Association Screening in the Epidermal Differentiation Complex (EDC) Identifies an SPRR3 Repeat Number Variant as a Risk Factor for Eczema

Abstract

The genetically determined impairment of the skin barrier is a primary cause of eczema. As numerous genes essential for an intact epidermis reside within the epidermal differentiation complex (EDC), we screened the National Center for Biotechnology Information (NCBI) database for putatively functional polymorphisms in the EDC genes and tested them for association with eczema. We identified 20 polymorphisms with predicted major impact on protein function. Of these, 4 were validated in 94 eczema patients: a nonsense mutation in FLG2 (rs12568784), a stop codon mutation in LCE1D (rs41268500), a 24-bp deletion in SPRR3 (rs28989168), and a frameshift mutation in S100A3 (rs11390146). The minor allele frequencies were 15.1, 6.1, 47.2, and 0.4%, respectively. Association testing of the validated polymorphisms in 555 eczema patients and 375 controls identified a significant effect of rs28989168 (SPRR3) on eczema. The association was replicated in another 1,314 cases and 1,322 controls, yielding an overall odds ratio of 1.30 (95% confidence interval 1.12-1.51; P=0.00067) for a dominant mode of inheritance. Small proline-rich proteins (SPRRs) are crossbridging proteins in the cornified cell envelope (CE), which provides the main barrier function of stratified squamous epithelia. The SPRR3 variant associated with eczema carried an extra 24-bp repeat in the central domain, which may alter the physical properties of the CE.

New insights in the pathogenesis of atopic dermatitis

“…However, the majority of AD patients do not carry FLG. In children, FLG accounts for only 26.7% of the patients with AD, suggesting that other skin barrier genes, particularly those in the epidermal differentiation complex of chromosome 1q21, likely exist to account for the barrier defects in AD patients without FLG (10,11). Abnormalities in skin lipid composition (6), excessive serine protease activity (as illustrated by the ichthyosiform disease Netherton syndrome, which is caused by mutations in SPINK5 that encodes for lymphoepithelial Kazal-type-related inhibitor) (6), claudins of tight junction (12), or suppression of skin barrier protein expression by inflammation (9) may constitute other causes of skin barrier defects in AD.…”

Role of genetic aspect in pathogenesis of atopic dermatitis

“…The data suggested a dominant mode of inheritance for the risk allele of SPRR3 in eczema (Marenholz et al 2011). In this study the frequency of appearance of the gene polymorphism rs28989168 among the AD patients and control group was analyzed.…”

Molecular Genetic of Atopic Dermatitis : An Update

“…(41) These genes are very similar together in structure and function, and locate in close proximity to each other in the epidermal differentiation complex. (13,41,42) On the basis of previous illustrations with FLG, it has been postulated that a stopgain (null) mutation in exon 3 of any of the SFTP genes may be result in reduced or absent protein production. (41)(42)(43)(44) Genetic associations of FLG mutations with AD were confirmed and further verified by many independent groups using numerous cohorts of different populations e.g.…”

“…(13,41,42) On the basis of previous illustrations with FLG, it has been postulated that a stopgain (null) mutation in exon 3 of any of the SFTP genes may be result in reduced or absent protein production. (41)(42)(43)(44) Genetic associations of FLG mutations with AD were confirmed and further verified by many independent groups using numerous cohorts of different populations e.g. American, (45) Caucasian and Northern-American AD, (2) European and Asian ancestry, (43,(46)(47)(48)(49)(50)(51) Chinese, (52) German, (53) Irish, (43) and Japanese.…”

“…As for example, the FLG mutations are involved in AD and are featured in some review articles. (31,(42)(43)(44)(45) The AD associated major candidate genes and their chromosomal location or genetic variations have been summarized in Table 1. The following genes play a central role in the pathogenesis of AD and now have been offered a several novel potential therapeutic opportunities for AD.…”