Variants in a novel epidermal collagen gene (COL29A1) are associated with atopic dermatitis - PubMed (original) (raw)

doi: 10.1371/journal.pbio.0050242.

Ingo Marenholz, Tamara Kerscher, Franz Rüschendorf, Jorge Esparza-Gordillo, Margitta Worm, Christoph Gruber, Gabriele Mayr, Mario Albrecht, Klaus Rohde, Herbert Schulz, Ulrich Wahn, Norbert Hubner, Young-Ae Lee

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Variants in a novel epidermal collagen gene (COL29A1) are associated with atopic dermatitis

Cilla Söderhäll et al. PLoS Biol. 2007 Sep.

Abstract

Atopic dermatitis (AD) is a common chronic inflammatory skin disorder and a major manifestation of allergic disease. AD typically presents in early childhood often preceding the onset of an allergic airway disease, such as asthma or hay fever. We previously mapped a susceptibility locus for AD on Chromosome 3q21. To identify the underlying disease gene, we used a dense map of microsatellite markers and single nucleotide polymorphisms, and we detected association with AD. In concordance with the linkage results, we found a maternal transmission pattern. Furthermore, we demonstrated that the same families contribute to linkage and association. We replicated the association and the maternal effect in a large independent family cohort. A common haplotype showed strong association with AD (p = 0.000059). The associated region contained a single gene, COL29A1, which encodes a novel epidermal collagen. COL29A1 shows a specific gene expression pattern with the highest transcript levels in skin, lung, and the gastrointestinal tract, which are the major sites of allergic disease manifestation. Lack of COL29A1 expression in the outer epidermis of AD patients points to a role of collagen XXIX in epidermal integrity and function, the breakdown of which is a clinical hallmark of AD.

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Conflict of interest statement

Competing interests. The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Positional Cloning Strategy for the AD Disease Gene on Chromosome 3q21

(A) The candidate region spanned 12.75 cM between markers D3S1303 and D3S1292. The _y_-axis depicts the GENEHUNTER nonparametric Zall as previously reported [16]. (B) Fine mapping with 96 microsatellite markers narrowed the interval to 5.4 Mb between markers M3CS075 and M3CS233. An association scan using 212 SNPs of the region revealed association of AD with two adjacent SNPs, rs5852593 and rs1497309. Genotyping of 16 additional SNPs refined the associated region. (C) Genomic positions of the 42 exons of COL29A1 are shown. The gene entirely encompasses the associated region. (D) The COL29A1 mRNA consists of 9226 bp. Translation start site and stop codon are indicated. (E) The predicted open reading frame encodes a protein of 2614 amino acids including a secretion peptide (SP), six N-terminal and three C-terminal vWAs, flanking a short collagen triple helix.

Figure 2

Figure 2. Pairwise LD Values (D′) Between 28 SNPs Based on Genotypes of the Founders in the Discovery Cohort

Boxes contain the LD values (D′) between the respective markers indicated on top. Higher LD values correspond to a darker shade of red. Positions on Chromosome 3 are given in Mb; 131.547 denotes the start and 131.686 the end of COL29A1 on the genomic sequence. Boxes on the horizontal bar represent the 42 exons of COL29A1.

Figure 3

Figure 3. Gene Expression Analysis of COL29A1

(A) RT-PCR analysis of collagen XXIX in human tissues. (B) In situ gene expression analysis of COL29A1 in AD skin. In situ hybridization results of a _COL29A1_-specific antisense probe on cryostat sections (5 μm thick) of an AD skin biopsy (left) and a normal human control (right) are shown. COL29A1 mRNA detected by the digoxigenin-labelled probe is stained in blue (BCIP/NBT staining). The arrows point the different gene expression in the upper spinous and granular layer of the epidermis of an AD patient and a normal human control. Stratum basale (SB), stratum spinosum (SS), stratum granulosum (SG), and stratum corneum (SC) are indicated.

Figure 4

Figure 4. Immunohistochemical Analysis of Collagen XXIX Expression in AD Skin

Cryostat sections (5μm thick) of an AD skin biopsy (A) and a normal human control (B) are shown. In normal, human skin, collagen XXIX is expressed in the epidermis. In patients with atopic dermatitis, a striking lack of collagen XXIX staining was observed in the viable outermost spinous and granular layers of the epidermis (arrow). Stratum basale (SB), stratum spinosum (SS), stratum granulosum (SG), and stratum corneum (SC) are indicated. Collagen XXIX was stained with fuchsin (red). Sections were counterstained with hematoxylin (blue).

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