Fine Mapping Study On Disease Locus In A Follicular Occlusion Triad Pedigree

Backgrounds The follicular occlusion triad (FOT, OMIM: %142690)(alias hidradenitis suppurativa, acne inverse, HS/AI) is a chronic relapsing inflammatory skin disease characterized by recurrent draining sinuses and abscesses, predominantly in skin folds that carry terminal hairs and apocrine glands. In 1989, Plewig and Steger introduced the term acne inversa which is in use today, indicating a follicular source of the disease and replacing older terms such as Verneuil disease, hidradenitis suppurativa. Follicular occlusion triad may have a severe deleterious psychosocial impact on the patient, due to both its chronic nature and lack of response to standard therapeutic options. The prevalence of follicular occlusion triad has been estimated at 0.17%～1%, but the incidence in China is unknown. Although some publications had been reported that the pattern of transmission is consistent with autosomal dominant inheritance, the molecular basis is still unknown. A study of the molecular genetics of follicular occlusion triad has found the linkage to two loci on chromosome 6 and 19 in several families but no gene responsible for it has been identified. Recently, another locus for autosomal dominant form of follicular occlusion triad was reported at 1p21.1-1q25.3 in a large four-generation Chinese Han pedigree, but has not been replicated by other groups. This critical region contained about 900 genes, including a large number of known genes, predicted genes, and numerous expressed sequence tags. It is difficult to search for the responsible gene for follicular occlusion triad within this wide region.Objectives (1) To validate the previous mapped region in a Chinese follicular occlusion triad family. (2) To refine and identify the disease locus in this family. (3) To delineate the clinical and genetic features of the follicular occlusion triad cases. Methods (1) We collected available family members'information, summarized and analyzed the genetic and clinical features of follicular occlusion triad. (2) We performed a linkage analysis with 17 microsatellite markers in a large Chinese family to map the chromosome location of the follicular occlusion triad responsible gene by the Linkage software (5.20 Version). (3) Haplotypes were constructed with Cyrillic software (Version 2.02).Results (1) The five-generation pedigree we collected consisted with autosomal dominant inheritance and was composed of 7 affected and 15 unaffected members. The affected members have typical features supported the diagnosis of follicular occlusion triad. (2) We found the evidence for suggestive linkage in the region at 1p21.1-1q25.3 with a maximum two-point lod score of 2.11 at D1S2707 (θ=0.00 ). (3) Haplotype analysis localized the disease locus at 1q21.3-1q23.2 defined by D1S2715 and D1S484. This region overlaps by 9.8 cM with the previously reported region at 1p21.1-1q25.3.Conclusions (1) The pedigree we collected consisted with autosomal dominant inheritance. (2) We identified the suggestive gene locus within the previously reported region causing follicular occlusion triad at 1p21.1-1q25.3 and refined to a 9.8 cM interval at 1q21.3-1q23.2.