Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.
We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (chi2 test: P = 2.12 x 10(-51); Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9-11.3), and homozygote OR = 151 (95% c.i. = 20-1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.
Sandilands
Aileen
A
Epithelial Genetics Group, Human Genetics Unit, Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
Terron-Kwiatkowski
Ana
A
Hull
Peter R
PR
O'Regan
Gráinne M
GM
Clayton
Timothy H
TH
Watson
Rosemarie M
RM
Carrick
Thomas
T
Evans
Alan T
AT
Liao
Haihui
H
Zhao
Yiwei
Y
Campbell
Linda E
LE
Schmuth
Matthias
M
Gruber
Robert
R
Janecke
Andreas R
AR
Elias
Peter M
PM
van Steensel
Maurice A M
MA
Nagtzaam
Ivo
I
van Geel
Michel
M
Steijlen
Peter M
PM
Munro
Colin S
CS
Bradley
Daniel G
DG
Palmer
Colin N A
CN
Smith
Frances J D
FJ
McLean
W H Irwin
WH
Irvine
Alan D
AD
D001483:Base Sequence; D018389:Codon, Nonsense / Q000235:genetics; D003876:Dermatitis, Atopic / Q000235:genetics*; D004817:Epidermis / Q000378:metabolism; D000091344:Filaggrin Proteins; D016368:Frameshift Mutation / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D016112:Ichthyosis Vulgaris / Q000235:genetics*; D007381:Intermediate Filament Proteins / Q000235:genetics* / Q000378:metabolism; D007494:Ireland; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D044465:White People
D018389:Codon, Nonsense; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins