Analysis of genetic mutations in mevalonate pathway-related genes in patients with porokeratosis

SUN Ruifeng; ZHU Wei; LIAN Shi; CHEN Hui

doi:10.11786/sypfbxzz.1674-1293.20250104

Abstract：Objective To investigate the association between porokeratosis(PK)pathogenesis and mutations in mevalonate pathway-related genes(mevalonate kinase MVK,phosphomevalonate kinase PMVK,mevalonate diphosphate decarboxylase MVD,farnesyl diphosphate synthase FDPS)and analyze the pathogenicity of these mutations.Methods A retrospective study was conducted on PK patients diagnosed at the Dermatology Clinic of Xuanwu Hospital,Capital Medical University,between September 2015 and June 2021.Mevalonate pathway-related genes were sequenced using Sanger sequencing(dideoxynucleotide chain termination method).Pathogenicity predictions for detected mutations were performed using MUpro,Polyphen-2,SIFT scoring,and HOPE protein prediction tools.Results A total of 19 PK patients were enrolled,including 11 sporadic cases and 8 familial cases.Mutations were identified in 6/11 sporadic PK and 7/8 familial PK patients.Eight mutated genes were detected:MVD(c.746T＞C,p.F249S),MVK(IVS4+1G＞A),FDPS(c.733C＞T,p.P245S),MVD(c.875A＞G,p.N292S),MVK(IVS3+5G＞A),MVD(c.149C＞T,p.T50I),MVD(c.1A＞G,p.M1?),and MVD(c.1203A＞G,p.X401W).Among these,MVD(c.746T＞C,p.F249S),MVD(c.875A＞G,p.N292S),MVD(c.1A＞G,p.M1?),and MVK(IVS4+1G＞A)have been previously reported to be associated with PK.MUpro,Polyphen-2,SIFT,and HOPE analysis predicted that all mutations were deleterious,altering protein structure.Conclusion PK pathogenesis is linked to mutations in mevalonate pathway-related genes.This study identified four novel mutations:FDPS(c.733C＞T,p.P245S),MVK(IVS3+5G＞A),MVD(c.149C＞T,p.T50I),and MVD(c.1203A＞G,p.X401W),enriching the genetic database for human PK.MUpro,Polyphen-2,SIFT scoring,and HOPE are valuable tools for predicting mutation pathogenicity.