Identification and association of recurrent ALOXE3 mutation with non-bullous congenital ichthyosiform erythroderma in two ethnically distinct Pakistani families.

Non-bullous congenital ichthyosiform erythroderma (NCIE) is characterized by skin scaling with erythema. In this study, two Pakistani families with NCIE are genetically characterized through Whole Exome and Sanger sequencing to identify molecular basis of the disease. We identified a nonsense homozygous c.2026C>T mutation of ALOXE3, causing premature termination of the eLOX3 protein (p.Q676X). In silico studies predicted impaired enzymatic activity of the premature truncated eLOX3, leading to abnormal synthesis of specific hepoxilin derivatives, essential for epidermal barrier formation. It is the first ever study reporting homozygotes of p.Q676X mutation in ethnically distinct two Pakistani families; otherwise, heterozygotes of the said mutation have been reported in South Asian population only. Hence, mutation seems to be region-specific and may be useful for molecular diagnosis of NCIE. Moreover, our findings should help in genetic counseling and career screening.

Summary of mutations underlying autosomal recessive congenital ichthyoses (ARCI) in Arabs with four novel mutations in ARCI-related genes from the United Arab Emirates.

BACKGROUND: Clinical and molecular heterogeneity is a prominent characteristic of congenital ichthyoses, with the involvement of numerous causative loci. Mutations in these loci feature in autosomal recessive congenital ichthyoses (ARCIs) quite variably, with certain genes/mutations being more frequently uncovered in particular populations. METHODS: In this study, we used whole exome sequencing as well as direct Sanger sequencing to uncover four novel mutations in ARCI-related genes, which were found in families from the United Arab Emirates. In silico tools such as CADD and SIFT Indel were used to predict the functional consequences of these mutations. RESULTS: The here-presented mutations occurred in three genes (ALOX12B, TGM1, ABCA12), and these are a mixture of missense and indel variants with damaging functional consequences on their encoded proteins. CONCLUSIONS: This study presents an overview of the mutations that were found in ARCI-related genes in Arabs and discusses molecular and clinical details pertaining to the above-mentioned Emirati cases and their novel mutations with special emphasis on the resulting protein changes.

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

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.

Strong founder effect for a transglutaminase 1 gene mutation in lamellar ichthyosis and congenital ichthyosiform erythroderma from Norway.

Autosomal recessive congenital ichthyosis (ARCI) is a clinically heterogeneous disorder of keratinisation. It was recently shown that mutations in the transglutaminase 1 (TGM1) gene may be associated with the clinical subtypes lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (CIE). Thirty-six Norwegian families with LI and seven with non-bullous CIE were studied with microsatellite markers linked to the TGMI gene. One common haplotype for two markers was found on 74% of disease associated chromosomes. Three individuals homozygous for the common haplotype, two affected by LI and one affected by CIE, were analysed for mutations in the TGM1 gene. All three patients were found homozygous for a single A to G transition located in the canonical splice acceptor site of intron 5. Probands from the remaining 40 families with LI and CIE were screened for this mutation and the A to G transition was found on 61 out of 72 alleles associated with LI and on 9 out of 15 alleles associated with CIE. These findings suggest a single founder mutation for the majority of patients with LI and CIE in Norway. The 2526A-->G mutation results in the insertion of a guanosine at position 877 (876insG) in the mature cDNA and the frame shift creates a premature termination at codon 293. The mutation was previously observed in one family with a resulting cDNA that included the entire intron 5. These results suggest that the mutation can result in variant transcripts in different individuals.