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Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis


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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Figure 1: Pedigree, clinical phenotype and mutation information of family 1, which was used for the exome sequencing analysis.
Figure 2: Genomic structure of human MVK and the predicted functional domains of the mevalonate kinase protein showing the 14 MVK mutations found to be associated with DSAP.
Figure 3: The affect of MVK expression on the proliferation, differentiation and apoptosis of keratinocytes.

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

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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.

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Correspondence to Jun Wang or Xue-Jun Zhang.

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The authors declare no competing financial interests.

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Supplementary Figures 1–6, Supplementary Tables 1–5 and Supplementary Note. (PDF 1266 kb)

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Zhang, SQ., Jiang, T., Li, M. et al. Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis. Nat Genet 44, 1156–1160 (2012).

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