Mutations in ichthyin a new gene on chromosome 5q33 in a new form of autosomal recessive congenital ichthyosis

Abstract

We report the genomic localization by homozygosity mapping and the identification of a gene for a new form of non-syndromic autosomal recessive congenital ichthyosis. The phenotype usually presents as non-bullous congenital ichthyosiform erythroderma with fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. A few patients presented a more generalized lamellar ichthyosis. Palmoplantar keratoderma was present in all cases, whereas only 60% of the patients were born as collodion babies. Six homozygous mutations including one nonsense and five missense mutations were identified in a new gene, ichthyin, on chromosome 5q33 in 23 patients from 14 consanguineous families from Algeria, Colombia, Syria and Turkey. Ichthyin encodes a protein with several transmembrane domains which belongs to a new family of proteins of unknown function localized in the plasma membrane (PFAM: DUF803), with homologies to both transporters and G-protein coupled receptors. This family includes NIPA1, in which a mutation was recently described in a dominant form of spastic paraplegia (SPG6). We propose that ichthyin and NIPA1 are membrane receptors for ligands (trioxilins A3 and B3) from the hepoxilin pathway.

11(R),12(S),15(S)-trihydroxyeicosa-5(Z),8(Z),13(E)-trienoic acid: an endothelium-derived 15-lipoxygenase metabolite that relaxes rabbit aorta

“…Thus it was important to determine the potency of the synthetic 11(R),12(S), 15 Nothing is known about the metabolism of 11,12,15-THETA by vascular cells. Since there are strict structural and stereochemical requirements for vascular activity, metabolism of 11,12,15-THETA would result in a loss of activity.…”

“…Trioxilin A 3 and B 3 are THETAs formed by the 12-LO pathway (18,19). Ichthyin and NIPA1 are thought to be membrane receptors for these ligands (15).…”

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…Mutations in 6 genes have been described in non-HI ARCI to date, including TGM, the gene encoding transglutaminase (TGase)-1, 22,23 the genes ABCA12, 17 NIPAL4 (also known as ICHTHYIN ), 24 CYP4F22, 25 and the lipoxygenase genes ALOX12B and ALOXE3. 26 A large cohort of 520 affected families showed a mutation distribution of 32% for TGM1, 16% for NIPAL4, 12% for ALOX12B, 8% for CYP4F22, 5% for ALOXE3, and 5% for ABCA12, 27 which approximately correlated with a recent report of 250 patients.…”

“…A pathophysiologic/functional classification of all MEDOC is a long-term goal, which will require further studies before it can be fully realized. Currently, an initial pathophysiologic scheme for ichthyoses and related diseases is proposed recognizing the following main categories: disorders of keratinocyte proteins (''bricks''), eg, referring to cytoskeleton, cornified lipid/cell envelope, proteases/protease inhibitors, keratohyaline, and disorders of lipid metabolism, assembly, and/or transport (''mortar''), eg, referring to steroid sulfatase deficiency, the proposed hepoxilin pathway, 24 LB defects, and a variety of multisystem lipid metabolism defects such as lysosomal or neutral lipid storage disease. The inclusion of the connexin disorders, ie, EKV and KID, the ichthyosisehypotrichosisesclerosing cholangitis syndrome, and TTDs into the ichthyosis family indicates the additional categories of disorders of cell-cell junctions, and disorders of DNA transcription/repair, respectively.…”

ABCA12 mutations and autosomal recessive congenital ichthyosis: A review of genotype/phenotype correlations and of pathogenetic conceptsa

“…In contrast, CIE and LI are both heterogeneous genetic disorders and several causative or underlying molecules including ABCA12 have been identified [Jobard et al, 2002;Lefèvre et al, 2003Lefèvre et al, , 2004Lefèvre, 2006]. Mutations in six genes have been described in non-HI ARCI to date, including TGM1 [Huber et al, 1995;Russell et al, 1995], ABCA12 [Lefèvre et al, 2003;Natsuga et al, 2007], NIPAL4 (also known as ICHTHYIN) [Lefèvre et al, 2004], CYP4F22 [Lefèvre, 2006], ALOX12B and ALOXE3 [Jobard et al, 2002]. Among them, TGM1 is thought to be the most prevalent causative gene [Fischer, 2009;Herman et al, 2009].…”