A Nonsense Mutation in MSX1 Causes Witkop Syndrome

Abstract

Witkop syndrome, also known as tooth and nail syndrome (TNS), is a rare autosomal dominant disorder. Affected individuals have nail dysplasia and several congenitally missing teeth. To identify the gene responsible for TNS, we used candidate-gene linkage analysis in a three-generation family affected by the disorder. We found linkage between TNS and polymorphic markers surrounding the MSX1 locus. Direct sequencing and restriction-enzyme analysis revealed that a heterozygous stop mutation in the homeodomain of MSX1 cosegregated with the phenotype. In addition, histological analysis of Msx1-knockout mice, combined with a finding of Msx1 expression in mesenchyme of developing 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 littermates. The resemblance between the tooth and nail phenotype in the human family and that of Msx1-knockout mice strongly supports the conclusions that a nonsense mutation in MSX1 causes TNS and that Msx1 is critical for both tooth and nail development.

MSX1 mutations and associated disease phenotypes: genotype-phenotype relations

“…5,6 In humans, MSX1 variants show pleiotropic phenotypes with variable association with non-syndromic cleft lip with or without cleft palate (CL/P,OMIM #608874, Orofacial Cleft 5, OFC5), non-syndromic tooth agenesis (OMIM, #106600 -Tooth Agenesis, Selective, 1; STHAG1), Witkop syndrome (OMIM, #189500) and Wolf-Hirschhorn syndrome (WHS, OMIM, #194190). [7][8][9][10] Mice with a homozygous deletion of Msx1 exhibit a complete cleft palate and failure of tooth development. 11 Affected individuals from the same pedigree carrying the same MSX1 variant also show variable phenotype severity.…”

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

“…This tooth-loss pattern is consistent with previous reports of tooth agenesis among patients carrying MSX1 mutations, as well as with general tooth-loss patterns. 3,27,52 Our in vitro functional studies of this missense polymorphism suggest that it is a hypomorphic mutation that is mildly deleterious, which still retains some repression activity at higher doses. This dose-dependent response was a very interesting result; especially as MSX1 effects are known to be dose sensitive, as previously cited.…”

“…The proband (II-4) was an adult female, missing tooth I :: (Palmer notation system). Her sister (II-2) was missing teeth f and Jumlongras et al 3 Individuals III-1, lacking tooth b, and III-2, lacking teeth b and 1, were dizygotic twin daughters of II-2, who was married to an unaffected individual (II-1), not carrying a R151S mutation. Examination of the proband DNA from six other pedigrees revealed no additional DNA sequence variation in either MSX1 or PAX9.…”

“…This results from the well-documented early expression domains within these tissues during embryogenesis, 1 and is reflected in the phenotype of the Msx1 knockout mouse: cleft palate, tooth agenesis and nail dysplasia. 2,3 In humans, multiple MSX1 mutations have been identified in families exhibiting Mendelian inheritance of an oligodontia phenotype (either non-syndromic or syndromic). [3][4][5][6][7][8][9][10][11][12][13][14] However, MSX1 also clearly affects the common human oral cleft phenotypes, as demonstrated through multiple genetic studies.…”

“…2,3 In humans, multiple MSX1 mutations have been identified in families exhibiting Mendelian inheritance of an oligodontia phenotype (either non-syndromic or syndromic). [3][4][5][6][7][8][9][10][11][12][13][14] However, MSX1 also clearly affects the common human oral cleft phenotypes, as demonstrated through multiple genetic studies. [15][16][17][18][19][20] Yet, in all but a single case report, 5 MSX1 apparently functions as a complex disease determinant for oral clefting.…”