原发性皮肤淀粉样变一家系全基因组测序结果及初步分析

Whole-genome sequencing results and preliminary analysis of primary cutaneous amyloidosis

目的 利用全基因组测序技术寻找家族性原发性皮肤淀粉样变(FPCA)候选致病基因。方法 采用二代测序技术对一FPCA家系进行全基因组测序;筛选可能的致病性候选基因/位点,并进行Sanger测序验证。结果 在筛选出的26个候选基因中,低密度脂蛋白受体相关蛋白(LRP6)基因在淀粉样前体蛋白的代谢过程、β淀粉样蛋白的产生中起重要作用;丝聚蛋白2(FLG2)基因与皮肤角化和屏障相关。另外,该家系患者抑瘤素M受体(OSMR)基因第1 538位鸟嘌呤G被腺嘌呤A取代(c.1 538G>A),导致第513号氨基酸序列由甘氨酸Gly转变为天冬氨酸Asp(p.Gly513Asp),而家族中健康成员均未检测出此突变。结论 ①LRP6、FLG2基因可能与原发性皮肤淀粉样变(PCA)相关,但需要进一步大样本量验证和相关的功能学研究。②OSMR基因p.Gly513Asp突变可能参与PCA发病。

Objective To search for candidate pathogenic genes by whole-genome sequencing technology in a familial primary cutaneous amyloidosis(FPCA).Methods Whole-genome sequencing was conducted on FPCA members of the family,and the candidate gene/site was obtained after the quality control and filtration.Then the candidate variants were confirmed by Sanger sequencing.Results Among 26 candidate gene,the low density lipoprotein receptor-related protein(LRP6)gene plays a vital role in the metabolism of amyloid precursor protein and the production of beta-amyloid protein.The filaggrin 2(FLG2)gene is associated with skin keratinization and barrier function.Besides,a nonsynonymous mutation site c.1538 G>A,which located in exon 11 of the OSMR gene,was found in patients of this family.This mutation lead to the substitution of glycine by aspartic acid at position 513 and was not detected in the healthy members of this family.Conclusion In addition to strong replication for one mutation(p.Gly513 Asp)in OSMR gene for PCA,LRP6 and FLG2 may be the susceptibility genes of PCA,but functional validation is still needed in a larger population.