary lateral incisor is peg-shaped. <b>C</b>. Severe tooth agenesis in a 13-year old boy (family 46) with a p.R357W mutation affecting the TNF domain of EDA. 10 permanent and 8 deciduous teeth, mostly in the anterior region, are missing. Maxillary left central incisor is conical. <b>D</b>. 19-year-old woman (family 266) lacks all third molars and lateral incisors, both maxillary canines, three second premolars and two deciduous lateral maxillary incisors. She was heterozygous for p.R325W in <i>EDAR</i>, p. S103F in <i>EDARADD</i> and p.G165R in <i>WNT10A</i>. <b>E</b>. Only 12 permanent teeth have developed in 27-year old woman (family 208) with a compound heterozygote mutations p.R113C and p.E194AfsX28 in <i>WNT10A</i>. Maxillary deciduous lateral incisors were also missing. <b>F</b>. 16-year old boy (family 261) with a heterozygous p.F228I variant in <i>WNT10A</i> lacks 13 permanent teeth including all third molars, mandibular second premolars, maxillary canines and five incisors.</p

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

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