Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.
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. 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 approximately 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.
Smith
Frances J D
FJ
Epithelial Genetics Group, Human Genetics Unit, Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.
Irvine
Alan D
AD
Terron-Kwiatkowski
Ana
A
Sandilands
Aileen
A
Campbell
Linda E
LE
Zhao
Yiwei
Y
Liao
Haihui
H
Evans
Alan T
AT
Goudie
David R
DR
Lewis-Jones
Sue
S
Arseculeratne
Gehan
G
Munro
Colin S
CS
Sergeant
Ann
A
O'Regan
Gráinne
G
Bale
Sherri J
SJ
Compton
John G
JG
DiGiovanna
John J
JJ
Presland
Richard B
RB
Fleckman
Philip
P
McLean
W H Irwin
WH
D002648:Child; D005260:Female; D000091344:Filaggrin Proteins; D006580:Genetic Carrier Screening; D006801:Humans; D016112:Ichthyosis Vulgaris / Q000235:genetics*; D007381:Intermediate Filament Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics; D012016:Reference Values; D017384:Sequence Deletion
C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D010750:Phosphoproteins