title: Genomic variations of the mevalonate pathway in porokeratosis.
abstract: Porokeratosis (PK) is a heterogeneous group of keratinization disorders. No causal genes except MVK have been identified, even though the disease was linked to several genomic loci. Here, we performed massively parallel sequencing and exonic CNV screening of 12 isoprenoid genes in 134 index PK patients (61 familial and 73 sporadic) and identified causal mutations in three novel genes (PMVK, MVD, and FDPS) in addition to MVK in the mevalonate pathway. Allelic expression imbalance (AEI) assays were performed in 13 lesional tissues. At least one mutation in one of the four genes in the mevalonate pathway was found in 60 (98%) familial and 53 (73%) sporadic patients, which suggests that isoprenoid biosynthesis via the mevalonate pathway may play a role in the pathogenesis of PK. Significantly reduced expression of the wild allele was common in lesional tissues due to gene conversion or some other unknown mechanism. A G-to-A RNA editing was observed in one lesional tissue without AEI. In addition, we observed correlations between the mutations in the four mevalonate pathway genes and clinical manifestations in the PK patients, which might support a new and simplified classification of PK under the guidance of genetic testing.
authors.affiliation: Department of Dermatology, Huashan Hospital, Shanghai Medical College of Fudan University, Shanghai, China.
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Caihua
authors.initials: C
authors.lastname: Li
authors.affiliation: Shanghai Dermatology Hospital, Shanghai, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Wu
authors.affiliation: Genesky Biotechnologies Inc, Shanghai, China.
authors.forename: Ruixiao
authors.initials: R
authors.lastname: Ma
authors.affiliation: Department of Dermatology, Huashan Hospital, Shanghai Medical College of Fudan University, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Luan
authors.affiliation: Genesky Biotechnologies Inc, Shanghai, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.affiliation: Institute of Dermatology, Chinese Academy of Medical Sciences, Nanjing, China.
authors.forename: Weida
authors.initials: W
authors.lastname: Liu
authors.affiliation: Genesky Biotechnologies Inc, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Henan Provincial People's Hospital, Zhengzhou, China.
authors.forename: Shoumin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Genesky Biotechnologies Inc, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
authors.affiliation: Genesky Biotechnologies Inc, Shanghai, China.
authors.forename: Wenlian
authors.initials: W
authors.lastname: Hua
authors.affiliation: Shenzhen Ruimin Dermatology Hospital, Shenzhen, China.
authors.forename: Min
authors.initials: M
authors.lastname: Fan
authors.affiliation: Genesky Biotechnologies Inc, Shanghai, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Peng
authors.affiliation: Department of Dermatology, Central Hospital of China National Petroleum Corp, Langfang, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Dermatology, Tongji Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Ningjing
authors.initials: N
authors.lastname: Song
authors.affiliation: Department of Dermatology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Xinling
authors.initials: X
authors.lastname: Bi
authors.affiliation: Department of Dermatology, Huashan Hospital, Shanghai Medical College of Fudan University, Shanghai, China.
authors.forename: Chaoying
authors.initials: C
authors.lastname: Gu
authors.affiliation: Department of Dermatology, Huashan Hospital, Shanghai Medical College of Fudan University, Shanghai, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Huashan Hospital, Shanghai Medical College of Fudan University, Shanghai, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Dermatology, Huashan Hospital, Shanghai Medical College of Fudan University, Shanghai, China.
authors.forename: Lianjun
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Dermatology, Huashan Hospital, Shanghai Medical College of Fudan University, Shanghai, China.
authors.forename: Leihong
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Department of Dermatology, Huashan Hospital, Shanghai Medical College of Fudan University, Shanghai, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Dermatology, Huashan Hospital, Shanghai Medical College of Fudan University, Shanghai, China.
authors.forename: Zhizhong
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Genesky Biotechnologies Inc, Shanghai, China.
authors.forename: Zhengwen
authors.initials: Z
authors.lastname: Jiang
mesh_terms: D002262:Carboxy-Lyases / Q000235:genetics; D051228:Geranyltranstransferase / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008798:Mevalonic Acid / Q000378:metabolism*; D050505:Mutant Proteins / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000235:genetics; D017499:Porokeratosis / Q000235:genetics*
chemical_list: D050505:Mutant Proteins; D051228:Geranyltranstransferase; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D017856:Phosphotransferases (Phosphate Group Acceptor); C022371:phosphomevalonate kinase; D002262:Carboxy-Lyases; C022503:pyrophosphomevalonate decarboxylase; D008798:Mevalonic Acid
keywords: genetic testing; human; human biology; medicine; mevalonate pathway; porokeratosis