Identification Of The Causative Gene Of A DSAP Edigree Using Exome Sequencing

Porokeratosis (porokeratosis, PK) is a specia cutaneous disorder of keratinization,which first described in1893by Mibelli. Lesions of this disease are circular or irregular patches with sharp edges, adike-like bulges. The central part of the lesion is smooth and dry, atrophy. The lesions usually appear in the limbs,face, neck, etc. genital mucosa and even the cornea may also be involved. The porokeratosis disease divided into4-6subtypes, diffuse superficial photosensitivity porokeratosis (disseminated superficial actinic porokeratosis, DSAP) is a relatively common subtype of PK, which general appear after10years of age. This subtype charactered by smaller lesions, superficial tufted, mainly involving the exposure site. Ultraviolet ray, immunosuppression and inflammation are factors may add to DSAP or cause illness.Etiology of porokeratosis is so far unknown. As a incomplete dominant genetic disease with genetic heterogeneity, four DSAP susceptibility loci were localized:12q23.2-24.1,15q25.1-26.1,1p31.3-p31.1,16q24.1-24.3. Dozens of genes in these intervals, such as: CRY1, C4ST1, and TXNRD1, HCF2,etc, have been screened for mutations by previous studies, but no disease-associated mutation was detected.The object of this study are three DSAP families (family1, family2, family3). Family1and family3are from Hunan Province, family2is from Huainan Anhui Province. In the past a genome-wide scan and linkage analysis were carried out in family1and family2, eventually mapped DSAP1to a4.4cM region between D12S338to D12S1605. Mutations screening was carried out by the candidate cloning technology in the genes at the locus, such as C4ST1, TXNRD1, CRY1, HCF2, CMKLR1and KIAA0789, but no mutations assoicate with DSAP was identified. Since2009, the development of exomes capture and next-generation sequencing technology have provided a new strategy to find causative genes of monogenic diseases. In this study we selected two patients and one normal individual from the family1to analyze their exomes sequences by exomes sequencing method,meanwhile, Sanger sequencing will be used to verify the results. Mutation screening will be carried out in all the three family.Our results revealed the MVK in12q24.11gene carried c.566C> T mutation, leading to amino acid change ALA> VAL, in family1. By Sanger sequencing we identified c.1039+2T>C mutation in the MVK gene in family2, and C.935A>G in family3. All these MVK mutations are not detected in normals, Suggestting MVK gene is the causative gene for DSAP.