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

被引:76
作者
Hunt, DM
Rickman, L
Whittock, NV
Eady, RA
Simrak, D
Dopping-Hepenstal, PJC
Stevens, HP
Armstrong, DKB
Hennies, HC
Küster, W
Hughes, AE
Arnemann, J
Leigh, IM
McGrath, JA
Kelsell, DP
Buxton, RS
机构
[1] Natl Inst Med Res, Div Membrane Biol, London NW7 1AA, England
[2] St Thomas Hosp, Guys Kings & St Thomas Hosp Sch Med, St Johns Inst Dermatol, Dept Cell & Mol Pathol, London SE1 7EH, England
[3] Univ Frankfurt Klinikum, Inst Humangenet, D-60590 Frankfurt 70, Germany
[4] Queen Mary Univ London, St Bartholomews & Royal London Sch Med & Dent, Ctr Cutaneous Res, London E1 2AT, England
[5] Queens Univ Belfast, Belfast City Hosp, Dept Med Genet, Belfast BT9 7AB, Antrim, North Ireland
[6] Max Delbruck Ctr Berlin Buch, Dept Mol Genet, D-13092 Berlin, Germany
[7] Max Delbruck Ctr Berlin Buch, Gene Mapping Ctr, D-13092 Berlin, Germany
[8] TOMESA Fachklin, D-36361 Bad Salzschlirf, Germany
基金
英国医学研究理事会; 英国惠康基金;
关键词
desmosome; cadherin; desmoglein; dominance; epidermis; keratoderma;
D O I
10.1038/sj.ejhg.5200605
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:197 / 203
页数:7
相关论文
共 46 条
[1]  
Adams MJ, 1998, BIOCHEM J, V329, P165
[2]   ASSIGNMENT OF THE HUMAN GENES FOR DESMOCOLLIN-3 (DSC3) AND DESMOCOLLIN-4 (DSC4) TO CHROMOSOME-18Q12 [J].
AMAGAI, M ;
WANG, YM ;
MINOSHIMA, S ;
KAWAMURA, K ;
GREEN, KJ ;
NISHIKAWA, T ;
SHIMIZU, N .
GENOMICS, 1995, 25 (01) :330-332
[3]  
ARNEMANN J, 1992, HUM GENET, V89, P347
[4]   CHROMOSOMAL ASSIGNMENT OF THE HUMAN GENES-CODING FOR THE MAJOR PROTEINS OF THE DESMOSOME JUNCTION, DESMOGLEIN DGI (DSG), DESMOCOLLINS DGII/III (DSC), DESMOPLAKINS DPI/II (DSP), AND PLAKOGLOBIN DPIII (JUP) [J].
ARNEMANN, J ;
SPURR, NK ;
WHEELER, GN ;
PARKER, AE ;
BUXTON, RS .
GENOMICS, 1991, 10 (03) :640-645
[5]  
ARNEMANN J, 1993, J CELL SCI, V104, P741
[6]   THE HUMAN GENE (DSG2) CODING FOR HDGC, A SECOND MEMBER OF THE DESMOGLEIN SUBFAMILY OF THE DESMOSOMAL CADHERINS, IS, LIKE DSG1 CODING FOR DESMOGLEIN DGI, ASSIGNED TO CHROMOSOME-18 [J].
ARNEMANN, J ;
SPURR, NK ;
MAGEE, AI ;
BUXTON, RS .
GENOMICS, 1992, 13 (02) :484-486
[7]   CLONING AND CHARACTERIZATION OF THE HUMAN INVASION SUPPRESSOR GENE E-CADHERIN (CDH1) [J].
BERX, G ;
STAES, K ;
VANHENGEL, J ;
MOLEMANS, F ;
BUSSEMAKERS, MJG ;
VANBOKHOVEN, A ;
VANROY, F .
GENOMICS, 1995, 26 (02) :281-289
[8]   Aspects of the structure and assembly of desmosomes [J].
Burdett, IDJ .
MICRON, 1998, 29 (04) :309-328
[9]  
Buxton R S, 1992, Semin Cell Biol, V3, P157
[10]  
Corden L D, 1996, Exp Dermatol, V5, P297, DOI 10.1111/j.1600-0625.1996.tb00133.x