Exome sequencing identifies<i>SLC17A9</i>pathogenic gene in two Chinese pedigrees with disseminated superficial actinic porokeratosis

Cui, Hongzhou; Li, Longnian; Wang, Wenjun; Shen, Jie; Yue, Zhen; Zheng, Xiaodong; Zuo, Xianbo; Liang, Bo; Gao, Min; Fan, Xing; Yin, Xianyong; Shen, Changbing; Yang, Chao; Zhang, Change; Zhang, Xiaoguang; Sheng, Yujun; Gao, Jinping; Zhu, Zhengwei; Lin, Da; Zhang, Anping; Wang, Zaixing; Liu, Shengxiu; Sun, Liangdan; Yang, Sen; Cui, Yong; Zhang, Xuejun

doi:10.1136/jmedgenet-2014-102486

Cited by 34 publications

(28 citation statements)

References 21 publications

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“…) and disseminated superficial actinic porokeratosis (DSAP) (Cui et al . ). Our study may also help to uncover the molecular mechanisms underlying vesicular ATP release in keratinocytes and the pathogenic mechanisms for DSAP, although further studies are needed to confirm the identity of the vesicles.…”

Section: Discussionmentioning

confidence: 97%

Activation of lysosomal P2X4 by ATP transported into lysosomes via VNUT/SLC17A9 using V‐ATPase generated voltage gradient as the driving force

Zhong

Cao

Sun

et al. 2016

The Journal of Physiology

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Key pointsr SLC17A9 proteins function as a lysosomal ATP transporter responsible for lysosomal ATP accumulation.r P2X4 receptors act as lysosomal ion channels activated by luminal ATP. r SLC17A9-mediated ATP transport across the lysosomal membrane is suppressed by Bafilomycin A1, the V-ATPase inhibitor.r SLC17A9 mainly uses voltage gradient but not pH gradient generated by the V-ATPase as the driving force to transport ATP into the lysosome to activate P2X4.Abstract The lysosome contains abundant ATP which plays important roles in lysosome functions and in cell signalling. Recently, solute carrier family 17 member 9 (SLC17A9, also known as VNUT for vesicular nucleotide transporter) proteins were suggested to function as a lysosomal ATP transporter responsible for lysosomal ATP accumulation, and P2X4 receptors were suggested to be lysosomal ion channels that are activated by luminal ATP. However, the molecular mechanism of SLC17A9 transporting ATP and the regulatory mechanism of lysosomal P2X4 are largely unknown. In this study, we report that SLC17A9-mediated ATP transport across lysosomal membranes is suppressed by Bafilomycin A1, the V-ATPase inhibitor. By measuring P2X4 activity, which is indicative of ATP transport across lysosomal membranes, we further demonstrated that SLC17A9 mainly uses voltage gradient but not pH gradient as the driving force to transport ATP into lysosomes. This study provides a molecular mechanism for lysosomal ATP transport mediated by SLC17A9. It also suggests a regulatory mechanism of lysosomal P2X4 by SLC17A9. Abbreviations Baf-A1, bafilomycin A1; CBX, carbenoxolone; DIDS, 4,4 -diisothiocyano-2,2 -stilbenedisulfonic acid; GPN, glycyl-phenylalanine 2-naphthylamide; Lamp1, lysosomal-associated membrane protein 1; SLC, solute carrier; SLC17A9, solute carrier family 17 member 9; V-ATPase, vacuolar H + -ATPase; VNUT, vesicular nucleotide transporter.

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Section: Discussionmentioning

confidence: 97%

Activation of lysosomal P2X4 by ATP transported into lysosomes via VNUT/SLC17A9 using V‐ATPase generated voltage gradient as the driving force

Zhong

Cao

Sun

et al. 2016

The Journal of Physiology

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“…Porokeratosis encompasses a group of keratinization disorders characterized by circular or annular skin lesions with a distinct hyperkeratotic rim termed the cornoid lamella (Sertznig et al, 2012). Known causative genes are MVD, MVK, PMVK, FDPS, and SLC17A9 (Cui et al, 2014;Zhang et al, 2012;Zhang et al, 2015). Clinically, porokeratosis is classified based on the lesional skin distribution.…”

Section: Introductionmentioning

confidence: 99%

Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes

Kubo

Sasaki

Suzuki

et al. 2019

Journal of Investigative Dermatology

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Patients with disseminated superficial actinic porokeratosis (DSAP) and linear porokeratosis (LP) exhibit monoallelic germline mutations in genes encoding mevalonate pathway enzymes, such as MVD or MVK. Here, we showed that each skin lesion of DSAP exhibited an individual second hit genetic change in the wild-type allele of the corresponding gene specifically in the epidermis, indicating that a postnatal second hit triggering biallelic deficiency of the gene is required for porokeratosis to develop. Most skin lesions exhibited one of two principal second hits, either somatic homologous recombinations rendering the monoallelic mutation biallelic or C>T transition mutations in the wild-type allele. The second hits differed among DSAP lesions but were identical in those of congenital LP, suggesting that DSAP is attributable to sporadic postnatal second hits and congenital LP to a single second hit in the embryonic period. In the characteristic annular skin lesions of DSAP, the central epidermis featured mostly second hit keratinocytes, and that of the annular ring featured a mixture of such cells and naïve keratinocytes, implying that each lesion reflects the clonal expansion of single second hit keratinocytes. DSAP is therefore a benign intraepidermal neoplasia, which can be included in the genetic tumor disorders explicable by Knudson's two-hit hypothesis.

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“…3 Beside the mutations in the mevalonate pathway genes MVK, PMVK, MVD and FDPS, 1,4 mutations in SSH1, SART3 and SLC17A9 have also been suggested to be responsible for DSAP. [5][6][7] However, it is suspected that SSH1 is probably not causal to DSAP for it is not confirmed in other previous studies. While in the current study we reported two novel mutations of SSH1 in 1 familial and 1 sporadic Chinese DSAP patient, and immunohistochemical analysis of anti-Slingshot homolog 1 antibody in one typical patient.…”

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confidence: 74%

Two novel SSH1 mutations in Chinese patients with disseminated superficial actinic porokeratosis and immunohistochemical analysis of anti‐Slingshot homolog 1 antibody in one typical patient

Liu

Wang

et al. 2019

Acad Dermatol Venereol

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Exome sequencing identifiesSLC17A9pathogenic gene in two Chinese pedigrees with disseminated superficial actinic porokeratosis

Abstract: The result identified SLC17A9 as another pathogenic gene for DSAP, which suggests a correlation between the aberrant vesicular nucleotide transporter and the pathogenesis of DSAP.

Cited by 34 publications

References 21 publications

Activation of lysosomal P2X4 by ATP transported into lysosomes via VNUT/SLC17A9 using V‐ATPase generated voltage gradient as the driving force

Activation of lysosomal P2X4 by ATP transported into lysosomes via VNUT/SLC17A9 using V‐ATPase generated voltage gradient as the driving force

Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes

Two novel SSH1 mutations in Chinese patients with disseminated superficial actinic porokeratosis and immunohistochemical analysis of anti‐Slingshot homolog 1 antibody in one typical patient

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