Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma

Debbie M. Hunt, Lisa Rickman, Neil V. Whittock, Robin A.J. Eady, Danijela Ŝimrak, Patricia J.C. Dopping-Hepenstal, Howard P. Stevens, D. Keith B. Armstrong, Hans Christian Hennies, Wolfgang Küster, Anne E. Hughes, Joachim Arnemann, Irene M. Leigh, John A. Mcgrath, David P. Kelsell, Roger S. Buxton

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Abstract

The adhesive proteins of the desmosome type of cell junction consist of two types of cadherin found exclusively in that structure, the desmogleins and desmocollins, coded by two closely linked loci on human chromosome 18q12.1. Recently we have identified a mutation in the DSG1 gene coding for desmoglein 1 as the cause of the autosomal dominant skin disease striate palmoplantar keratoderma (SPPK) in which affected individuals have marked hyperkeratotic bands on the palms and soles. In the present study we present the complete exon-intron structure of the DSG1 gene, which occupies approximately 43 kb, and intron primers sufficient to amplify all the exons. Using these we have analysed the mutational changes in this gene in five further cases of SPPK. All were heterozygotic mutations in the extracellular domain leading to a truncated protein, due either to an addition or deletion of a single base, or a base change resulting in a stop codon. Three mutations were in exon 9 and one in exon 11, both of which code for part of the third and fourth extracellular domains, and one was in exon 2 coding for part of the prosequence of this processed protein. This latter mutation thus results in the mutant allele synthesising only 25 amino acid residues of the prosequence of the protein so that this is effectively a null mutation implying that dominance in the case of this mutation was caused by haploinsufficiency. The most severe consequences of SPPK mutations are in regions of the body where pressure and abrasion are greatest and where desmosome function is most necessary. SPPK therefore provides a very sensitive measure of desmosomal function.

Original languageEnglish
Pages (from-to)197-203
Number of pages7
JournalEuropean Journal of Human Genetics
Volume9
Issue number3
DOIs
Publication statusPublished - 5 Apr 2001
Externally publishedYes

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Desmosomal Cadherins
Desmoglein 1
Palmoplantar Keratoderma
Cadherins
Skin Diseases
Mutation
Exons
Desmosomes
Introns
Proteins
Desmocollins
Desmogleins
Genes
Haploinsufficiency
Body Regions
Intercellular Junctions
Terminator Codon
Human Chromosomes
Adhesives
Alleles

Cite this

Hunt, D. M., Rickman, L., Whittock, N. V., Eady, R. A. J., Ŝimrak, D., Dopping-Hepenstal, P. J. C., ... Buxton, R. S. (2001). Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma. European Journal of Human Genetics, 9(3), 197-203. https://doi.org/10.1038/sj.ejhg.5200605
Hunt, Debbie M. ; Rickman, Lisa ; Whittock, Neil V. ; Eady, Robin A.J. ; Ŝimrak, Danijela ; Dopping-Hepenstal, Patricia J.C. ; Stevens, Howard P. ; Armstrong, D. Keith B. ; Hennies, Hans Christian ; Küster, Wolfgang ; Hughes, Anne E. ; Arnemann, Joachim ; Leigh, Irene M. ; Mcgrath, John A. ; Kelsell, David P. ; Buxton, Roger S. / Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma. In: European Journal of Human Genetics. 2001 ; Vol. 9, No. 3. pp. 197-203.
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abstract = "The adhesive proteins of the desmosome type of cell junction consist of two types of cadherin found exclusively in that structure, the desmogleins and desmocollins, coded by two closely linked loci on human chromosome 18q12.1. Recently we have identified a mutation in the DSG1 gene coding for desmoglein 1 as the cause of the autosomal dominant skin disease striate palmoplantar keratoderma (SPPK) in which affected individuals have marked hyperkeratotic bands on the palms and soles. In the present study we present the complete exon-intron structure of the DSG1 gene, which occupies approximately 43 kb, and intron primers sufficient to amplify all the exons. Using these we have analysed the mutational changes in this gene in five further cases of SPPK. All were heterozygotic mutations in the extracellular domain leading to a truncated protein, due either to an addition or deletion of a single base, or a base change resulting in a stop codon. Three mutations were in exon 9 and one in exon 11, both of which code for part of the third and fourth extracellular domains, and one was in exon 2 coding for part of the prosequence of this processed protein. This latter mutation thus results in the mutant allele synthesising only 25 amino acid residues of the prosequence of the protein so that this is effectively a null mutation implying that dominance in the case of this mutation was caused by haploinsufficiency. The most severe consequences of SPPK mutations are in regions of the body where pressure and abrasion are greatest and where desmosome function is most necessary. SPPK therefore provides a very sensitive measure of desmosomal function.",
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Hunt, DM, Rickman, L, Whittock, NV, Eady, RAJ, Ŝimrak, D, Dopping-Hepenstal, PJC, Stevens, HP, Armstrong, DKB, Hennies, HC, Küster, W, Hughes, AE, Arnemann, J, Leigh, IM, Mcgrath, JA, Kelsell, DP & Buxton, RS 2001, 'Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma', European Journal of Human Genetics, vol. 9, no. 3, pp. 197-203. https://doi.org/10.1038/sj.ejhg.5200605

Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma. / Hunt, Debbie M.; Rickman, Lisa; Whittock, Neil V.; Eady, Robin A.J.; Ŝimrak, Danijela; Dopping-Hepenstal, Patricia J.C.; Stevens, Howard P.; Armstrong, D. Keith B.; Hennies, Hans Christian; Küster, Wolfgang; Hughes, Anne E.; Arnemann, Joachim; Leigh, Irene M.; Mcgrath, John A.; Kelsell, David P.; Buxton, Roger S.

In: European Journal of Human Genetics, Vol. 9, No. 3, 05.04.2001, p. 197-203.

Research output: Contribution to journalArticle

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T1 - Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma

AU - Hunt, Debbie M.

AU - Rickman, Lisa

AU - Whittock, Neil V.

AU - Eady, Robin A.J.

AU - Ŝimrak, Danijela

AU - Dopping-Hepenstal, Patricia J.C.

AU - Stevens, Howard P.

AU - Armstrong, D. Keith B.

AU - Hennies, Hans Christian

AU - Küster, Wolfgang

AU - Hughes, Anne E.

AU - Arnemann, Joachim

AU - Leigh, Irene M.

AU - Mcgrath, John A.

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AU - Buxton, Roger S.

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N2 - The adhesive proteins of the desmosome type of cell junction consist of two types of cadherin found exclusively in that structure, the desmogleins and desmocollins, coded by two closely linked loci on human chromosome 18q12.1. Recently we have identified a mutation in the DSG1 gene coding for desmoglein 1 as the cause of the autosomal dominant skin disease striate palmoplantar keratoderma (SPPK) in which affected individuals have marked hyperkeratotic bands on the palms and soles. In the present study we present the complete exon-intron structure of the DSG1 gene, which occupies approximately 43 kb, and intron primers sufficient to amplify all the exons. Using these we have analysed the mutational changes in this gene in five further cases of SPPK. All were heterozygotic mutations in the extracellular domain leading to a truncated protein, due either to an addition or deletion of a single base, or a base change resulting in a stop codon. Three mutations were in exon 9 and one in exon 11, both of which code for part of the third and fourth extracellular domains, and one was in exon 2 coding for part of the prosequence of this processed protein. This latter mutation thus results in the mutant allele synthesising only 25 amino acid residues of the prosequence of the protein so that this is effectively a null mutation implying that dominance in the case of this mutation was caused by haploinsufficiency. The most severe consequences of SPPK mutations are in regions of the body where pressure and abrasion are greatest and where desmosome function is most necessary. SPPK therefore provides a very sensitive measure of desmosomal function.

AB - The adhesive proteins of the desmosome type of cell junction consist of two types of cadherin found exclusively in that structure, the desmogleins and desmocollins, coded by two closely linked loci on human chromosome 18q12.1. Recently we have identified a mutation in the DSG1 gene coding for desmoglein 1 as the cause of the autosomal dominant skin disease striate palmoplantar keratoderma (SPPK) in which affected individuals have marked hyperkeratotic bands on the palms and soles. In the present study we present the complete exon-intron structure of the DSG1 gene, which occupies approximately 43 kb, and intron primers sufficient to amplify all the exons. Using these we have analysed the mutational changes in this gene in five further cases of SPPK. All were heterozygotic mutations in the extracellular domain leading to a truncated protein, due either to an addition or deletion of a single base, or a base change resulting in a stop codon. Three mutations were in exon 9 and one in exon 11, both of which code for part of the third and fourth extracellular domains, and one was in exon 2 coding for part of the prosequence of this processed protein. This latter mutation thus results in the mutant allele synthesising only 25 amino acid residues of the prosequence of the protein so that this is effectively a null mutation implying that dominance in the case of this mutation was caused by haploinsufficiency. The most severe consequences of SPPK mutations are in regions of the body where pressure and abrasion are greatest and where desmosome function is most necessary. SPPK therefore provides a very sensitive measure of desmosomal function.

KW - Cadherin

KW - Desmoglein

KW - Desmosome

KW - Dominance

KW - Epidermis

KW - Keratoderma

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DO - 10.1038/sj.ejhg.5200605

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