Mol Biol Rep (2014) 41:7229–7233 DOI 10.1007/s11033-014-3609-4
A novel MVK missense mutation in one Chinese family with disseminated superficial actinic porokeratosis Wen-sheng Lu • Xiao-dong Zheng • Xiu-hua Yao • Lan-fang Zhang • Mu-Qiu Wang • Fa-Xing Jiang • Si-Ping Zhang • Bai Hu
Received: 7 June 2013 / Accepted: 12 July 2014 / Published online: 25 July 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Disseminated superficial actinic porokeratosis (DSAP) is a severe chronic autosomal dominant cutaneous disorder with high genetic heterogeneity. mevalonate kinase, (MVK) a gene know to play an important role in regulation of calcium-induced keratinocyte differentiation and proliferation, has recently been suggested as the disease-causing gene for DSAP. Here we report a direct sequencing analysis of this gene in 3 DSAP families, 6 sporadic cases, and 100 unrelated healthy controls. We detected a heterozygous T to A transition at nucleotide 205 in exon 3 of MVK gene in one familial case. This mutation will result in an amino acid change at codon 69 (P.Ser69Thr), which is from a serine codon (TCA) to a threonine codon (ACA). No such mutation was detected in the unaffected family members or the 100 unrelated healthy controls. Our results demonstrated a novel missense mutation in MVK gene. This will be valuable for the diagnosis of DSAP as well as for genetic counseling and prenatal diagnosis of affected families.
Wen-sheng Lu and Xiao-dong Zheng have contributed equally to this study. W. Lu (&) X. Yao L. Zhang F.-X. Jiang S.-P. Zhang B. Hu Department of Dermatology, Anhui Provincial Hospital, No. 17, Lujiang Road, Hefei 230001, China e-mail: [email protected] X. Zheng Department of Dermatology, Anhui Medical University, Hefei 230032, China M.-Q. Wang Department of Electrocardiography, Anhui Provincial Hospital, No. 17, Lujiang Road, Hefei 230001, China
Keywords Disseminated superficial actinic porokeratosis Mevalonate kinase gene Mutation analysis
Introduction As the most common subtype of porokeratosis, disseminated superficial actinic porokeratosis (DSAP) has been recognized for more than 50 years since its first description [1]. DSAP is characterized by multiple small, annular, anhidrotic, keratotic lesions in the skin that exposes to sun frequently. The lesions began to develop in adolescence with near complete penetrance during the third to fourth decades of life [2]. Etiologically, DSAP is a severe chronic autosomal dominant cutaneous disorder with high genetic heterogeneity. Previous studies have shown that DSAP was linked to five chromosome loci (12q23.2–24.1, 12q24.1– q24.2, 15q25.1–26.1, 1p31.3–p31.1 and 16q24.1–24.3) [3– 6]. Two genes, SSH1 and SART3 have also been suggested as candidate disease-causing genes for DSAP, as SSH1 and SART3 mutations were identified in two Chinese DSAP families [3–6]. However, the findings were not supported by subsequent studies in additional patients with DSAP. The variations in the SSH1gene may only reflect an innocuous polymorphism rather than a true mutation [6–8]. The mevalonate kinase (MVK) gene has recently been demonstrated as the disease-causing gene for DSAP [8–10]. MVK gene is located at chromosome 12q24 and contains ten coding exons and one noncoding exon (exon 1) spanning over 21 kb. The MVK is a 396-resi-due protein encoded by two MVK transcripts that differ in the 50 -untranslated region (UTR). MVK plays an important role in the mevalonate pathway [9]. In this study, we obtained 3 families and 6 sporadic cases with DSAP. By direct sequencing, we identified a novel missense mutation in the MVK gene in one
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Chinese family with DSAP. We also confirmed a previously reported mutation in a sporadic DSAP.
Materials and methods DSAP cases and controls All the patients diagnosed as DSAP were recruited from the Department of Dermatology, Anhui Provincial Hospital, China. These patients include 3 families and 6 sporadic cases. The diagnosis of DSAP was based on clinical characteristics and histological examination that were described in detail in the result section. The unaffected individuals from the 3 families with DSAP and 100 unrelated healthy individuals were used as controls.
Mol Biol Rep (2014) 41:7229–7233
and its flanking 200-bp intronic sequence of the MVK gene (GenBank accession number NG_007702.1). The PCR conditions were: DNA Taq Polymerase activation at 94 °C for 3 min, followed by 40 cycles. Each cycle has a denaturation at 94 °C for 40 s, annealing at 57 °C for 50 s and extension at 72 °C for 50 s, except that in the first 14 cycles the annealing temperature decreased from 64 °C to 57 °C by 0.5 °C per cycle, and the final extension was 72 °C for 10 min. The PCR products were purified using Exonuclease I (New England Biolabs UK) and Shrimp Alkaline Phosphatase (Promega USA), and subjected to direct sequencing on ABI PRISM 3730 automated sequencer (Applied Biosystems). Sequence comparisons and analysis were performed by Phred-Phrap-Consed program, version 12.0. The study was approved by the Ethical Committee of the Anhui Provincial Hospital and was conducted according to Declaration of Helsinki Principles.
PCR and direct sequencing Histopathological analysis of DSAP After informed consent, genomic DNA was isolated from peripheral blood of the patients and controls using a Qiagen kit (Hilden, Germany). PCR was performed using above genomic DNA as a template and the MVK gene-specific primers. The primers cover each of the 10 coding exons
Patients suspicious of having DSAP were determined and selected by experienced dermatologists. Typical annular, anhidrotic, and keratotic lesions from proband, affected family members and sporadic cases were subjected to skin
Fig. 1 a This picture shows the lower limb of one of the sporadic cases b the right one comes from the proband who carries the missense mutation c Biopsy of an individual shows no cornoid lamella in the upper part of the dermis. d Biopsy of a patient revealed a typical cornoid lamella in the epidermis. The granular layer was
absent or decreased in this patient. Mild lymphocytic infiltration around the blood vessels in the upper dermis was also present. The images were visualized using hematoxylin and eosin (H&E) staining and are shown at either 940 or 9100 magnification. The image on the right is an enlarged version of the boxed area on the left
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Mol Biol Rep (2014) 41:7229–7233
biopsy and standard hematoxylin and eosine (H&E) staining. Histological examination and analysis were conducted by experienced skin pathologist. Diagnosis of DSAP was based on the clinical and histopathological findings.
Conservation analysis between species We performed a blastp searches by using the polypeptide of MVK to get 24 amino acid sequences of 24 species. Then, all the sequences were aligned by using MEGA4.0 (http://www.megasoftware.net/) with default settings. The aligned sequences were examined of their amino acid residues. The aligned sequences were shaded in the GeneDoc Multiple Sequence Alignment Editor and Shading Utility (ver. 2.6.02) and copied to an RTF (rich text file) for further annotation.
Fig. 2 a This patient had a T ? A transition at position 205 of the MVK gene, which results in serine acid codon 69 (TCA) substituted by a threonine acid codon (ACA); p.Ser69Thr; b a cytosine insertion
7231
Results Clinical and histological characteristics of DSAP We collected 3 familial and 6 sporadic cases of DSAP. Typically, these patients displayed multiple small, annular, anhidrotic, and keratotic lesions that are predominantly in sun-exposed areas of the skin. The photograph on the left showed the lesions of the right limb of a representative sporadic DSAP (Fig. 1a), while the right one shows a male patient (proband of the familial DSAP) who carries the missense mutation (Fig. 1b). We also performed biopsy and histological examination/staining of the lesions from patients and controls using standard protocols. As illustrated in Fig. 1c, no cornoid lamella was shown in the upper part of the dermis of control samples, while biopsy of DSAP lesions revealed a typical cornoid lamella in the epidermis. The granular layer was absent or decreased with
between position 417 and position 418 of the MVK gene, which results in a frameshift mutation; p.Gly140ArgfsX47
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Mol Biol Rep (2014) 41:7229–7233
DSAP is a subtype of porokeratosis that occurs due to genetic factors, ultraviolet (UV) exposure, and other unknown factors. Although the etiology of DSAP remains unclear, however, MVK gene has recently been suggested as the candidate gene causing DSAP [8–10]. MVK gene
encodes a 396-residue protein, the MVK, which is an important enzyme in the mevalonate pathway. The mevalonate pathway is vital for multiple cellular processes and provides cells with essential bioactive molecules [11, 12]. The intermediate products of the mevalonate pathway are the short-chain isoprenoids farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These molecules covalently attach to small G proteins and act as molecular switches in various biochemical pathways. Cholesterol, another product of the mevalonate pathway, is known to be essential for skin barrier function. A recent study has also reported the involvement of the mevalonate system in regulation of keratin gene expression [12]. These findings support that the mevalonate pathway might be a crucial metabolic pathway in skin. To date, multiple MVK gene mutations have been demonstrated in cases with DSAP [8–10]. In this study, we performed a direct DNA sequencing of MVK gene in 3 familial and 6 sporadic cases as well as 100 unrelated healthy controls. We detected a novel missense mutation in exon 3 of MVK gene. We also confirmed an insertion mutation that was previously reported in familial cases. However, we did not detect any other mutation of MVK gene in the remaining 2 DSAP families and 5 sporadic cases. This may reflect the genetic heterogeneity of DSAP. Previous studies have indicated that the same genotype of DSAP may have different phenotypes, possibly due to interactions between genetic and environmental factors [9]. Meanwhile, different genotypes of DSAP may show the same phenotype which needs further investigation (Fig. 3).
Fig. 3 Multiple sequence alignment of 24 species amino acid sequence of MVK gene. The heterozygous T to A transition at nucleotide 205 in exon 3 of MVK gene is indicated by asterisks. The
amino acid at codon 69 is highly conserved across species of primates (Pan troglodytes, Nomascus leucogenys, Ceratotherium simum simum)
mild lymphocytic infiltration in the upper dermis, (Fig 1d). Above all, the clinical and histological characteristics of the cases supported the clinical diagnosis of DSAP. Mutation analysis of DSAP cases All the coding exons of MVK gene including 200 bp flanking intronic sequences were amplified by polymerase chain reaction. The PCR products were subjected to direct sequencing and analyzed by comparison with the NCBI (National Center for Biotechnology Information) database. The result showed that a familial 40-year-old male patient carries a missense mutation in exon 3 (c. 205A [ T) which was not found in previous studies (Fig. 2a). This mutation cause an amino acid change at codon 69 (p.Ser69Thr.) which is from a serine codon (TCA) to a threonine codon (ACA). Meanwhile, we detected an insertion in exon 5 (c.417_418insC) in a sporadic case (Fig. 2b) which has been reported previously [9]. No mutations were detected in the remaining 2 DSAP families and 5 sporadic cases, the non-affected family members and the one hundred healthy controls.
Discussion
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Mol Biol Rep (2014) 41:7229–7233
The novel missense mutation (c.205A [ T) in exon 3 will cause an amino acid change at codon 69(P.Ser69Thr). This change is very likely to affect the structure and function of the protein encoded by MVK, as.codon 69 is highly conserved across species of primates, including Pan troglodytes, Nomascus leucogenys, and Ceratotherium simum simum) [9]. However, the exact mechanism of MVK participating in the pathogenesis of DSAP remains to be determined. In summary, we report a novel mutation of the MVK gene in Chinese patients with DSAP. Our result confirms the involvement of MVK gene in human DSAP. This study should be useful for genetic counseling and prenatal diagnosis of DSAP in affected families. Acknowledgments We would like to thank the patients for participating in the study. This study was funded by the National Natural Youth Science Foundation (81101185) and Anhui Provincial Natural Science Foundation in year 2015. Conflict of interest interest.
The authors have no financial conflict of
References 1. Liu P, Zhang S, Yao Q et al (2008) Identification of a genetic locus for autosomal dominant disseminated superficial actinic porokeratosis on chromosome 1p31.3–p31.1. Hum Genet 123:507–513
7233 2. Xia JH, Yang YF, Deng H et al (2000) Identification of a locus for disseminated superficial actinic porokeratosis at chromosome 12q23.2–24.1. J Invest Dermatol 114:1071–1074 3. Zhang ZH, Niu ZM, Yuan WT et al (2005) A mutation in SART3 gene in a Chinese pedigree with disseminated superficial actinic porokeratosis. Br J Dermatol 152:658–663 4. Xia K, Deng H, Xia JH et al (2002) A novel locus (DSAP2) for disseminated superficial actinic porokeratosis maps to chromosome 15q25.1–26.1. Br J Dermatol 147:650–654 5. Luan J, Niu Z, Zhang J et al (2011) A novel locus for disseminated superficial actinic porokeratosis maps to chromosome 16q24.1–24.3. Hum Genet 129:329–334 6. Frank J, van Geel M, van Steensel MA (2007) Loss of heterozygosity studies on chromosome 12q in disseminated superficial actinic porokeratosis: lessons to be learned. J Invest Dermatol 127:2058–2059 7. Zhang Z, Niu Z, Yuan W et al (2004) Fine mapping and identification of a candidate gene SSH1 in disseminated superficial actinic porokeratosis. Hum Mutat 24(5):438 8. Zhou Y, Liu J, Fu X et al (2013) Identification of three novel frameshift mutations of the MVK gene in four Chinese families with disseminated superficial actinic porokeratosis. Br J Dermatol 169(1):193–195 9. Zhang SQ, Jiang T, Li M et al (2012) Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis. Nat Genet 44:1156–1160 10. Dai J, Chen M, Fu X et al (2013) Mutation analysis of the MVK gene in Chinese patients with disseminated superficial actinic porokeratosis. J Dermatol Sci 72(3):320–322 11. Bouwstra JA, Ponec M (2006) The skin barrier in healthy and diseased state Biochim. Biophys Acta 1758:2080–2095 12. Zhao Y, Gartner U, Smith FJ, McLean WH (2011) Statins downregulate K6a promoter activity: a possible therapeutic avenue for pachyonychia congenita. J Invest Dermatol 131:1045–1052
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A novel MVK missense mutation in one Chinese family with disseminated superficial actinic porokeratosis Wen-sheng Lu • Xiao-dong Zheng • Xiu-hua Yao • Lan-fang Zhang • Mu-Qiu Wang • Fa-Xing Jiang • Si-Ping Zhang • Bai Hu
Received: 7 June 2013 / Accepted: 12 July 2014 / Published online: 25 July 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Disseminated superficial actinic porokeratosis (DSAP) is a severe chronic autosomal dominant cutaneous disorder with high genetic heterogeneity. mevalonate kinase, (MVK) a gene know to play an important role in regulation of calcium-induced keratinocyte differentiation and proliferation, has recently been suggested as the disease-causing gene for DSAP. Here we report a direct sequencing analysis of this gene in 3 DSAP families, 6 sporadic cases, and 100 unrelated healthy controls. We detected a heterozygous T to A transition at nucleotide 205 in exon 3 of MVK gene in one familial case. This mutation will result in an amino acid change at codon 69 (P.Ser69Thr), which is from a serine codon (TCA) to a threonine codon (ACA). No such mutation was detected in the unaffected family members or the 100 unrelated healthy controls. Our results demonstrated a novel missense mutation in MVK gene. This will be valuable for the diagnosis of DSAP as well as for genetic counseling and prenatal diagnosis of affected families.
Wen-sheng Lu and Xiao-dong Zheng have contributed equally to this study. W. Lu (&) X. Yao L. Zhang F.-X. Jiang S.-P. Zhang B. Hu Department of Dermatology, Anhui Provincial Hospital, No. 17, Lujiang Road, Hefei 230001, China e-mail: [email protected] X. Zheng Department of Dermatology, Anhui Medical University, Hefei 230032, China M.-Q. Wang Department of Electrocardiography, Anhui Provincial Hospital, No. 17, Lujiang Road, Hefei 230001, China
Keywords Disseminated superficial actinic porokeratosis Mevalonate kinase gene Mutation analysis
Introduction As the most common subtype of porokeratosis, disseminated superficial actinic porokeratosis (DSAP) has been recognized for more than 50 years since its first description [1]. DSAP is characterized by multiple small, annular, anhidrotic, keratotic lesions in the skin that exposes to sun frequently. The lesions began to develop in adolescence with near complete penetrance during the third to fourth decades of life [2]. Etiologically, DSAP is a severe chronic autosomal dominant cutaneous disorder with high genetic heterogeneity. Previous studies have shown that DSAP was linked to five chromosome loci (12q23.2–24.1, 12q24.1– q24.2, 15q25.1–26.1, 1p31.3–p31.1 and 16q24.1–24.3) [3– 6]. Two genes, SSH1 and SART3 have also been suggested as candidate disease-causing genes for DSAP, as SSH1 and SART3 mutations were identified in two Chinese DSAP families [3–6]. However, the findings were not supported by subsequent studies in additional patients with DSAP. The variations in the SSH1gene may only reflect an innocuous polymorphism rather than a true mutation [6–8]. The mevalonate kinase (MVK) gene has recently been demonstrated as the disease-causing gene for DSAP [8–10]. MVK gene is located at chromosome 12q24 and contains ten coding exons and one noncoding exon (exon 1) spanning over 21 kb. The MVK is a 396-resi-due protein encoded by two MVK transcripts that differ in the 50 -untranslated region (UTR). MVK plays an important role in the mevalonate pathway [9]. In this study, we obtained 3 families and 6 sporadic cases with DSAP. By direct sequencing, we identified a novel missense mutation in the MVK gene in one
123
7230
Chinese family with DSAP. We also confirmed a previously reported mutation in a sporadic DSAP.
Materials and methods DSAP cases and controls All the patients diagnosed as DSAP were recruited from the Department of Dermatology, Anhui Provincial Hospital, China. These patients include 3 families and 6 sporadic cases. The diagnosis of DSAP was based on clinical characteristics and histological examination that were described in detail in the result section. The unaffected individuals from the 3 families with DSAP and 100 unrelated healthy individuals were used as controls.
Mol Biol Rep (2014) 41:7229–7233
and its flanking 200-bp intronic sequence of the MVK gene (GenBank accession number NG_007702.1). The PCR conditions were: DNA Taq Polymerase activation at 94 °C for 3 min, followed by 40 cycles. Each cycle has a denaturation at 94 °C for 40 s, annealing at 57 °C for 50 s and extension at 72 °C for 50 s, except that in the first 14 cycles the annealing temperature decreased from 64 °C to 57 °C by 0.5 °C per cycle, and the final extension was 72 °C for 10 min. The PCR products were purified using Exonuclease I (New England Biolabs UK) and Shrimp Alkaline Phosphatase (Promega USA), and subjected to direct sequencing on ABI PRISM 3730 automated sequencer (Applied Biosystems). Sequence comparisons and analysis were performed by Phred-Phrap-Consed program, version 12.0. The study was approved by the Ethical Committee of the Anhui Provincial Hospital and was conducted according to Declaration of Helsinki Principles.
PCR and direct sequencing Histopathological analysis of DSAP After informed consent, genomic DNA was isolated from peripheral blood of the patients and controls using a Qiagen kit (Hilden, Germany). PCR was performed using above genomic DNA as a template and the MVK gene-specific primers. The primers cover each of the 10 coding exons
Patients suspicious of having DSAP were determined and selected by experienced dermatologists. Typical annular, anhidrotic, and keratotic lesions from proband, affected family members and sporadic cases were subjected to skin
Fig. 1 a This picture shows the lower limb of one of the sporadic cases b the right one comes from the proband who carries the missense mutation c Biopsy of an individual shows no cornoid lamella in the upper part of the dermis. d Biopsy of a patient revealed a typical cornoid lamella in the epidermis. The granular layer was
absent or decreased in this patient. Mild lymphocytic infiltration around the blood vessels in the upper dermis was also present. The images were visualized using hematoxylin and eosin (H&E) staining and are shown at either 940 or 9100 magnification. The image on the right is an enlarged version of the boxed area on the left
123
Mol Biol Rep (2014) 41:7229–7233
biopsy and standard hematoxylin and eosine (H&E) staining. Histological examination and analysis were conducted by experienced skin pathologist. Diagnosis of DSAP was based on the clinical and histopathological findings.
Conservation analysis between species We performed a blastp searches by using the polypeptide of MVK to get 24 amino acid sequences of 24 species. Then, all the sequences were aligned by using MEGA4.0 (http://www.megasoftware.net/) with default settings. The aligned sequences were examined of their amino acid residues. The aligned sequences were shaded in the GeneDoc Multiple Sequence Alignment Editor and Shading Utility (ver. 2.6.02) and copied to an RTF (rich text file) for further annotation.
Fig. 2 a This patient had a T ? A transition at position 205 of the MVK gene, which results in serine acid codon 69 (TCA) substituted by a threonine acid codon (ACA); p.Ser69Thr; b a cytosine insertion
7231
Results Clinical and histological characteristics of DSAP We collected 3 familial and 6 sporadic cases of DSAP. Typically, these patients displayed multiple small, annular, anhidrotic, and keratotic lesions that are predominantly in sun-exposed areas of the skin. The photograph on the left showed the lesions of the right limb of a representative sporadic DSAP (Fig. 1a), while the right one shows a male patient (proband of the familial DSAP) who carries the missense mutation (Fig. 1b). We also performed biopsy and histological examination/staining of the lesions from patients and controls using standard protocols. As illustrated in Fig. 1c, no cornoid lamella was shown in the upper part of the dermis of control samples, while biopsy of DSAP lesions revealed a typical cornoid lamella in the epidermis. The granular layer was absent or decreased with
between position 417 and position 418 of the MVK gene, which results in a frameshift mutation; p.Gly140ArgfsX47
123
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Mol Biol Rep (2014) 41:7229–7233
DSAP is a subtype of porokeratosis that occurs due to genetic factors, ultraviolet (UV) exposure, and other unknown factors. Although the etiology of DSAP remains unclear, however, MVK gene has recently been suggested as the candidate gene causing DSAP [8–10]. MVK gene
encodes a 396-residue protein, the MVK, which is an important enzyme in the mevalonate pathway. The mevalonate pathway is vital for multiple cellular processes and provides cells with essential bioactive molecules [11, 12]. The intermediate products of the mevalonate pathway are the short-chain isoprenoids farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These molecules covalently attach to small G proteins and act as molecular switches in various biochemical pathways. Cholesterol, another product of the mevalonate pathway, is known to be essential for skin barrier function. A recent study has also reported the involvement of the mevalonate system in regulation of keratin gene expression [12]. These findings support that the mevalonate pathway might be a crucial metabolic pathway in skin. To date, multiple MVK gene mutations have been demonstrated in cases with DSAP [8–10]. In this study, we performed a direct DNA sequencing of MVK gene in 3 familial and 6 sporadic cases as well as 100 unrelated healthy controls. We detected a novel missense mutation in exon 3 of MVK gene. We also confirmed an insertion mutation that was previously reported in familial cases. However, we did not detect any other mutation of MVK gene in the remaining 2 DSAP families and 5 sporadic cases. This may reflect the genetic heterogeneity of DSAP. Previous studies have indicated that the same genotype of DSAP may have different phenotypes, possibly due to interactions between genetic and environmental factors [9]. Meanwhile, different genotypes of DSAP may show the same phenotype which needs further investigation (Fig. 3).
Fig. 3 Multiple sequence alignment of 24 species amino acid sequence of MVK gene. The heterozygous T to A transition at nucleotide 205 in exon 3 of MVK gene is indicated by asterisks. The
amino acid at codon 69 is highly conserved across species of primates (Pan troglodytes, Nomascus leucogenys, Ceratotherium simum simum)
mild lymphocytic infiltration in the upper dermis, (Fig 1d). Above all, the clinical and histological characteristics of the cases supported the clinical diagnosis of DSAP. Mutation analysis of DSAP cases All the coding exons of MVK gene including 200 bp flanking intronic sequences were amplified by polymerase chain reaction. The PCR products were subjected to direct sequencing and analyzed by comparison with the NCBI (National Center for Biotechnology Information) database. The result showed that a familial 40-year-old male patient carries a missense mutation in exon 3 (c. 205A [ T) which was not found in previous studies (Fig. 2a). This mutation cause an amino acid change at codon 69 (p.Ser69Thr.) which is from a serine codon (TCA) to a threonine codon (ACA). Meanwhile, we detected an insertion in exon 5 (c.417_418insC) in a sporadic case (Fig. 2b) which has been reported previously [9]. No mutations were detected in the remaining 2 DSAP families and 5 sporadic cases, the non-affected family members and the one hundred healthy controls.
Discussion
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Mol Biol Rep (2014) 41:7229–7233
The novel missense mutation (c.205A [ T) in exon 3 will cause an amino acid change at codon 69(P.Ser69Thr). This change is very likely to affect the structure and function of the protein encoded by MVK, as.codon 69 is highly conserved across species of primates, including Pan troglodytes, Nomascus leucogenys, and Ceratotherium simum simum) [9]. However, the exact mechanism of MVK participating in the pathogenesis of DSAP remains to be determined. In summary, we report a novel mutation of the MVK gene in Chinese patients with DSAP. Our result confirms the involvement of MVK gene in human DSAP. This study should be useful for genetic counseling and prenatal diagnosis of DSAP in affected families. Acknowledgments We would like to thank the patients for participating in the study. This study was funded by the National Natural Youth Science Foundation (81101185) and Anhui Provincial Natural Science Foundation in year 2015. Conflict of interest interest.
The authors have no financial conflict of
References 1. Liu P, Zhang S, Yao Q et al (2008) Identification of a genetic locus for autosomal dominant disseminated superficial actinic porokeratosis on chromosome 1p31.3–p31.1. Hum Genet 123:507–513
7233 2. Xia JH, Yang YF, Deng H et al (2000) Identification of a locus for disseminated superficial actinic porokeratosis at chromosome 12q23.2–24.1. J Invest Dermatol 114:1071–1074 3. Zhang ZH, Niu ZM, Yuan WT et al (2005) A mutation in SART3 gene in a Chinese pedigree with disseminated superficial actinic porokeratosis. Br J Dermatol 152:658–663 4. Xia K, Deng H, Xia JH et al (2002) A novel locus (DSAP2) for disseminated superficial actinic porokeratosis maps to chromosome 15q25.1–26.1. Br J Dermatol 147:650–654 5. Luan J, Niu Z, Zhang J et al (2011) A novel locus for disseminated superficial actinic porokeratosis maps to chromosome 16q24.1–24.3. Hum Genet 129:329–334 6. Frank J, van Geel M, van Steensel MA (2007) Loss of heterozygosity studies on chromosome 12q in disseminated superficial actinic porokeratosis: lessons to be learned. J Invest Dermatol 127:2058–2059 7. Zhang Z, Niu Z, Yuan W et al (2004) Fine mapping and identification of a candidate gene SSH1 in disseminated superficial actinic porokeratosis. Hum Mutat 24(5):438 8. Zhou Y, Liu J, Fu X et al (2013) Identification of three novel frameshift mutations of the MVK gene in four Chinese families with disseminated superficial actinic porokeratosis. Br J Dermatol 169(1):193–195 9. Zhang SQ, Jiang T, Li M et al (2012) Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis. Nat Genet 44:1156–1160 10. Dai J, Chen M, Fu X et al (2013) Mutation analysis of the MVK gene in Chinese patients with disseminated superficial actinic porokeratosis. J Dermatol Sci 72(3):320–322 11. Bouwstra JA, Ponec M (2006) The skin barrier in healthy and diseased state Biochim. Biophys Acta 1758:2080–2095 12. Zhao Y, Gartner U, Smith FJ, McLean WH (2011) Statins downregulate K6a promoter activity: a possible therapeutic avenue for pachyonychia congenita. J Invest Dermatol 131:1045–1052
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