Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema

Aileen Sandilands; Ana Terron-Kwiatkowski; Peter R. Hull; Gráinne M. O'Regan; Timothy H. Clayton; Rosemarie M. Watson; Thomas Carrick; Alan T. Evans; Haihui Liao; Yiwei Zhao; Linda E. Campbell; Matthias Schmuth; Robert Gruber; Andreas R. Janecke; Peter M. Elias; Maurice A.M. Van Steensel; Ivo Nagtzaam; Michel Van Geel; Peter M. Steijlen; Colin S. Munro; Daniel G. Bradley; Colin N.A. Palmer; Frances J.D. Smith; W. H.Irwin McLean; Alan D. Irvine

doi:10.1038/ng2020

Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema

Aileen Sandilands, Ana Terron-Kwiatkowski, Peter R. Hull, Gráinne M. O'Regan, Timothy H. Clayton, Rosemarie M. Watson, Thomas Carrick, Alan T. Evans, Haihui Liao, Yiwei Zhao, Linda E. Campbell, Matthias Schmuth, Robert Gruber, Andreas R. Janecke, Peter M. Elias, Maurice A.M. Van Steensel, Ivo Nagtzaam, Michel Van Geel, Peter M. Steijlen, Colin S. MunroDaniel G. Bradley, Colin N.A. Palmer, Frances J.D. Smith, W. H.Irwin McLean, Alan D. Irvine

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553 Citas (Scopus)

Resumen

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 (χ² test: P = 2.12 × 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.

Idioma original	English
Páginas (desde-hasta)	650-654
Número de páginas	5
Publicación	Nature Genetics
Volumen	39
N.º	5
DOI	https://doi.org/10.1038/ng2020
Estado	Published - may. 2007
Publicado de forma externa	Sí

Nota bibliográfica

Funding Information:
clerical assistance. The Irvine group is supported by the Children’s Medical and Research Foundation of Our Lady’s Children’s Hospital. The McLean/Smith group is supported by grants from the Dystrophic Epidermolysis Bullosa Research Association, the Pachyonychia Congenita Project and the British Skin Foundation/ National Eczema Society (W.H.I.M and F.J.D.S.). The Palmer group is supported by the Biotechnology and Biological Sciences Research Council (award D13460), Scottish Enterprise Tayside and the Gannochy Trust and the Scottish Executive Genetic Health Initiative. The Innsbruck group is supported by the Medical Research Fund of the Innsbruck University Medical Center (Medical Finance Fund numbers 71 and 153) and the Austrian National Bank (Austrian National Bank number 10822).

ASJC Scopus Subject Areas

Genetics

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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Sandilands, A., Terron-Kwiatkowski, A., Hull, P. R., O'Regan, G. M., Clayton, T. H., Watson, R. M., Carrick, T., Evans, A. T., Liao, H., Zhao, Y., Campbell, L. E., Schmuth, M., Gruber, R., Janecke, A. R., Elias, P. M., Van Steensel, M. A. M., Nagtzaam, I., Van Geel, M., Steijlen, P. M., ... Irvine, A. D. (2007). Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nature Genetics, 39(5), 650-654. https://doi.org/10.1038/ng2020

Sandilands, A, Terron-Kwiatkowski, A, Hull, PR, O'Regan, GM, Clayton, TH, Watson, RM, Carrick, T, Evans, AT, Liao, H, Zhao, Y, Campbell, LE, Schmuth, M, Gruber, R, Janecke, AR, Elias, PM, Van Steensel, MAM, Nagtzaam, I, Van Geel, M, Steijlen, PM, Munro, CS, Bradley, DG, Palmer, CNA, Smith, FJD, McLean, WHI & Irvine, AD 2007, 'Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema', Nature Genetics, vol. 39, n.º 5, pp. 650-654. https://doi.org/10.1038/ng2020

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title = "Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema",

abstract = "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 (χ2 test: P = 2.12 × 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.",

author = "Aileen Sandilands and Ana Terron-Kwiatkowski and Hull, {Peter R.} and O'Regan, {Gr{\'a}inne M.} and Clayton, {Timothy H.} and Watson, {Rosemarie M.} and Thomas Carrick and Evans, {Alan T.} and Haihui Liao and Yiwei Zhao and Campbell, {Linda E.} and Matthias Schmuth and Robert Gruber and Janecke, {Andreas R.} and Elias, {Peter M.} and {Van Steensel}, {Maurice A.M.} and Ivo Nagtzaam and {Van Geel}, Michel and Steijlen, {Peter M.} and Munro, {Colin S.} and Bradley, {Daniel G.} and Palmer, {Colin N.A.} and Smith, {Frances J.D.} and McLean, {W. H.Irwin} and Irvine, {Alan D.}",

note = "Funding Information: clerical assistance. The Irvine group is supported by the Children{\textquoteright}s Medical and Research Foundation of Our Lady{\textquoteright}s Children{\textquoteright}s Hospital. The McLean/Smith group is supported by grants from the Dystrophic Epidermolysis Bullosa Research Association, the Pachyonychia Congenita Project and the British Skin Foundation/ National Eczema Society (W.H.I.M and F.J.D.S.). The Palmer group is supported by the Biotechnology and Biological Sciences Research Council (award D13460), Scottish Enterprise Tayside and the Gannochy Trust and the Scottish Executive Genetic Health Initiative. The Innsbruck group is supported by the Medical Research Fund of the Innsbruck University Medical Center (Medical Finance Fund numbers 71 and 153) and the Austrian National Bank (Austrian National Bank number 10822).",

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AU - Hull, Peter R.

AU - O'Regan, Gráinne M.

AU - Clayton, Timothy H.

AU - Watson, Rosemarie M.

AU - Carrick, Thomas

AU - Evans, Alan T.

AU - Liao, Haihui

AU - Zhao, Yiwei

AU - Campbell, Linda E.

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AU - Gruber, Robert

AU - Janecke, Andreas R.

AU - Elias, Peter M.

AU - Van Steensel, Maurice A.M.

AU - Nagtzaam, Ivo

AU - Van Geel, Michel

AU - Steijlen, Peter M.

AU - Munro, Colin S.

AU - Bradley, Daniel G.

AU - Palmer, Colin N.A.

AU - Smith, Frances J.D.

AU - McLean, W. H.Irwin

AU - Irvine, Alan D.

N1 - Funding Information: clerical assistance. The Irvine group is supported by the Children’s Medical and Research Foundation of Our Lady’s Children’s Hospital. The McLean/Smith group is supported by grants from the Dystrophic Epidermolysis Bullosa Research Association, the Pachyonychia Congenita Project and the British Skin Foundation/ National Eczema Society (W.H.I.M and F.J.D.S.). The Palmer group is supported by the Biotechnology and Biological Sciences Research Council (award D13460), Scottish Enterprise Tayside and the Gannochy Trust and the Scottish Executive Genetic Health Initiative. The Innsbruck group is supported by the Medical Research Fund of the Innsbruck University Medical Center (Medical Finance Fund numbers 71 and 153) and the Austrian National Bank (Austrian National Bank number 10822).

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N2 - 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 (χ2 test: P = 2.12 × 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.

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Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema

Resumen

Nota bibliográfica

ASJC Scopus Subject Areas

PubMed: MeSH publication types

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