Advertisement
Journal of Investigative Dermatology Home

Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis

  • Lihi Atzmony
    Affiliations
    Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA

    Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA

    Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Search for articles by this author
  • Keith A. Choate
    Correspondence
    Correspondence: Keith A. Choate, Departments of Dermatology, Genetics, and Pathology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
    Affiliations
    Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA

    Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA

    Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
    Search for articles by this author
      Familial and sporadic porokeratosis are associated with germline heterozygous mutations in mevalonate pathway genes. Kubo et al. show that each skin lesion of disseminated superficial actinic porokeratosis originates from a postnatal keratinocyte clone with a different second-hit genetic event in the wild-type allele of the corresponding gene. They also confirm that linear porokeratosis derives from a single prenatal clone of keratinocytes with a second-hit genetic event.
      • Germline heterozygous mutations in mevalonate pathway genes are associated with familial and sporadic porokeratosis.
      • Somatic second-hit mutations in mevalonate pathway genes cause linear porokeratosis (LP) and disseminated superficial actinic porokeratosis (DSAP) skin lesions.
      • While in LP the second-hit is an embryonic event, in DSAP it occurs in the postnatal period and can be caused by UV exposure, which emphasizes the importance of sun protection in the prevention of DSAP skin lesions.
      Porokeratosis is a phenotypically heterogeneous disorder characterized by the histopathological feature cornoid lamella, which is a vertical column of parakeratosis situated above dyskeratotic cells within the granular layer (
      • Biswas A.
      Cornoid lamellation revisited: apropos of porokeratosis with emphasis on unusual clinicopathological variants.
      ). Classically, four clinical variants are recognized: disseminated superficial actinic porokeratosis (DSAP), disseminated superficial porokeratosis, porokeratosis palmaris et plantaris disseminata, and linear porokeratosis (LP), with DSAP being the most common variant. Several subtypes can coexist in one individual (
      • Zhang Z.
      • Li C.
      • Wu F.
      • Ma R.
      • Luan J.
      • Yang F.
      • et al.
      Genomic variations of the mevalonate pathway in porokeratosis.
      ). Porokeratosis is considered to be a premalignant condition, and higher rates of skin cancer have been described in linear and large plaques, with the most common malignancy being squamous cell carcinoma (
      • Sasson M.
      • Krain A.D.
      Porokeratosis and cutaneous malignancy.
      ). Recent studies have identified heterozygous germline mutations of the mevalonate pathway genes MVK, MVD, PMVK, and FDPS (which encode the corresponding enzymes) in familial as well as sporadic porokeratosis (
      • Wang J.
      • Liu Y.
      • Liu F.
      • Huang C.
      • Han S.
      • Lv Y.
      • et al.
      Loss-of-function Mutation in PMVK Causes Autosomal Dominant Disseminated Superficial porokeratosis.
      ,
      • Zhang Z.
      • Li C.
      • Wu F.
      • Ma R.
      • Luan J.
      • Yang F.
      • et al.
      Genomic variations of the mevalonate pathway in porokeratosis.
      ,
      • Zhang S.Q.
      • Jiang T.
      • Li M.
      • Zhang X.
      • Ren Y.Q.
      • Wei S.C.
      • et al.
      Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis.
      ).
      Genetic inheritance patterns for enzyme deficiency are typically recessive and the result of “loss-of-function” mutations. Second-hit genetic mosaicism is a rare cause of enzymatic loss of function, and
      • Kubo A.
      • Sasaki T.
      • Suzuki H.
      • Shiohama A.
      • Aoki S.
      • Sato S.
      • et al.
      Clonal expansion of second-hit cells with somatic recombinations or C>T transitions form porokeratosis in MVD or MVK mutant heterozygotes.
      confirm recent findings that second-hit postzygotic mutations or homologous recombination in mevalonate pathway genes cause the mosaic presentation of porokeratosis—LP (
      • Atzmony L.
      • Khan H.M.
      • Lim Y.H.
      • Paller A.S.
      • Levinsohn J.L.
      • Holland K.E.
      • et al.
      Second-hit, postzygotic PMVK and MVD mutations in linear porokeratosis.
      ). They further show that the autosomal dominant disorder DSAP, which typically presents with lesions later in life also results from second-hit mutations of the remaining wild-type allele. Although previous efforts in the field had been underpowered to detect somatic mutations in an admixed cell population, the authors show that DSAP lesions result from second-hit somatic mitotic recombination or point mutations with a UV signature, validating the clinical observation that DSAP lesions arise on sun-exposed skin. They identified somatic events in 36 out of 40 DSAP lesions, with mitotic recombination being the most common second-hit, suggesting that this may be a common mechanism of loss of heterozygosity in the skin, as seen in the revertant mosaic disorder ichthyosis with confetti (
      • Choate K.A.
      • Lu Y.
      • Zhou J.
      • Elias P.M.
      • Zaidi S.
      • Paller A.S.
      • et al.
      Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti.
      ,
      • Choate K.A.
      • Lu Y.
      • Zhou J.
      • Choi M.
      • Elias P.M.
      • Farhi A.
      • et al.
      Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10.
      ,
      • Lim Y.H.
      • Qiu J.
      • Saraceni C.
      • Burrall B.A.
      • Choate K.A.
      Genetic reversion via mitotic recombination in ichthyosis with confetti due to a KRT10 polyalanine frameshift mutation.
      ). The finding that some of the second-hit mutations have UV signatures proves the importance of sun protection as a preventive measure in DSAP.

       Phenotypic spectrum of MVK mutations

      Although somatic recessive loss-of-function mutations in MVK cause DSAP and LP, germline recessive or compound heterozygous mutations in MVK cause a disease spectrum known as mevalonate kinase deficiency (MKD), with mevalonic aciduria and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) representing the severe and mild ends of the clinical and biochemical spectrum of MKD, respectively. Mevalonic aciduria is characterized by dysmorphic features, failure to thrive, progressive visual impairment, psychomotor retardation, and recurrent febrile attacks that are often accompanied by hepatosplenomegaly, lymphadenopathy, arthralgia and arthritis, gastrointestinal symptoms, and erythematous macules and urticarial plaques. In HIDS, which results from less severe MVK deficiency, most often only febrile attacks are present, with erythematous and edematous papules and plaques, which may become purpuric (
      • Farasat S.
      • Aksentijevich I.
      • Toro J.R.
      Autoinflammatory diseases: clinical and genetic advances.
      ). Of note, although some MVK mutations identified in DSAP were found in a compound heterozygous state in HIDS, no porokeratosis lesions were described in patients with HIDS (
      • Zhang S.Q.
      • Jiang T.
      • Li M.
      • Zhang X.
      • Ren Y.Q.
      • Wei S.C.
      • et al.
      Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis.
      ), exemplifying how recessive MVK loss of function that is restricted to keratinocytes is phenotypically different from generalized recessive MVK loss of function.

       The mevalonate pathway as a potential target for porokeratosis therapy

      The finding that porokeratosis lesions derive from somatic recessive loss of function of mevalonate pathway genes may enable the development of novel therapies for the disease. The mevalonate pathway utilizes acetyl-coenzyme A (CoA), NADPH, and ATP to produce sterol and nonsterol isoprenoids. In the first committed step, HMG-CoA is metabolized to mevalonate by HMG-CoA reductase (HMGCR). MVK, PMVK, and MVD further metabolize mevalonate to isopentenyl pyrophosphate (IPP). IPP is the precursor of the sterol isoprenoids (cholesterol and steroid hormones) and the nonsterol isoprenoids (FPP, GGPP, dolichols, and ubiquitone [coenzyme Q]). Cholesterol is well-known for its contribution in establishing and maintaining skin barrier function. In addition to being an essential component of most cellular membranes, cholesterol is also a significant component of the extracellular lipid matrix in the stratum corneum. FPP and GGPP serve as adjuncts for posttranslational modification of hundreds of proteins, including the γ subunit of heterotrimeric G proteins, nuclear lamins, and the small guanosine triphosphate-binding proteins (e.g., Ras, Rho) (
      • Thurnher M.
      • Nussbaumer O.
      • Gruenbacher G.
      Novel aspects of mevalonate pathway inhibitors as antitumor agents.
      ). Uniquitone is involved in ATP production in the mitochondria and, therefore, is crucial for ATP production in cells that rely on oxidative phosphorylation to produce energy (
      • Mullen P.J.
      • Yu R.
      • Longo J.
      • Archer M.C.
      • Penn L.Z.
      The interplay between cell signalling and the mevalonate pathway in cancer.
      ). Dolichol is required for the glycosylation of nascent polypeptides in the endoplasmic reticulum (
      • Mullen P.J.
      • Yu R.
      • Longo J.
      • Archer M.C.
      • Penn L.Z.
      The interplay between cell signalling and the mevalonate pathway in cancer.
      ). Finally, isopentenyl modification of tRNA contributes to tRNA fit in the ribosome decoding center and codon-anticodon interactions, and its absence alters mRNA decoding (
      • Lamichhane T.N.
      • Blewett N.H.
      • Crawford A.K.
      • Cherkasova V.A.
      • Iben J.R.
      • Begley T.J.
      • et al.
      Lack of tRNA modification isopentenyl-A37 alters mRNA decoding and causes metabolic deficiencies in fission yeast.
      ). Altogether the involvement of mevalonate pathway metabolites and end-products in cell growth and differentiation, gene expression, cytoskeleton assembly, and intracellular signaling is pronounced. Understanding metabolism in porokeratosis lesions in the context of mevalonate pathway gene mutations has the potential to drive the development of targeted therapies. Ideally, enzyme replacement or gene therapies would correct the metabolic anomaly. However, these options often remain remote owing to the widespread distribution of the skin disease, obstacles in transcutaneous drug delivery, the enormous costs of developing these treatments, and uncertain long-term effects of viral transduction. An appealing option is pathogenesis-directed therapy that aims to correct the metabolic anomalies that result from the diminished enzymatic activity. This approach has been used successfully in congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome, in which correction of the metabolic error (which results from NSDHL deficiency) via topical application of cholesterol and statin that corrected the phenotype (
      • Paller A.S.
      • Steensel MAM van
      • Rodriguez-Martín M.
      • Sorrell J.
      • Heath C.
      • Crumrine D.
      • et al.
      Pathogenesis-based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism.
      ). Studying the metabolic consequences of diminished MVK, PMVK, MVD, or FDPS enzymatic activity or the effects of mevalonate pathway end-products replenishment and proximal blockage via pharmacological agents in in vitro and in vivo models, would enable such a therapeutic approach in porokeratosis as well.

       Some further questions: The enigma of cornoid lamella formation

      A DSAP lesion starts as a small papule that gradually expands to form a plaque with a clinical “cornoid lamella” at the periphery.
      • Kubo A.
      • Sasaki T.
      • Suzuki H.
      • Shiohama A.
      • Aoki S.
      • Sato S.
      • et al.
      Clonal expansion of second-hit cells with somatic recombinations or C>T transitions form porokeratosis in MVD or MVK mutant heterozygotes.
      show that the ratio of second-hit cells to naive cells (with a single allele that is mutated) was higher in the center of DSAP plaque than at the outer ring, where the cornoid lamella is located, suggesting that each skin lesion forms via expansion of the second-hit cell clone. They hypothesized that a cornoid lamella forms owing to the mixture of naive and second-hit cells, and because an inflammatory infiltrate was located beneath the cornoid lamella, they suggested that the cornoid lamella might induce the inflammatory reaction (
      • Kubo A.
      • Sasaki T.
      • Suzuki H.
      • Shiohama A.
      • Aoki S.
      • Sato S.
      • et al.
      Clonal expansion of second-hit cells with somatic recombinations or C>T transitions form porokeratosis in MVD or MVK mutant heterozygotes.
      ). Although the restriction of further expansion of each skin lesion might be explained by competition between naive and wild-type keratinocytes, or by the inflammatory response, this hypothesis will require experimental validation. Although DSAP lesions show distinct keratotic rims, other porokeratosis variants such as LP, porokeratosis ptychotropica, and verrucous porokeratosis do not necessarily have such findings (Figure 1a, 1c ). Histopathological examination can reveal varying numbers of cornoid lamellae between samples and inflammatory infiltrates, in DSAP as well as in other variants, can be visualized not only beneath the cornoid lamella (Figure 1b, 1d), but also throughout lesional skin. Because LP results from a single clone of second-hit cells and can have one to many cornoid lamellae, and given the possibility that the admixture at the periphery of the lesion could result from sampling normal-appearing skin, further studies on DSAP, as well as other forms of porokeratosis, are necessary to understand how cornoid lamellae form.
      Figure thumbnail gr1
      Figure 1Clinical and histologic features of linear porokeratosis with PMVK mutations. Patients do not necessarily present with (a, c) a keratotic rim and minimal inflammation can be present. (b, d)Histopathologic evaluation reveals several cornoid lamellae across the sample.
      In summary, the work of
      • Kubo A.
      • Sasaki T.
      • Suzuki H.
      • Shiohama A.
      • Aoki S.
      • Sato S.
      • et al.
      Clonal expansion of second-hit cells with somatic recombinations or C>T transitions form porokeratosis in MVD or MVK mutant heterozygotes.
      has opened new avenues for further research on porokeratosis. Future studies should focus on the role of second-hit mutations in mevalonate pathway genes in other subtypes of porokeratosis, the roles of competition between naive and mutated cells, and the inflammatory response in the formation of cornoid lamella and porokeratosis plaque expansion, and, finally, the development of new therapeutic approaches that target the mevalonate pathway.

      ORCIDs

      Conflict of Interest

      The authors have no conflict of interest.

      References

        • Atzmony L.
        • Khan H.M.
        • Lim Y.H.
        • Paller A.S.
        • Levinsohn J.L.
        • Holland K.E.
        • et al.
        Second-hit, postzygotic PMVK and MVD mutations in linear porokeratosis.
        JAMA Dermatol. 2019; 155: 548-555
        • Biswas A.
        Cornoid lamellation revisited: apropos of porokeratosis with emphasis on unusual clinicopathological variants.
        Am J Dermpathol. 2015; 37: 145-155
        • Choate K.A.
        • Lu Y.
        • Zhou J.
        • Choi M.
        • Elias P.M.
        • Farhi A.
        • et al.
        Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10.
        Science. 2010; 330: 94-97
        • Choate K.A.
        • Lu Y.
        • Zhou J.
        • Elias P.M.
        • Zaidi S.
        • Paller A.S.
        • et al.
        Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti.
        J Clin Invest. 2015; 125: 1703-1707
        • Farasat S.
        • Aksentijevich I.
        • Toro J.R.
        Autoinflammatory diseases: clinical and genetic advances.
        Arch Dermatol. 2008; 144: 392-402
        • Kubo A.
        • Sasaki T.
        • Suzuki H.
        • Shiohama A.
        • Aoki S.
        • Sato S.
        • et al.
        Clonal expansion of second-hit cells with somatic recombinations or C>T transitions form porokeratosis in MVD or MVK mutant heterozygotes.
        J Invest Dermatol. 2019; 139: 2458-2466.e9
        • Lamichhane T.N.
        • Blewett N.H.
        • Crawford A.K.
        • Cherkasova V.A.
        • Iben J.R.
        • Begley T.J.
        • et al.
        Lack of tRNA modification isopentenyl-A37 alters mRNA decoding and causes metabolic deficiencies in fission yeast.
        Mol Cell Biol. 2013; 33: 2918-2929
        • Lim Y.H.
        • Qiu J.
        • Saraceni C.
        • Burrall B.A.
        • Choate K.A.
        Genetic reversion via mitotic recombination in ichthyosis with confetti due to a KRT10 polyalanine frameshift mutation.
        J Invest Dermatol. 2016; 136: 1725-1728
        • Mullen P.J.
        • Yu R.
        • Longo J.
        • Archer M.C.
        • Penn L.Z.
        The interplay between cell signalling and the mevalonate pathway in cancer.
        Nat Rev Cancer. 2016; 16: 718-731
        • Paller A.S.
        • Steensel MAM van
        • Rodriguez-Martín M.
        • Sorrell J.
        • Heath C.
        • Crumrine D.
        • et al.
        Pathogenesis-based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism.
        J Invest Dermatol. 2011; 131: 2242-2248
        • Sasson M.
        • Krain A.D.
        Porokeratosis and cutaneous malignancy.
        A review. Dermatol Surg. 1996; 22: 339-342
        • Thurnher M.
        • Nussbaumer O.
        • Gruenbacher G.
        Novel aspects of mevalonate pathway inhibitors as antitumor agents.
        Clin Cancer Res. 2012; 18: 3524-3531
        • Wang J.
        • Liu Y.
        • Liu F.
        • Huang C.
        • Han S.
        • Lv Y.
        • et al.
        Loss-of-function Mutation in PMVK Causes Autosomal Dominant Disseminated Superficial porokeratosis.
        Sci Rep. 2016; 6: 24226
        • Zhang S.Q.
        • Jiang T.
        • Li M.
        • Zhang X.
        • Ren Y.Q.
        • Wei S.C.
        • et al.
        Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis.
        Nat Genet. 2012; 44: 1156-1160
        • Zhang Z.
        • Li C.
        • Wu F.
        • Ma R.
        • Luan J.
        • Yang F.
        • et al.
        Genomic variations of the mevalonate pathway in porokeratosis.
        eLife. 2015; 4e06322

      Linked Article