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.
Highlights
Osteogenesis imperfecta (OI) is a hereditary, bone fragility disease that varies in severity from mild bone defects to neonatal lethality
Non-syndromic dentin defects categorized as dentin dysplasia type II (DD-II), dentinogenesis imperfecta type II (DGI-II) and type III (DGI-III) are generally caused by dominant mutations in dentin sialophosphoprotein (DSPP), which encodes the most abundant non-collagenous matrix component of dentin [3]
In this study we identified a Caucasian family with familial tooth agenesis going back at least three generations, but isolated dentin defects occurred only in the proband
Summary
Osteogenesis imperfecta (OI) is a hereditary, bone fragility disease that varies in severity from mild bone defects to neonatal lethality. Non-syndromic dentin defects categorized as dentin dysplasia type II (DD-II), dentinogenesis imperfecta type II (DGI-II) and type III (DGI-III) are generally caused by dominant mutations in dentin sialophosphoprotein (DSPP), which encodes the most abundant non-collagenous matrix component of dentin [3]. Familial tooth agenesis is distinguished from conditions with multiple missing teeth occurring in syndromes, such as ectodermal dysplasia. In this study we identified a Caucasian family with familial tooth agenesis going back at least three generations, but isolated dentin defects occurred only in the proband. Using a target gene approach, we identified a novel missense mutation in PAX9 (p.Phe15Ile) that is responsible for the tooth agenesis. Despite the absence of skeletal abnormalities, mutational analyses of the COL1A1 and COL1A2 genes identified a novel COL1A2 mutation (p.Gly391Ser) only in the proband that explains his dentin phenotype
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