Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients

Abstract

The autosomal recessive congenital ichthyoses (ARCI) are a nonsyndromic group of cornification disorders that includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. To date mutations in ten genes have been identified to cause ARCI: TGM1, ALOX12B, ALOXE3, NIPAL4, CYP4F22, ABCA12, PNPLA1, CERS3, SDR9C7, and SULT2B1. The main focus of this report is the mutational spectrum of the genes ALOX12B and ALOXE3, which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively. Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation. The type and the position of the mutations may influence the ARCI phenotype; most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma. To date, 88 pathogenic mutations in ALOX12B and 27 pathogenic mutations in ALOXE3 have been reported in the literature. Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in ALOX12B and 25 novel mutations in ALOXE3. We investigated the spectrum of mutations in ALOX12B and ALOXE3 in our cohort and additionally in the published mutations, the distribution of these mutations within the gene and gene domains, and potential hotspots and recurrent mutations.

Ichthyoses—A Clinical and Pathological Spectrum from Heterogeneous Cornification Disorders to Inflammation

“…Autosomal recessive congenital ichthyosis (ARCI) represents a genetically heterogeneous group of non-syndromic congenital ichthyoses with widely varying severity. The group comprises lamellar ichthyosis, which is most often due to tranglutaminase−1 deficiency (Table 3), congenital ichthyosiform erythroderma, and the most severe but rare subtype of harlequin ichthyosis [12]. Newborns can be born with a tight and shiny stratum corneum, which is associated with ectropion, eclabium, fluid loss, and thermal dysregulation, and resulting in potentially life-threatening complications.…”

Report of a Novel ALOX12B Mutation in Self-Improving Collodion Ichthyosis with an Overview of the Genetic Background of the Collodion Baby Phenotype

“…Before that, this particular mutation was only documented in case of other forms of ARCI (LI/CIE) [ 19 ]. In a new meta-analysis exploring the genotypic spectrum of ALOX12B and ALOXE3 mutations, c.1526A>G (p.Tyr521Cys) was the most frequent mutation, with an allelic frequency of 22% (61 out of 282 alleles) [ 5 ]. Although c.1526A>G (p.Tyr521Cys) frequently occurs in SICI cases, it was detected in numerous LI and CIE patients as well, both in homozygote and compound heterozygote form [ 5 ].…”

“…In a new meta-analysis exploring the genotypic spectrum of ALOX12B and ALOXE3 mutations, c.1526A>G (p.Tyr521Cys) was the most frequent mutation, with an allelic frequency of 22% (61 out of 282 alleles) [ 5 ]. Although c.1526A>G (p.Tyr521Cys) frequently occurs in SICI cases, it was detected in numerous LI and CIE patients as well, both in homozygote and compound heterozygote form [ 5 ]. Based on this meta-analysis, CB phenotype was documented in 25 out of 44 cases with either heterozygous or homozygous form of c.1526A>G (p.Tyr521Cys) mutation, including five SICI cases.…”

“…Of note, in case of mutations of genes encoding the lipoxygenase enzymes, the outcome of CB cannot be accurately predicted neither based on genetic analysis nor the initial clinical presentation [ 5 ]. In addition, in our experience, the severity of the disease, e.g., the degree of erythema, can show relapses and remissions that probably are influenced by variable exogenous and endogenous factors.…”

“…ARCI has diverse clinical manifestations. To date, the mutational spectrum encompasses ten genes that encode proteins (enzymes, transport proteins) responsible for the formation of the stratum corneum [ 4 , 5 ]. Subtypes of ARCI traditionally include lamellar ichthyosis (LI) with large, dark, plate-like scales without erythroderma, and congenital ichthyosiform erythroderma (CIE) with generalized fine scaling and erythroderma.…”