title: Loss-of-function Mutation in PMVK Causes Autosomal Dominant Disseminated Superficial Porokeratosis.
abstract: Disseminated superficial porokeratosis (DSP) is a rare keratinization disorder of the epidermis. It is characterized by keratotic lesions with an atrophic center encircled by a prominent peripheral ridge. We investigated the genetic basis of DSP in two five-generation Chinese families with members diagnosed with DSP. By whole-exome sequencing, we sequencing identified a nonsense variation c.412C > T (p.Arg138*) in the phosphomevalonate kinase gene (PMVK), which encodes a cytoplasmic enzyme catalyzing the conversion of mevalonate 5-phosphate to mevalonate 5-diphosphate in the mevalonate pathway. By co-segregation and haplotype analyses as well as exclusion testing of 500 normal control subjects, we demonstrated that this genetic variant was involved in the development of DSP in both families. We obtained further evidence from studies using HaCaT cells as models that this variant disturbed subcellular localization, expression and solubility of PMVK. We also observed apparent apoptosis in and under the cornoid lamella of PMVK-deficient lesional tissues, with incomplete differentiation of keratinocytes. Our findings suggest that PMVK is a potential novel gene involved in the pathogenesis of DSP and PMVK deficiency or abnormal keratinocyte apoptosis could lead to porokeratosis.
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Jiuxiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, PR China.
authors.forename: Changzheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Han
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Yuexia
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, PR China.
authors.forename: Chun-Jie
authors.initials: CJ
authors.lastname: Liu
authors.affiliation: Hubei Polytechnic Institute, Xiaogan, 432000, PR China.
authors.forename: Su
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Yayun
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Dermatology, Chibi People's Hospital, Hubei, 537300, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Ling
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Meng
authors.initials: M
authors.lastname: Gao
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Yu
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Chang
authors.initials: C
authors.lastname: Li
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Mi
authors.initials: M
authors.lastname: Huang
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Shengjie
authors.initials: S
authors.lastname: Liao
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Xuebin
authors.initials: X
authors.lastname: Hu
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Zhaojing
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Xiliang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, PR China.
authors.forename: An-Yuan
authors.initials: AY
authors.lastname: Guo
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Mugen
authors.initials: M
authors.lastname: Liu
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D002681:China; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D009154:Mutation; D010375:Pedigree; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D017499:Porokeratosis / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D055815:Young Adult
chemical_list: D017856:Phosphotransferases (Phosphate Group Acceptor); C022371:phosphomevalonate kinase