A nonsense mutation in MSX1 causes Witkop syndrome

Witkop syndrome, also known as tooth and nail syndrome (TNS), is a rare aut osomal dominant disorder. Affected individuals have nail dysplasia and seve ral congenitally missing teeth. To identify the gene responsible for TNS, w e used candidate-gene linkage analysis in a three-generation family affecte d by the disorder. We found linkage between TNS and polymorphic markers sur rounding the MSX1 locus. Direct sequencing and restriction-enzyme analysis revealed that a heterozygous stop mutation in the homeodomain of MSX1 coseg regated with the phenotype. In addition, histological analysis of Msx1-knoc kout mice, combined with a finding of Msx1 expression in mesenchyme of deve loping nail beds, revealed that not only was tooth development disrupted in these mice, but nail development was affected as well. Nail plates in Msx1 -null mice were defective and were thinner than those of their wild-type li ttermates. The resemblance between the tooth and nail phenotype in the huma n family and that of Msx1-knockout mice strongly supports the conclusions t hat a nonsense mutation in MSX1 causes TNS and that Msx1 is critical for bo th tooth and nail development.