Detection of two Alu insertions in the CFTR gene

Background LINE-1 (long interspersed element-1) or L1-mediated retrotransposition is a potent force in human genome evolution and an occasional cause of human genetic disease. Since the first report of two de novo L1 insertions in the F8 gene causing hemophilia A, more than 50 L1-mediated retrotranspositional events have been identified as causing human genetic disease. However, a significant bias has generally militated against the detection of these pathological events at autosomal loci. Based upon this and other observations, we surmised that some previously unresolved cystic fibrosis chromosomes might carry hitherto undetected L1-mediated retrotranspositional insertions at the CFTR locus. This study represents an attempt to identify such mutational events. Methods 100 previously unresolved cystic fibrosis chromosomes were carefully reanalyzed using quantitative high-performance liquid chromatography (QHPLC). Results Two simple Alu insertions were identified in the CFTR gene, within exons 16 and 17b respectively. Conclusions Our findings have not only revealed a previously unknown mutational mechanism responsible for cystic fibrosis but also represent an important addition to the already diverse spectrum of known CFTR gene mutations. Experience with the CFTR gene suggests that pathological L1-mediated retrotranspositional events may also have been overlooked at other gene loci and should always be considered in cases that appear to be refractory to analysis

Association screening in the epidermal differentiation complex (EDC) identifies an SPRR3 repeat number variant as a risk factor for eczema

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

A common variant on chromosome 11q13 is associated with atopic dermatitis.

We conducted a genome-wide association study in 939 individuals with atopic dermatitis and 975 controls as well as 270 complete nuclear families with two affected siblings. SNPs consistently associated with atopic dermatitis in both discovery sets were then investigated in two additional independent replication sets totalling 2,637 cases and 3,957 controls. Highly significant association was found with allele A of rs7927894 on chromosome 11q13.5, located 38 kb downstream of C11orf30 (P-combined = 7.6 x 10(-10)). Approximately 13% of individuals of European origin are homozygous for rs7927894[A], and their risk of developing atopic dermatitis is 1.47 times that of noncarriers