Abstract

Disseminated superficial actinic porokeratosis (DSAP) is an autosomal dominantly inherited epidermal keratinization disorder whose etiology remains unclear. We performed exome sequencing in one unaffected and two affected individuals from a DSAP family. The mevalonate kinase gene (MVK) emerged as the only candidate gene located in previously defined linkage regions after filtering against existing SNP databases, eight HapMap exomes and 1000 Genomes Project data and taking into consideration the functional implications of the mutations. Sanger sequencing in 57 individuals with familial DSAP and 25 individuals with sporadic DSAP identified MVK mutations in 33% and 16% of these individuals (cases), respectively. All 14 MVK mutations identified in our study were absent in 676 individuals without DSAP. Our functional studies in cultured primary keratinocytes suggest that MVK has a role in regulating calcium-induced keratinocyte differentiation and could protect keratinocytes from apoptosis induced by type A ultraviolet radiation. Our results should help advance the understanding of DSAP pathogenesis.

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Acknowledgements

We thank the individuals and their families who participated in this project. This study was funded by Ministry of Education of China (IRT-1046).

Author information

Author notes

    • Sheng-Quan Zhang
    • , Tao Jiang
    • , Min Li
    • , Xin Zhang
    •  & Yun-Qing Ren

    These authors contributed equally to this work.

Affiliations

  1. Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China.

    • Sheng-Quan Zhang
    • , Min Li
    • , Xin Zhang
    • , Yun-Qing Ren
    • , Sheng-Cai Wei
    • , Liang-Dan Sun
    • , Hui Cheng
    • , Yang Li
    • , Xian-Yong Yin
    • , Yuan Liu
    • , Bi-Rong Guo
    • , Hua-Yang Tang
    • , Xian-Fa Tang
    • , Yan-Tao Ding
    • , Jian-Bo Wang
    • , Ping Li
    • , Bao-Yu Wu
    • , Wen Wang
    • , Xiang-Feng Yuan
    • , Jun-Sheng Hou
    • , Wei-Wei Ha
    • , Wen-Ju Wang
    • , Yu-Juan Zhai
    • , Jing Wang
    • , Fang-Fang Qian
    • , Yu-Jun Sheng
    • , Jin-Ping Gao
    • , Bo Liang
    • , Pan Li
    • , Jun Zhu
    • , Feng-Li Xiao
    • , Pei-Guang Wang
    • , Yong Cui
    • , Hui Li
    • , Sheng-Xiu Liu
    • , Min Gao
    • , Xing Fan
    • , Song-Ke Shen
    • , Ming Zeng
    • , Zhong-Yi Yu
    • , Hui-Feng Zhang
    • , Xin Hu
    • , Ke Yang
    • , Jie Wang
    • , Shi-Xiang Zhao
    • , You-Wen Zhou
    • , Jian-Jun Liu
    • , Wei-Dong Du
    • , Sen Yang
    •  & Xue-Jun Zhang
  2. State Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology, Hefei, Anhui, China.

    • Sheng-Quan Zhang
    • , Min Li
    • , Xin Zhang
    • , Yun-Qing Ren
    • , Sheng-Cai Wei
    • , Liang-Dan Sun
    • , Hui Cheng
    • , Yang Li
    • , Xian-Yong Yin
    • , Yuan Liu
    • , Bi-Rong Guo
    • , Hua-Yang Tang
    • , Xian-Fa Tang
    • , Yan-Tao Ding
    • , Jian-Bo Wang
    • , Ping Li
    • , Bao-Yu Wu
    • , Wen Wang
    • , Xiang-Feng Yuan
    • , Jun-Sheng Hou
    • , Wei-Wei Ha
    • , Wen-Ju Wang
    • , Yu-Juan Zhai
    • , Jing Wang
    • , Fang-Fang Qian
    • , Fu-Sheng Zhou
    • , Gang Chen
    • , Xian-Bo Zuo
    • , Xiao-Dong Zheng
    • , Yu-Jun Sheng
    • , Jin-Ping Gao
    • , Bo Liang
    • , Pan Li
    • , Jun Zhu
    • , Feng-Li Xiao
    • , Pei-Guang Wang
    • , Yong Cui
    • , Hui Li
    • , Sheng-Xiu Liu
    • , Min Gao
    • , Xing Fan
    • , Song-Ke Shen
    • , Ming Zeng
    • , Zhong-Yi Yu
    • , Hui-Feng Zhang
    • , Xin Hu
    • , Ke Yang
    • , Jie Wang
    • , Shi-Xiang Zhao
    • , You-Wen Zhou
    • , Jian-Jun Liu
    • , Wei-Dong Du
    • , Sen Yang
    •  & Xue-Jun Zhang
  3. BGI-Shenzhen, Shenzhen, China.

    • Tao Jiang
    • , Guang-Qing Sun
    • , Yu Xu
    • , Jing-Chu Hu
    • , Ting-Ting He
    • , Ying-Rui Li
    • , Huan-Ming Yang
    • , Jian Wang
    •  & Jun Wang
  4. State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.

    • Zheng-Mao Hu
    •  & Kun Xia
  5. Department of Dermatology, Provincial Hospital affiliated to Shandong University, Shandong, China.

    • Zhen-Ying Wang
    •  & Li Zhang
  6. Institute of Life Science, Anhui Medical University, Hefei, Anhui, China.

    • Jian-Jun Liu
  7. Department of Dermatology, No. 2 Hospital, Anhui Medical University, Hefei, Anhui, China.

    • Xue-Jun Zhang

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Contributions

X.-J.Z., S.Y. and Jun Wang conceived of this study and obtained financial support. X.-J.Z., L.-D.S., Y.C., M.G. and X.F. participated in the design of the study and project management. S.-C.W., Z.-M.H., Z.-Y.W., Ping Li, B.-Y.W., W.W., X.-F.Y., J.-S.H., L.Z. and K.X. performed blood sample collection and selection. F.-S.Z., G.C., G.-Q.S., Y.X., J.-C.H. and T.-T.H. performed exome capture and paired-end sequencing. T.J., X.-B.Z., Y.-R.L., H.-M.Y. and Jian Wang performed next-generation sequencing analysis and filtering. X.Z., X.-F.T., W.-W.H., W.-J.W., Y.-J.Z., Jing Wang, F.-F.Q., B.L., J.Z., Z.-Y.Y., H.-F.Z., X.H., K.Y., Jie Wang and S.-X.Z. performed PCR and Sanger sequencing. X.-Y.Y., Y. Liu, B.-R.G., X.-D.Z., P.-G.W., H.L., S.-X.L., S.-K.S. and M.Z. performed other data analyses. S.-Q.Z., M.L., Y.-Q.R., H.C., Y. Li, H.-Y.T., Y.-T.D., J.-B.W., Y.-J.S., J.-P.G., Pan Li and F.-L.X. performed the cell culture and protein expression studies, gene sequencing, protein blot analysis and other function studies. M.L., X.Z., Y.-W.Z., J.-J.L. and W.-D.D. wrote and revised the manuscript. All the authors contributed to the final paper, with X.-J.Z., Jun Wang, S.-Q.Z., T.J., M.L., X.Z. and L.-D.S. having key roles.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jun Wang or Xue-Jun Zhang.

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https://doi.org/10.1038/ng.2409

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