Exome resequencing combined with linkage analysis identifies novel PTH1R variants in primary failure of tooth eruption in Japanese

Abstract

Massively parallel sequencing of target regions, exomes, and complete genomes has begun to increase the opportunities for identifying genetic variants underlying rare and common diseases dramatically. Here we applied exome resequencing to primary failure of tooth eruption (PFE) to identify the genetic causality of the disease. Two Japanese families having PFE were recruited and examined by genome-wide linkage study and subsequently exome analyses. Linkage analyses of these two families comprising eight affected individuals and two unaffected individuals revealed linkage signals at 10 loci with a maximum LOD score of 1.5. Four affected individuals in one family were pooled and further processed for exome analysis, followed by massive parallel sequencing. After three-step filtering including annotation and functional expectation, three variants were found to be candidates for PFE. Among the three variants, only a novel variant of parathyroid hormone 1 receptor gene (PTH1R), R383Q, was cosegregated in the first PFE family. Accordingly, we screened the gene for variants at all coding exons and the respective intron-exon boundaries in the second family and two sporadic individuals with PFE. We also identified a novel missense variant, P119L, cosegregating in the second family and missense variants P132L and R147C in the sporadic cases. These variants all were in the highly conserved region across zebrafish to chimpanzee and not observed in 192 unrelated controls, supporting the pathogenicity of the variants. The combination of linkage and exome analyses employed in this study provides a powerful strategy for identifying genes responsible for Mendelian disorders. ß

Disease gene identification strategies for exome sequencing

“…Yamaguchi et al 56 Glazov et al 57 Puente et al 58 Gunay-Aygun et al 59 Weedon et al 60 Homozygosity (Figure 3b Becker et al 31 Walsh et al 35 Wang et al 51a Bolze et al 61 Caliskan et al 62 Bilguvar et al 63 O'Sullivan et al 64 Barak et al 65 Hanson et al 66 Shaheen et al 67 Doi et el Only a single experiment is required.…”

International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors—Family B G Protein–Coupled Receptors

“…In the heterozygous state, the P132L mutation, as well as several other predicted loss-of-function mutations in the PTHR1 gene have been linked to familial cases of defective tooth eruption (Decker et al, 2008;Frazier-Bowers et al, 2010;Yamaguchi et al, 2011;Risom et al, 2013). Four other heterozygous PTHR1 point mutations: G121E, A122T, R150C, and R255H, the first three of which also map to the receptor's ECD region and impair receptor function, have been identified in Ollier disease, a development condition defined by the occurrence of multiple enchondromas (Hopyan et al, 2002;Couvineau et al, 2008).…”

Genetic Disorders Caused by Mutations in the PTH/PTHrP Receptor and Downstream Effector Molecules

“…Tooth buds were present, but developing teeth were severely impacted within the surrounding alveolar bone, leading to distortions in their architecture and orientation. 108 Interestingly, heterozygous loss-of-function mutations in the PTH1R have been associated with autosomal dominant, isolated primary failure of tooth eruption (PFE) 109,110 (see below). Radiological studies of patients with BLC reveal pronounced hyperdensity of the entire skeleton and markedly advanced ossification (Figure 40.4).…”