title: 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.
authors: Department of Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Japan.
authors: Munefumi
authors: M
authors: Kamamoto
authors: Junichiro
authors: J
authors: Machida
authors: Seishi
authors: S
authors: Yamaguchi
authors: Masashi
authors: M
authors: Kimura
authors: Takao
authors: T
authors: Ono
authors: Peter A
authors: PA
authors: Jezewski
authors: Yujiro
authors: Y
authors: Higashi
authors: Atsuo
authors: A
authors: Nakayama
authors: Kazuo
authors: K
authors: Shimozato
authors: Yoshihito
authors: Y
authors: Tokita
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000848:Anodontia / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D002467:Cell Nucleus / Q000737:chemistry; D018900:Dinucleotide Repeats; D005260:Female; D006801:Humans; D007564:Japan; D051957:MSX1 Transcription Factor / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D017570:MyoD Protein / Q000235:genetics; D010375:Pedigree; D019683:Penetrance; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D016415:Sequence Alignment; D012907:Smoking
chemical_list: D051957:MSX1 Transcription Factor; C484083:MSX1 protein, human; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein