Gene Mapping Of Atrophia Maculosa Varioliformis Cutis

Since Heidingsfeld described the first case of atrophia maculosa varioliformis cutis (AMVC) in 1918, a rarely reported form of idiopathic macular atrophy on the cheeks, only 25 cases had been reported in the past 86 years. The onset age of the dermatoses was teens. Most of the previously reported cases were sporadic, but four authors had reported familial occurrence. The etiology of this clinical entity remains unclear even though it is suggested that it is a congenital disorder(OMIM 601341). Its inheritance pattern is not confirmed up to now, though OMIM speculates that it is autosomal recessive. The molecular basis of AMVC is also unknown. AMVC is generally classified into abnormalities of dermal connective tissue, because histological findings reveal that it is a slight decrease in the number of elastic fibers below a shallow depression of the epidermis. So far, the AMVC disease gene and its chromosomal localization have not been identified.In this study, we report a 25-year-old woman whose clinical and pathological findings suggested the diagnosis of atrophia maculosa varioliformis cutis. The similar skin rash was observed in members of the same family. As far as we know, we are first to draw the pedigree chart of AMVC and report the largest family of AMVC. Based on it, we presumed that AVMV is an autosomal dominant inheritance. We undertook an entire genome-wide scan in this AMVC pedigree and located the AMVC disease gene between D7S493 and D7S502 at chromosome 7p with maximum LOD score of 3.01 at marker D7S519. The genetic distance is as large as 44cM. Within the above region we selected 19 high-heterozygosity microsatellite markers for fine mapping. Haplotype construction showed that the distal border of the crossover region was defined inâ…¢: 6 between d7s2548 and d7s678, as well as the proximal border of the cosegregation point inâ…¡: 3 between d7s665 and d7s2506. These results suggested that the gene responsible for AMVC in this family lies in 8.1cM interval between d7s2548 and d7s2506. This result not only confirmed that inheritance pattern of AMVC in our degree has autosomal dominance trait, but also provided the probilities for idenfiying disease gene and pathogenesis of AMVC.There are about 56 known genes, pseudogenes and predicted genes within this region. Based on the literatures, we selected five relatively-known genes as candidates, which included TBRG4,RAMP3,IGFBP3,IGFBP1 and TNS3. The exons and splicing region of these genes were sequenced with no significant mutation except some reported SNPs.In a summary, the research first localized the disease gene of AMVC and made it possible to further narrow down the region and finally identify the disease gene. This may be helpful for understand the pathogenesis of diseases characterized by elasin disorder, especially for exploring the same molecular basis of a group diseases with various manifestations.