A genetic cluster of patients with variant xeroderma pigmentosum with two different founder mutations

作者：Munford V; Castro L P; Souto R; Lerner L K; Vilar J B; Quayle C; Asif H; Schuch A P; de Souza T A; Ienne S; Alves F I A; Moura L M S; Galante P A F; Camargo A A; Liboredo R; Pena S D J; Sarasin A; Chaibub S C; Menck C F M^*

来源：British Journal of Dermatology, 2017, 176(5): 1270-1278.

DOI：10.1111/bjd.15084

BackgroundXeroderma pigmentosum (XP) is a rare human syndrome associated with hypersensitivity to sunlight and a high frequency of skin tumours at an early age. We identified a community in the state of Goias (central Brazil), a sunny and tropical region, with a high incidence of XP (17 patients among approximately 1000 inhabitants).
ObjectivesTo identify gene mutations in the affected community and map the distribution of the affected alleles, correlating the mutations with clinical phenotypes.
MethodsFunctional analyses of DNA repair capacity and cell-cycle responses after ultraviolet exposure were investigated in cells from local patients with XP, allowing the identification of the mutated gene, which was then sequenced to locate the mutations. A specific assay was designed for mapping the distribution of these mutations in the community.
ResultsSkin primary fibroblasts showed normal DNA damage removal but abnormal DNA synthesis after ultraviolet irradiation and deficient expression of the Pol protein, which is encoded by POLH. We detected two different POLH mutations: one at the splice donor site of intron 6 (c.764 +1 G>A), and the other in exon 8 (c.907 C>T, p.Arg303X). The mutation at intron 6 is novel, whereas the mutation at exon 8 has been previously described in Europe. Thus, these mutations were likely brought to the community long ago, suggesting two founder effects for this rare disease.
ConclusionsThis work describes a genetic cluster involving POLH, and, particularly unexpected, with two independent founder mutations, including one that likely originated in Europe.

• 出版日期2017-5