Porokeratosis (PK) is a heterogeneous group of keratinization disorders. No causal genes except MVK have been identified, even though the disease was linked to several genomic loci. Here, we performed massively parallel sequencing and exonic CNV screening of 12 isoprenoid genes in 134 index PK patients (61 familial and 73 sporadic) and identified causal mutations in three novel genes (PMVK, MVD, and FDPS) in addition to MVK in the mevalonate pathway. Allelic expression imbalance (AEI) assays were performed in 13 lesional tissues. At least one mutation in one of the four genes in the mevalonate pathway was found in 60 (98%) familial and 53 (73%) sporadic patients, which suggests that isoprenoid biosynthesis via the mevalonate pathway may play a role in the pathogenesis of PK. Significantly reduced expression of the wild allele was common in lesional tissues due to gene conversion or some other unknown mechanism. A G-to-A RNA editing was observed in one lesional tissue without AEI. In addition, we observed correlations between the mutations in the four mevalonate pathway genes and clinical manifestations in the PK patients, which might support a new and simplified classification of PK under the guidance of genetic testing.
Porokeratosis refers to a group of around twenty skin conditions that involve a build-up of a protein called keratin in skin cells. Keratin forms the tough fibres that give strength to hair and nails, and people suffering from porokeratosis develop hardened skin lesions. Porokeratosis is an uncommon condition; most cases are inherited and have been linked to exposure to ultraviolet light and having a weakened immune system.
Mutations in one gene called MVK are known to cause two forms of the disorder, but it is suspected that other genetic causes of porokeratosis will also be identified. The MVK gene encodes an enzyme that is involved in making chemicals called isoprenoids. This large and diverse class of chemicals provides the building blocks for making many other important molecules in all living species. Zhang, Li et al. have now analysed genetic material from 134 different porokeratosis patients to search for mutations in other genes involved in the production of isoprenoids. The patients examined include 61 people with a family history of the disorder, and 73 cases in which the condition seems to be a one-off occurrence.
This search identified mutations in three additional genes (called PMVK, MVD and FDPS) that are all linked to porokeratosis. Further analysis of these three genes and MVK revealed that about half of the patients with mutations in the MVK gene developed large lesions (that were over 5 centimetres in diameter). However, those with mutations in the other three genes did not develop such large lesions. Mutations in some of the newly identified genes were instead linked to porokeratosis affecting specific areas of the body; for example, PMVK and MVD mutations are linked to porokeratosis localized to the genitals and around the eyes, respectively. This means that, in the future, doctors might be able to simplify the diagnosis of the different varieties of porokeratosis based on information gained via genetic tests.