A nonsense mutation in MSX1 causes Witkop syndrome - PubMed (original) (raw)

A nonsense mutation in MSX1 causes Witkop syndrome

D Jumlongras et al. Am J Hum Genet. 2001 Jul.

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.

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Figures

Figure 1

TNS phenotype. A, Panoramic radiograph of individual II-5 at age 33 years. Asterisks (*) indicate congenitally missing permanent teeth. This individual has a total of 14 congenitally missing teeth. B, Toenail dysplasia in individual III-7. Note that the fifth toenail is hypoplastic and more affected than the others. C, Toenail dysplasia of individual III-6. All nail plates are concave and hypoplastic. Note that the fifth toenail is almost absent.

Figure 2

MSX1 mutation analysis. A, DNA and amino acid sequence of part of exon 2 of MSX1 in unaffected (wild type; II-8) and affected (mutant; II-7) individuals. C→A transversion at nucleotide position 605 in mutant sequence results in a premature stop codon in the homeodomain of MSX1. B, TNS pedigree and restriction-enzyme analysis of PCR-generated DNA fragments of exon 2 of MSX1. The S202X mutation cosegregates with the TNS phenotype. The PCR fragments of 411 bp in length were subjected to _Nhe_I digestion. The mutant fragment was cleaved into 279-bp and 132-bp fragments, whereas the wild-type fragment was not.

Figure 3

Histology and in situ hybridization of developing mouse nails. A, In wild-type embryos at E16.5, the epithelial layers of the nail bed above distal phalanx are thickened. Arrow indicates epithelial invagination site where the future proximal nail fold forms. B, Msx1 is expressed only in mesenchyme subjacent to the epithelium of the nail bed. C and D, At E18.5, the wild-type nail plate is longer and thicker than that of _Msx1_-null mice. Pitting defects are observed in some areas of the epithelium (asterisk). NB = nail bed; PNF = proximal nail fold; NP = nail plate; DP = distal phalanx; MP = middle phalanx. Bar, 50 mm.

References

Electronic-Database Information

1. Genbank, http://www.ncbi.nlm.nih.gov/GenBank/ (for MSX1 [previously known as HOX7] genomic sequence [accession numbers M76731 and M76732])
1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for TNS [MIM <189500>] and tooth agenesis [MIM <106600>])

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A nonsense mutation in MSX1 causes Witkop syndrome - PubMed (original) (raw)