Orodental malformations associated with human MSX1 sequence variants.

BACKGROUND: MSX1 sequence variants have been known to cause human tooth agenesis (TA) with or without orofacial clefts. However, their roles during the whole processes of tooth development are not fully understood. This study aimed to characterize a 4-membered family with TA carrying a novel MSX1 pathogenic variant and investigate the disease mechanism. METHODS: The authors conducted whole exome analysis to define the disease-causing sequence variant. They performed microcomputed tomography, morphometric analyses, transcriptome profiling, and molecular characterization to study the affected teeth and the gene variant. RESULTS: The authors identified an MSX1 pathogenic variant, p.Glu232∗, in affected family members with TA and concomitant orodental anomalies, namely, prominent maxillary labial frenum, central incisor diastema, median maxillary anterior alveolar cleft, tooth fusion, mandibular molar dysmorphology, thin dentin layer, and slender dental roots. MSX1-defective teeth were not apparently microdontic but had thin dentin layers. The mandibular molars showed a homeotic transformation to maxillary counterparts. Genes involved in extracellular matrix organization and dentinogenesis, such as DMP1 and MMP20, were downregulated in dental pulp tissues of MSX1-defective teeth. The p.Glu232∗-truncated MSX1 properly localized to the nucleus but partially lost its transactivation ability. Analyzing reported cases indicated that truncation sequence variants within the homeobox domain of MSX1 caused a more severe TA phenotype than those outside of the homeobox domain, probably due to dominant negativity compared with haploinsufficiency. CONCLUSIONS: This study provides in vivo evidence that MSX1 contributes to developmental processes of various orodental tissues in humans. PRACTICAL IMPLICATIONS: Clinically, hypertrophic labial frenum, incisor diastema, and median maxillary anterior alveolar cleft might be considered diagnostic for MSX1-associated TA.

A novel ODAPH mutation causing amelogenesis imperfecta and its expression in human dental tissues.

Background/purpose: Amelogenesis imperfecta (AI), an assemblage of genetic diseases with dental enamel malformations, is generally grouped into hypoplastic, hypomaturation, and hypocalcified types. This study aimed to identify the genetic etiology for a consanguineous Iranian family with autosomal recessive hypocalcified AI. Materials and methods: Dental defects were characterized, and whole exome analysis conducted to search for disease-causing mutations. Minigene assay and RT-PCR were performed to evaluate molecular consequences of the identified mutation and expression of the causative gene in human dental tissues. Results: The defective enamel of erupted teeth showed extensive post-eruptive failure and discoloration. Partial enamel hypoplasia and indistinct dentino-enamel junction were evident on unerupted teeth, resembling hypocalcified AI. A novel homozygous ODAPH (previously designated C4orf26) mutation of single-nucleotide deletion (NG_032974.1:g.5103del, NM_178497.5:c.67+1del) was identified to be disease-causing. The mutation would cause a frameshift to different ODAPH transcript variant (TV) products: p.(Ala23Hisfs∗29) for TV1 and p.(Gly23Aspfs∗140) for TV2. Both dental pulps of developing and exfoliating primary teeth expressed ODAPH TV2. Conclusion: Loss-of-function ODAPH mutations can cause AI type IIIB (the hypocalcified, autosomal recessive type), rather than type IIA4 (the hypomaturation, pigmented autosomal recessive type). This study supports a hypothesis that the product of ODAPH TV2 is the single dominant ODAPH protein isoform critical for dental enamel formation and may also play an unappreciated role in development and homeostasis of dentin-pulp complex. Due to genetic heterogeneity and a nonideal genotype-phenotype correlation of AI, it is essential to perform genetic testing for patients with inherited enamel defects to make a definitive diagnosis.