Alternative titles; symbols
ORPHA: 735, 79152;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.11 | Porokeratosis 3, multiple types | 175900 | Autosomal dominant | 3 | MVK | 251170 |
A number sign (#) is used with this entry because of evidence that multiple types of porokeratosis (POROK3) are caused by heterozygous mutation in the MVK gene (251170) on chromosome 12q24.
Porokeratosis is a rare skin disorder characterized by one or more annular plaques with a surrounding raised horny border that spreads centrifugally. Variants of porokeratosis have been described that differ in morphologic shapes, distribution, and clinical course (Schamroth et al., 1997). However, as noted by Sybert (2010), several families with expression of more than one variant of porokeratosis among members, and individuals expressing more than one variant, have been reported, suggesting that the distinctions among these variants may be artificial.
Mutations in the MVK gene have been found to cause multiple types of porokeratosis, which have been described as disseminated superficial actinic porokeratosis (DSAP), nonactinic disseminated superficial porokeratosis (DSP), porokeratosis of Mibelli, giant plaque of porokeratosis ptychotropica, hyperkeratotic porokeratosis, and linear porokeratosis.
The preferred title of this entry was formerly 'Porokeratosis 3, Disseminated Superficial Actinic Type; POROK3.'
Disseminated superficial actinic porokeratosis is the most common subtype of porokeratosis. It is characterized by multiple small, annular, anhidrotic, keratotic lesions that are located predominantly on sun-exposed areas of the skin, such as the face, neck, and distal limbs. The lesions typically begin to develop in adolescence and reach near-complete penetrance by the third or fourth decade of life (summary by Wu et al., 2004 and Zhang et al., 2012).
For a discussion of genetic heterogeneity of porokeratosis, see 175800.
Chernosky and Freeman (1967) first suggested the existence of a photosensitive variety of porokeratosis. Lesions, which occur almost only in sun-exposed areas of the skin, develop after age 16 years, with penetrance nearly complete by age 30 or 40. DSAP is much more frequent than porokeratosis of Mibelli (175800) from which it must be distinguished. The histopathologic picture is typical. Ultraviolet radiation provokes typical porokeratotic lesions in DSAP (Chernosky and Anderson, 1969).
Linear porokeratosis appears to be a nonhereditary trait (Rahbari et al., 1974), although its occurrence in families with DSAP has been reported (Welton, 1972; Moreland and Wyre, 1981; Commens and Shumack, 1987). Happle (1991) suggested that somatic recombination may explain linear porokeratosis. Somatic crossing-over at an early stage of embryogenesis may involve the DSAP locus, resulting in a precursor cell for a clone growing out in a linear fashion. Homozygosity would explain the observation that the lesions of linear porokeratosis are far more pronounced than those of associated DSAP, as well as the fact that linear porokeratosis occurs sporadically. Disseminated porokeratosis of intensified severity similar to that observed in the linear type would be expected to occur in 25% of the children of parents who are both affected with DSAP.
Wu et al. (2004) reported a 5-generation Chinese family from the Anhui province with DSAP. Affected individuals developed cutaneous lesions in their teenage years, with the earliest age of onset at 10 years. The lesions were multiple, small, annular keratotic lesions ranging from 0.1 to 0.2 cm in diameter. They tended to occur on sun-exposed sites, such as the face, neck, and distal limbs. Skin biopsy of 1 patient showed cornoid lamella consisting of a compact column of parakeratotic cells.
Clinical Variability
Cao et al. (2012) reported a large 6-generation Chinese family with autosomal dominant disseminated superficial porokeratosis. Most had onset of skin lesions between ages 20 and 30 years. The lesions were annular, ranging from 2 to 6 mm in diameter, with brown raised borders and slightly atrophic centers. Histologic studies showed absent granular layers below the parakeratotic column. The lesions were not limited to sun-exposed areas such as the face and limbs, but were also found on nonexposed areas, including the chest and back.
The transmission pattern of DSAP in the families reported by Wu et al. (2004) and Zhang et al. (2012) was consistent with autosomal dominant inheritance.
Using a genomewide search in a large Chinese family, Xia et al. (2000) identified a locus at chromosome 12q23.2-q24.1 responsible for disseminated superficial actinic porokeratosis. Fine mapping studies indicated that the DSAP gene is located within a 9.6-cM region between markers D12S1727 and D12S1605, with a maximum 2-point lod score of 20.53 (theta = 0.00) at D12S78.
In a 5-generation Chinese family with DSAP, Wu et al. (2004) found linkage to a 4.4-cM interval on chromosome 12q23.2-q24.1 (maximum 2-point lod score of 6.92 at D12S1342). Mutation analysis of several candidate genes did not reveal any pathogenic mutations.
Zhang et al. (2005) performed a genomewide scan and linkage analysis in a 6-generation Chinese family with DSAP and obtained a maximum 2-point lod score of 5.56 at D12S79 (theta = 0.0). Haplotype analysis defined a critical region between D12S330 and D12S1612 on chromosome 12q24.1-q24.2, which partially overlaps the previously mapped DSAP1 region.
By genomewide linkage analysis of a Chinese family with disseminated superficial porokeratosis, Cao et al. (2012) found linkage to a 38-Mb region on chromosome 12q21.2-q24.21 between D12S326 and D12S79 (maximum 2-point lod score of 3.06 at D12S78). The region partially overlapped with that of DSAP1 (Xia et al., 2000); Cao et al. (2012) referred to the locus identified by them as 'DSP2.' Sequencing of 50 candidate genes, including SART3 (611684) and SSH1 (606778), did not reveal any pathogenic mutations in the family reported by Cao et al. (2012).
By exome sequencing of 3 members (2 affected and 1 unaffected) of a 4-generation Chinese family with autosomal dominant DSAP, Zhang et al. (2012) identified a heterozygous mutation in the MVK gene (251170.0009). Sanger sequencing confirmed that the mutation segregated with the disorder in 6 affected individuals. Sequencing of the MVK gene in 57 additional pedigrees and 25 patients with sporadic disease identified 13 additional heterozygous MVK mutations in 22 cases. Overall, 14 mutations (see, e.g., 251170.0009-251170.0010; 251170.0012-251170.0015) were found in 18 probands (33%) with familial DSAP, including the family previously reported by Wu et al. (2004), and in 4 (16%) of 25 patients with sporadic occurrence. The mutational spectrum included missense, truncating, and splice site mutations. There was no evidence of secondary somatic MVK mutations within skin lesions of 5 patients. The phenotypic severity was variable, even among those with the same mutation. Two of the mutations, G202R (251170.0010) and 417insC (251170.0012), had previously been identified in patients with hyper-IgD syndrome (260920) and mevalonic aciduria (610377). However, the patients with DSAP1 had no clinical features of either disorder, including normal IgD levels. Although porokeratosis lesions have not been reported in individuals with mevalonic aciduria, some cases with hyper-IgD syndrome can have transient inflammatory skin lesions. In addition, heterozygous parents of patients with recessive MVK mutations do not have features of DSAP1. This clinical diversity suggests the involvement of additional factors, such as environmental exposure, particularly ultraviolet radiation, in disease manifestation. Functional studies in keratinocytes suggested that MVK plays a role in regulating calcium-induced keratinocyte differentiation and may protect keratinocytes from UV radiation-induced apoptosis. Sequencing the MVK gene in 5 individuals with porokeratosis of Mibelli (175800), 2 with linear porokeratosis, and 4 with disseminated superficial porokeratosis found no mutations, suggesting that MVK mutations may be specific for the DSAP subtype of porokeratosis.
Zeng et al. (2014) sequenced the MVK gene in 3 unrelated Chinese families with porokeratosis and identified heterozygosity for a splice site mutation (251170.0018) in a 52-year-old mother and her 36-year-old daughter and 34-year-old son, who exhibited porokeratosis of the Mibelli type. No mutations were detected in patients from the other 2 families, who had DSAP. Features in the mutation-positive family that differed from the other 2 families included onset in the second decade of life versus the third to fifth, initial lesions located on buttocks or hands rather than the face, and more severe disease, including bigger and more widespread keratinized plaques, verrucous proliferation, and nail dystrophy. Histopathology of lesional skin showed atrophy of the epidermis, cornoid lamella with absent granular layers, infiltration of inflammatory cells, and melanocyte clusters below the parakeratotic column.
Zhang et al. (2015) analyzed 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified heterozygosity for 28 mutations in the MVK gene in 39 probands, including a large 10,076-bp deletion in 4 of them (251170.0019). The mutations segregated completely with disease in all pedigrees for which DNA was available, including 3 large 4- to 5-generation families, and none were found in 270 ethnically matched controls. The probands exhibited a wide range in number and size of lesions as well as a variety of porokeratosis subtypes, with more than 1 type present within some patients, including DSAP and/or nonactinic DSP in 26 patients, porokeratosis of the Mibelli type in 23, giant plaques of porokeratosis ptychotropica in 19, hyperkeratotic porokeratosis in 13, and linear porokeratosis in 1. The authors observed that even within families, affected individuals carrying the same mutation showed different clinical manifestations and varying degrees of severity. All examined lesional tissue showed cornoid lamella, a histologic hallmark of porokeratosis with vertical columns of parakeratosis overlying an area of hypogranulosis with dyskeratotic cells. Zhang et al. (2015) noted that although 1 female proband was heterozygous for missense mutations in both the MVK gene (D79N) and the MVD gene (F249S; 603236.0001), she did not exhibit a more severe phenotype or earlier age of onset or any other unique clinical features.
Associations Pending Confirmation
Zhang et al. (2004) performed genomewide linkage analysis in 3 Chinese families with DSAP and localized the gene to an 8.0-cM region on chromosome 12 that partially overlapped the DSAP1 locus identified by Xia et al. (2000). Screening of 30 candidate genes in this region identified 3 different variants in the SSH1 gene (606778) in 2 families and in 1 nonfamilial case. The SSH1 gene mapped outside of the DSAP1 locus identified by Xia et al. (2000). Two of the SSH1 variants occurred in an alternative isoform (isoform f) of the gene. As SSH1 encodes a phosphatase with a role in actin dynamics, the authors suggested that cytoskeletal disorganization in epidermal cells may be associated with the pathogenesis.
Frank et al. (2007) and Frank et al. (2007) disputed the findings of Zhang et al. (2004) and Zhang et al. (2005). Frank et al. (2007) found no variation in the SSH1 gene in 5 unrelated Dutch patients with DSAP, and noted that variation in the SSH1 and SART3 genes have not been replicated in additional DSAP families. Frank et al. (2007) and Frank et al. (2007) also found inconsistencies in some of the methodology used by the other authors. Zhang (2007) defended the validity of their work.
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