Splicing mutation in MVK is a cause of porokeratosis of Mibelli

Abstract

Porokeratosis is a chronic skin disorder characterized by the presence of patches with elevated, thick, keratotic borders, with histological cornoid lamella. Classic porokeratosis of Mibelli (PM) frequently appears in childhood with a risk of malignant transformation. Disseminated superficial actinic porokeratosis (DSAP) is the most common subtype of porokeratosis with genetic heterogeneities, and mevalonate kinase gene (MVK) mutations have been identified in minor portion of DSAP families of Chinese origin. To confirm the previous findings about MVK mutations in DSAP patients and test MVK's role(s) in PM development, we performed genomic sequence analysis for 3 DSAP families and 1 PM family of Chinese origin. We identified a splicing mutation of MVK gene, designated as c.1039+1G>A, in the PM family. No MVK mutations were found in three DSAP families. Sequence analysis for complementary DNA templates from PM lesions of all patients revealed a mutation at splice donor site of intron 10, designated as c.1039+1G>A, leading to the splicing defect and termination codon 52 amino acids after exon 10. Although no MVK mutations in DSAP patients were found as reported previously, we identified MVK simultaneously responsible for PM development.

Genomic variations of the mevalonate pathway in porokeratosis

“…At least five linkage loci (i.e., 12q23.2-24.1, 15q25.1-26.1, 18p11.3, 1p31.3-p31.1, 16q24.1-24.3) have been reported for the disseminated forms of PK which include DSAP, DSP, porokeratosis palmaris et plantaris disseminata (PPPD), and immunosuppression-induced porokeratosis (ISIP) ( Schamroth et al, 1997 ; Luan et al, 2011 ). However, only one causal gene, the mevalonate kinase gene ( MVK ) at 12q24, has been identified in DSAP and porokeratosis of Mibille (PM) ( Zhang et al, 2012 ; Li and Zhang, 2014 ; Zeng et al, 2014 ). Here we performed genetic analysis in 134 index patients with PK to identify additional causal genes and to establish new parameters for better differential diagnosis of PK.…”

Loss-of-function Mutation in PMVK Causes Autosomal Dominant Disseminated Superficial Porokeratosis

“…PMVK is located at 1q21.3, and it contains five exons and encodes a 192-amino acid protein, which is expressed in many tissues including epidermal cells in human skin. PMVK, which belongs to the nucleoside monophosphate kinase family, converts mevalonate 5-phosphate to mevalonate 5-diphosphate in the mevalonate pathway, following the biochemical reaction catalyzed by the MVK kinase 11 , which is encoded by MVK, a causal gene already known to be associated with DSAP 3 and PM 5 .…”

“…Although porokeratosis was first described more than one hundred years ago, its etiology and pathogenesis are still not fully understood. The mevalonate kinase gene ( MVK ) (MIM: 251170) 2 and the solute carrier family 17 (vesicular nucleotide transporter), member 9 gene ( SLC17A9 ) (MIM: 612107) 2 have been identified to be the causal genes for DSAP 3 4 and PM 5 . Two linkage loci have been mapped to chromosome 18p11.3 and 12q21.2-24.21, respectively, in two Chinese families with DSP affected members 6 7 .…”

Identification of a novel mutation in the mechanoreceptor-encoding gene CXCR1 in patients with keloid

“…Quantitative polymerase chain reaction (qPCR) was performed on an ABI 7500 thermocycler (Applied Biosystems, Foster City, CA, USA) using 1 µL of cDNA and SYBR Green real-time PCR Master Mix (Takara, China). GAPDH was used as a housekeeping gene for normalization as previously described [17]. The primers are listed in Table S2.…”