Novel PAX9 and COL1A2 Missense Mutations Causing Tooth Agenesis and OI/DGI without Skeletal Abnormalities

Abstract

Inherited dentin defects are classified into three types of dentinogenesis imperfecta (DGI) and two types of dentin dysplasia (DD). The genetic etiology of DD-I is unknown. Defects in dentin sialophosphoprotein (DSPP) cause DD type II and DGI types II and III. DGI type I is the oral manifestation of osteogenesis imperfecta (OI), a systemic disease typically caused by defects in COL1A1 or COL1A2. Mutations in MSX1, PAX9, AXIN2, EDA and WNT10A can cause non-syndromic familial tooth agenesis. In this study a simplex pattern of clinical dentinogenesis imperfecta juxtaposed with a dominant pattern of hypodontia (mild tooth agenesis) was evaluated, and available family members were recruited. Mutational analyses of the candidate genes for DGI and hypodontia were performed and the results validated. A spontaneous novel mutation in COL1A2 (c.1171G>A; p.Gly391Ser) causing only dentin defects and a novel mutation in PAX9 (c.43T>A; p.Phe15Ile) causing hypodontia were identified and correlated with the phenotypic presentations in the family. Bone radiographs of the proband’s dominant leg and foot were within normal limits. We conclude that when no DSPP mutation is identified in clinically determined isolated DGI cases, COL1A1 and COL1A2 should be considered as candidate genes. PAX9 mutation p.Phe15Ile within the N-terminal β-hairpin structure of the PAX9 paired domain causes tooth agenesis.

Phenotype and genotype analyses in seven families with dentinogenesis imperfecta or dentin dysplasia

“…Song et al () reported eight families with exclusion mutations in the DSP region; they found mutations in the DPP region in five families, while the remaining three families showed no pathogenic mutations. Wang et al () found a mutation in COL1A2 in a DGI family without bone defects, and they suggested that COL1A1 and COL1A2 should be considered candidate genes in isolated DGI cases without a DSPP mutation. However, we found several polymorphisms, but no pathogenic mutations, in these two genes in Family E. Plausible explanations include other genes responsible for these dentin defects (whole‐exon sequencing could be used to investigate new underlying genes); polymorphisms may mitigate a defect when they appear together (this possibility could be investigated using in vitro assays and/or animal experiments); and copy number variation may lead to the occurrence and development of disease to some degree (Almal and Padh, ).…”

Tooth agenesis in osteogenesis imperfecta related to mutations in the collagen type I genes

“…A female patient with OI type IV in our cohort had DGI, no missing teeth, and a COL1A2 missense mutation, c.1171G>A, p.(Gly391Ser), reported previously in a male patient of European origin (Wang et al , ) with both DGI and tooth agenesis. He had agenesis of ten teeth while his mother had agenesis of four teeth and no DGI.…”

Novel PAX9 mutation associated with syndromic tooth agenesis

“…It is noteworthy that, in a recent paper, Wang et al . described a family with tooth agenesis in whom isolated dentin defects occurred only in the proband. Mutational analysis of candidate genes revealed a novel PAX9 mutation causing hypodontia and a novel COL1A2 mutation causing only dentin defects .…”