The genetic basis of epidermolysis bullosa simplex with mottled pigmentation

被引:138
作者
Uttam, J
Hutton, E
Coulombe, PA
AntonLamprecht, I
Yu, QC
GeddeDahl, T
Fine, JD
Fuchs, E
机构
[1] JOHNS HOPKINS UNIV, SCH MED, DEPT BIOCHEM & BIOPHYS, BALTIMORE, MD 21218 USA
[2] UNIV OSLO, NATL HOSP, DEPT DERMATOL, N-0027 OSLO, NORWAY
[3] UNIV OSLO, NATL HOSP, INST FORENS MED, N-0027 OSLO, NORWAY
[4] UNIV HEIDELBERG, INST ULTRASTRUKTURFORSCH HAUT, D-69115 HEIDELBERG, GERMANY
[5] UNIV N CAROLINA, DEPT DERMATOL, CHAPEL HILL, NC 27514 USA
关键词
keratin filaments; cytoskeleton; genetic disease; intermediate filament function;
D O I
10.1073/pnas.93.17.9079
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Epidermolysis bullosa simplex (EBS) is a group of autosomal dominant skin diseases characterized by blistering, due to mechanical stress-induced degeneration of basal epidermal cells, It is now well-established that the three major subtypes of EBS are genetic disorders of the basal epidermal keratins, keratin 5 (K5) and keratin 14 (K14). Here we show that a rare subtype, referred to as EBS with mottled pigmentation (MP), is also a disorder of these keratins, Affected members of two seemingly unrelated families with EBS-MP had a C to T point mutation in the second base position of codon 24 of one of two K5 alleles, leading to a Pro:Leu mutation. This mutation was not present in unaffected members nor in 100 alleles from normal individuals. Linkage analyses mapped the defect to this type II keratin gene (peak logarithm of odds score at phi = 0 of 3.9), which is located on chromosome 12q11-q13. This provides strong evidence that this mutation is responsible for the EBS-MP phenotype, Only conserved between K5 and K6, and not among any of the other type II keratins, Pro-24 is in the nonhelical head domain of K5, and only mildly perturbs the length of 10-nm keratin filaments assembled in vitro, However, this part of the K5 head domain is likely to protrude on the filament surface, perhaps leading to additional aberrations in intermediate filament architecture and/or in melanosome distribution that are seen ultrastructurally in patients with the mutation.
引用
收藏
页码:9079 / 9084
页数:6
相关论文
共 49 条
[41]   A FUNCTIONAL KNOCKOUT OF HUMAN KERATIN-14 [J].
RUGG, EL ;
MCLEAN, WHI ;
LANE, EB ;
PITERA, R ;
MCMILLAN, JR ;
DOPPINGHEPENSTAL, PJC ;
NAVSARIA, HA ;
LEIGH, IM ;
EADY, RAJ .
GENES & DEVELOPMENT, 1994, 8 (21) :2563-2573
[42]   MISSING LINKS - WEBER-COCKAYNE KERATIN MUTATIONS IMPLICATE THE L12 LINKER DOMAIN IN EFFECTIVE CYTOSKELETON FUNCTION [J].
RUGG, EL ;
MORLEY, SM ;
SMITH, FJD ;
BOXER, M ;
TIDMAN, MJ ;
NAVSARIA, H ;
LEIGH, IM ;
LANE, EB .
NATURE GENETICS, 1993, 5 (03) :294-300
[43]  
STEINERT PM, 1993, J BIOL CHEM, V268, P2878
[44]   KERATIN INTERMEDIATE FILAMENT STRUCTURE - CROSS-LINKING STUDIES YIELD QUANTITATIVE INFORMATION ON MOLECULAR DIMENSIONS AND MECHANISM OF ASSEMBLY [J].
STEINERT, PM ;
MAREKOV, LN ;
FRASER, RDB ;
PARRY, DAD .
JOURNAL OF MOLECULAR BIOLOGY, 1993, 230 (02) :436-452
[45]   COMPLETE AMINO-ACID-SEQUENCE OF A MOUSE EPIDERMAL KERATIN SUBUNIT AND IMPLICATIONS FOR THE STRUCTURE OF INTERMEDIATE FILAMENTS [J].
STEINERT, PM ;
RICE, RH ;
ROOP, DR ;
TRUS, BL ;
STEVEN, AC .
NATURE, 1983, 302 (5911) :794-800
[46]   A KERATIN-14 MUTATIONAL HOT-SPOT FOR EPIDERMOLYSIS-BULLOSA SIMPLEX, DOWLING-MEARA - IMPLICATIONS FOR DIAGNOSIS [J].
STEPHENS, K ;
SYBERT, VP ;
WIJSMAN, EM ;
EHRLICH, P ;
SPENCER, A .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 1993, 101 (02) :240-243
[47]   CLONING AND CHARACTERIZATION OF MULTIPLE HUMAN GENES AND CDNAS ENCODING HIGHLY RELATED TYPE-II KERATIN-6 ISOFORMS [J].
TAKAHASHI, K ;
PALADINI, RD ;
COULOMBE, PA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (31) :18581-18592
[48]   MUTANT KERATIN EXPRESSION IN TRANSGENIC MICE CAUSES MARKED ABNORMALITIES RESEMBLING A HUMAN GENETIC SKIN-DISEASE [J].
VASSAR, R ;
COULOMBE, PA ;
DEGENSTEIN, L ;
ALBERS, K ;
FUCHS, E .
CELL, 1991, 64 (02) :365-380
[49]   THE ROLES OF K5 AND K14 HEAD, TAIL, AND R/K L L E G E DOMAINS IN KERATIN FILAMENT ASSEMBLY INVITRO [J].
WILSON, AK ;
COULOMBE, PA ;
FUCHS, E .
JOURNAL OF CELL BIOLOGY, 1992, 119 (02) :401-414