Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris

被引:714
作者
Smith, FJD
Irvine, AD
Terron-Kwiatkowski, A
Sandilands, A
Campbell, LE
Zhao, YW
Liao, HH
Evans, AT
Goudie, DR
Lewis-Jones, S
Arseculeratne, G
Munro, CS
Sergeant, A
O'Regan, G
Bale, SJ
Compton, JG
DiGiovanna, JJ
Presland, RB
Fleckman, P
McLean, WHI [1 ]
机构
[1] Univ Dundee, Ninewells Hosp & Med Sch, Div Pathol & Neurosci, Human Genet Unit,Epithelial Genet Grp, Dundee DD1 9SY, Scotland
[2] Univ Dundee, Ninewells Hosp & Med Sch, Tayside Univ Hosp NHS Trust, Dundee DD1 9SY, Scotland
[3] Our Ladys Hosp Sick Children, Dept Paediat Dermatol, Dublin 12, Ireland
[4] S Glasgow Univ Hosp NHS Trust, Dept Dermatol, Glasgow G51 4TF, Lanark, Scotland
[5] Gene Dx, Gaithersburg, MD 20877 USA
[6] Rhode Isl Hosp, Providence, RI 02903 USA
[7] Brown Univ, Sch Med, Dept Dermatol, Div Dermatopharmacol, Providence, RI 02903 USA
[8] NCI, Basic Res Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA
[9] Univ Washington, Sch Dent, Seattle, WA 98195 USA
[10] Univ Washington, Dept Med, Div Dermatol, Seattle, WA 98195 USA
基金
英国医学研究理事会; 英国惠康基金;
关键词
D O I
10.1038/ng1743
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren(1). We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of similar to 4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.
引用
收藏
页码:337 / 342
页数:6
相关论文
共 30 条
[1]   Genetic heterogeneity in lamellar ichthyosis [J].
Bale, SJ ;
Compton, JG ;
Russell, LJ ;
DiGiovanna, JJ .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 1996, 107 (01) :140-140
[2]   Netherton syndrome:: Disease expression and spectrum of SPINK5 mutations in 21 families [J].
Bitoun, E ;
Chavanas, S ;
Irvine, AD ;
Lonie, L ;
Bodemer, C ;
Paradisi, M ;
Hamel-Teillac, D ;
Ansai, S ;
Mitsuhashi, Y ;
Taïeb, A ;
de Prost, Y ;
Zambruno, G ;
Harper, JI ;
Hovnanian, A .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2002, 118 (02) :352-361
[3]   The cornified envelope: A model of cell death in the skin [J].
Candi, E ;
Schmidt, R ;
Melino, G .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2005, 6 (04) :328-340
[4]   Mapping of the associated phenotype of an absent granular layer in ichthyosis vulgaris to the epidermal differentiation complex on chromosome 1 [J].
Compton, JG ;
DiGiovanna, JJ ;
Johnston, KA ;
Fleckman, P ;
Bale, SJ .
EXPERIMENTAL DERMATOLOGY, 2002, 11 (06) :518-526
[5]  
DALE BA, 1985, ANN NY ACAD SCI, V455, P330, DOI 10.1111/j.1749-6632.1985.tb50420.x
[6]  
Eady R. A. J., 1985, METHODS SKIN RES, P1
[7]   KERATINOCYTES CULTURED FROM SUBJECTS WITH ICHTHYOSIS VULGARIS ARE PHENOTYPICALLY ABNORMAL [J].
FLECKMAN, P ;
HOLBROOK, KA ;
DALE, BA ;
SYBERT, VP .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 1987, 88 (05) :640-645
[8]   ORGANIZATION, STRUCTURE, AND POLYMORPHISMS OF THE HUMAN PROFILAGGRIN GENE [J].
GAN, SQ ;
MCBRIDE, OW ;
IDLER, WW ;
MARKOVA, N ;
STEINERT, PM .
BIOCHEMISTRY, 1990, 29 (40) :9432-9440
[9]  
Ishida-Yamamoto A, 1998, LAB INVEST, V78, P1245
[10]  
JUDGE MR, 2004, ROOKS TXB DERMATOLOG, V2, P56