Conversely, alleles of <i>ABHD5</i> carrying point mutations associated with ichthyosis in humans failed to accelerate PNPLA1-mediated AcylCer biosynthesis.
Notably, topical application of epidermal lipids from wild-type onto Pnpla1-mutant mice promoted rebuilding of the corneocyte-bound lipid envelope, indicating that supplementation of ichthyotic skin with omega-O-acylceramides might be a therapeutic approach for the treatment of skin symptoms in individuals affected by omega-O-acylceramide deficiency.
Altogether, our results indicate that PNPLA1 is directly involved in acylceramide synthesis as a transacylase, and provide important insights into the molecular mechanisms of skin barrier formation and of ichthyosis pathogenesis.
The phenotype of the HID (hystrix-like ichthyosis, deafness)/KID (keratitis, ichthyosis, deafness) syndrome is primarily characterized by skin changes.
Mutations in connexin 26 are linked to diseases including Vohwinkel syndrome, keratitis-ichthyosis deafness, and hystrix-like ichthyosis deafness syndromes, palmoplantar keratoderma with deafness, deafness with Clouston-like phenotype, and Bart-Pumphrey syndrome.
In addition, whole exome sequencing approach also solved the genetics of some syndromic forms of PAI including IMAGe syndrome (<i>CDKN1C</i>), Irish traveler syndrome (<i>MCM4</i>), MIRAGE syndrome (<i>SAMD9</i>); and most recently a syndrome combining FGD with steroid-resistant nephrotic syndrome and ichthyosis caused by mutations in the gene for sphingosine-1-phosphate lyase 1 (<i>SGPL1</i>).
The diagnosis of multiple sulfatase deficiency was demonstrated by measuring sulfatase activities in fresh leukocytes: there were large deficiencies of arylsulfatase A and B plus reduced arylsulfatase C. The ichthyosis associated with multiple sulfatase deficiency has an autosomal recessive inheritance, is caused by steroid sulfatase deficiency, and the scaling is sometimes milder than in X-linked recessive ichthyosis.
Clinically typical phenotype of the TGM1 mutation carrier includes large, thick, brownish scales, but ichthyosis of some of these patients tends to be milder.
The TGM1 mutation spectrum was characterised and genotype-phenotype correlations investigated in 104 patients with ARCI ascertained through the National Registry for Ichthyosis and Related Disorders in the USA.
STS deficiency (STSD) due to deletions or inactivating mutations in the X-linked STS gene manifests with ichthyosis, but androgen synthesis and metabolism in STSD have not been studied in detail yet.
Two independent familial STS deletions, one of which is associated with a phenotype of ichthyosis plus ocular albinism (XI/OA1) and the other with nystagmus plus Rud syndrome, lack some but not all of the normal S232 PFGE fragments.
Recent work has shown that a number of diseases which display defective epidermal barrier function, generically known as ichthyoses, are the result of genetic defects of the synthesis of either CE proteins, the transglutaminase 1 cross-linking enzyme, or defective metabolism of skin lipids.
X-linked ichthyosis is a relatively common syndromic form of ichthyosis most often due to deletions in the gene encoding the microsomal enzyme, steroid sulfatase, located on the short area of the X chromosome.
This mixed phenotype suggests the need for a better understanding of the possible role of filaggrin loss and AP1 transcription factor deficiency in ichthyoses and collodion membrane formation.
Ichthyoses lacked the epidermal differentiation and tight junction alterations of patients with AD (loricrin, filaggrin, and claudin 1) but showed characteristic alterations in lipid metabolism genes (ELOVL fatty acid elongase 3 and galanin), with parallel reductions in extracellular lipids and corneocyte compaction in all ichthyoses except epidermolytic ichthyosis, suggesting phenotypic variations.
Combined with data from the literature, these findings confirm the hypothesis that only a restricted spectrum of TGM1 mutations leads to a BSI and/or an SICI phenotype.