Clinical and functional data implicate the Arg(151)Ser variant of MSX1 in familial hypodontia

Abstract

Multiple previous reports confirm that several missense alleles of MSX1 exhibit Mendelian inheritance of an oligodontia phenotype (agenesis of more than six secondary teeth besides third molars). However, the extent to which missense MSX1 alleles contribute to common, multifactorial disorders is less certain. It is still not yet clear whether multiple non-synonomous MSX1-coding variants identified among patients with oral clefting are merely neutral polymorphisms or whether any of these might represent real mutations with mild effects. The present work steps toward resolving these issues for at least one MSX1 allele: R151S, previously identified in a single Japanese proband with unilateral cleft lip and palate. Candidate gene sequencing within a patient cohort demonstrating mild tooth agenesis (loss of six or less secondary teeth besides third molars, hypodontia), secondarily identified this same MSX1 variant, functioning as a mildly deleterious, moderately penetrant allele. Four of five heterozygous R151S individuals from one Japanese family exhibited the hypodontia phenotype. The in vitro functional assays of the variant protein display partial repression activity with normal nuclear localization. These data establish that the MSX1-R151S allele is a low-frequency, mildly deleterious allele for familial hypodontia that alone is insufficient to cause oral facial clefting. Yet, as this work also establishes its hypomorphic nature, it suggests that it may in fact contribute to the likelihood of common birth disorder phenotypes, such as partial tooth agenesis and oral facial clefting. Nevertheless, the exact mechanism in which differential pleiotropy is manifested will need further and deeper clinical and functional analyses.

Contribution of MSX1 variants to the risk of non-syndromic cleft lip and palate in a Malay population

“…17,22,26,29 Oral clefts are more severe than tooth agenesis, and recent data suggest that MSX1 causative mutations for tooth agenesis may not be sufficient to cause oral clefts. 29 In addition, the change in amino acid itself may not be a sufficient criterion to predict disease in complex traits such as oral clefts. 24 Therefore, these rare variants could, at best, contribute to clefting as part of a complex inheritance pattern, with both additional genes and environmental factors having a role.…”

Novel nonsense mutation in MSX1 in familial nonsyndromic oligodontia: subcellular localization and role of homeodomain/MH4

“…Genomic DNA was extracted using a DNeasy Blood and Tissue Kit (Qiagen, Valencia, CA, USA). The entire coding regions of MSX1 , PAX9 , and AXIN2 , including splice sites, were amplified using specific primers for MSX1 and PAX9 described in previous reports or specific primers for AXIN2 that were synthesized on the basis of intronic sequences obtained from GenBank (Table S1). PCR products were resolved by electrophoresis through a 1.2% agarose gel and then purified using a Fast Gene Gel/PCR Extraction Kit (Nippon Genetics, Tokyo, Japan).…”

Novel nonsense mutation in MSX1 causes tooth agenesis with cleft lip in a Chinese family

“…Recently, Kamamoto et al. reported a p.R151S mutation with moderately penetrant non‐syndromic tooth agenesis . This mutation was also associated with unilateral cleft lip and palate in another single Japanese proband .…”

“…On the other hand, MSX1 p.S104X (4) and p.S202X (16) mutations, and the deletion of the short arm of chromosome 4 (17), produce tooth agenesis associated with other symptoms. Recently, Kamamoto et al reported a p.R151S mutation with moderately penetrant non-syndromic tooth agenesis (18). This mutation was also associated with unilateral cleft lip and palate in another single Japanese proband (19).…”