MSX1 – Tooth and Nail Syndrome

Tooth and nail syndrome (Witkop syndrome) is a rare autosomal dominant disorder characterized by nail dysplasia and congenitally missing teeth. Heterozygous loss‐of‐function variants in MSX1 underlie this condition through a haploinsufficiency mechanism. The critical role of MSX1 in both dental and nail development is supported by human genetic studies and animal models.

In a three‐generation family affected with Witkop syndrome, linkage analysis localized the disorder to the MSX1 locus. Direct sequencing identified a heterozygous nonsense variant, c.623C>A (p.Ser208Ter), which cosegregated with the phenotype in 6 affected individuals and was absent in unaffected relatives (PMID:11369996). This variant truncates the homeodomain of MSX1, consistent with a loss‐of‐function effect in an autosomal dominant inheritance pattern.

No additional pathogenic MSX1 coding variants have been reported in this family, and unaffected carriers were not observed, supporting full penetrance of the heterozygous null allele. The segregation of c.623C>A (p.Ser208Ter) with Witkop syndrome across multiple generations provides strong genetic evidence for causality.

Functional analysis in Msx1-null mice recapitulated the human phenotype: homozygous null animals exhibit severe tooth agenesis and defective nail plates, demonstrating that reduced MSX1 dosage disrupts both structures during development (PMID:11369996).

Biochemical studies of an MSX1 missense variant (Arg31Pro) associated with selective tooth agenesis showed the mutant protein to be inactive yet non–dominant‐negative, supporting haploinsufficiency rather than a dominant‐negative mechanism (PMID:9742121).

Together, these genetic and experimental data establish that heterozygous loss‐of‐function variants in MSX1 cause autosomal dominant tooth and nail syndrome via haploinsufficiency. MSX1 genetic testing should be considered in individuals with congenital nail dysplasia and tooth agenesis.

References

• American Journal of Human Genetics • 2001 • A nonsense mutation in MSX1 causes Witkop syndrome. PMID:11369996
• Molecular and Cellular Biology • 1998 • Haploinsufficiency of MSX1: a mechanism for selective tooth agenesis. PMID:9742121

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