PUBLICATION
Exome resequencing combined with linkage analysis identifies novel PTH1R variants in primary failure of tooth eruption in Japanese
- Authors
- Yamaguchi, T., Hosomichi, K., Narita, A., Shirota, T., Tomoyasu, Y., Maki, K., and Inoue, I.
- ID
- ZDB-PUB-110328-9
- Date
- 2011
- Source
- Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 26(7): 1655-61 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Adolescent
- Amino Acid Sequence
- Animals
- Asian People/genetics
- Exons/genetics*
- Female
- Genes, Dominant/genetics
- Genetic Linkage*
- Genome-Wide Association Study
- Humans
- Japan
- Lod Score
- Male
- Molecular Sequence Data
- Pedigree
- Polymorphism, Single Nucleotide/genetics*
- Receptor, Parathyroid Hormone, Type 1/chemistry
- Receptor, Parathyroid Hormone, Type 1/genetics*
- Sequence Alignment
- Sequence Analysis, DNA*
- Tooth Diseases/genetics*
- Tooth Eruption/genetics*
- Young Adult
- PubMed
- 21404329 Full text @ J. Bone Miner. Res.
Citation
Yamaguchi, T., Hosomichi, K., Narita, A., Shirota, T., Tomoyasu, Y., Maki, K., and Inoue, I. (2011) Exome resequencing combined with linkage analysis identifies novel PTH1R variants in primary failure of tooth eruption in Japanese. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 26(7):1655-61.
Abstract
Massively parallel sequencing of target regions, exomes, and complete genomes has begun to dramatically increase the opportunities for identifying genetic variants underlying rare and common diseases. 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 ten 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 co-segregated 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, co-segregating in the second family, and missense variants, P132L and R147C, in the sporadic cases. These variants were all 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping