Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis—Like Autosomal Recessive Congenital Ichthyosis

Abstract

Erythrokeratodermia variabilis (EKV) is a rare disorder of cornification usually associated with dominant mutations in the GJB3 and GJB4 genes encoding connexins (Cx)31 and 30.3. Genetic heterogeneity of EKV has already been suggested. We investigated at the clinical and genetic level a consanguineous Tunisian family with 2 sisters presenting an autosomal recessive form of EKV to better characterize this disease. Mutational analysis initially screened the connexin genes and Whole-exome sequencing (WES) was performed to identify the molecular aetiology of the particular EKV phenotype in the proband. Migratory shaped erythematous areas are the initial presenting sign followed by relatively stable hyperkeratotic plaques are the two predominates characteristics in both patients. However, remarkable variability of morphological and dominating features of the disease were observed between patients. In particular, the younger sister (proband) exhibited ichthyosiform-like appearance suggesting Autosomal Recessive Congenital Ichthyosis (ARCI) condition. No causative mutations were detected in the GJB3 and GJB4 genes. WES results revealed a novel missense homozygous mutation in NIPAL4 gene (c.835C>G, p.Pro279Ala) in both patients. This variant is predicted to be likely pathogenic. In addition, in silico analysis of the mutated 3D domain structure predicted that this variant would result in NIPA4 protein destabilization and Mg2+ transport perturbation, pointing out the potential role of NIPAL4 gene in the development and maintenance of the barrier function of the epidermis. Taken togheter, these results expand the clinical phenotype associated with NIPAL4 mutation and reinforce our hypothesis of NIPAL4 as the main candidate gene for the EKV-like ARCI phenotype.

Erythrokeratodermia Variabilis-like Phenotype in Patients Carrying ABCA12 Mutations

“…Since a later onset of symptoms is atypical for ARCI, this often leads to misdiagnosis. The younger sister in the study by Charfeddine et al [ 13 ] exhibited an ichthyosiform-like appearance, suggesting the ARCI condition. This is similar to P2, who was first suspected to have ARCI, whereas his sister presents a more classical EKV phenotype.…”

“…An EKV-like phenotype in patients with mutations in genodermatoses-related genes has already been described in several studies. Two sisters with an EKV-like phenotype from a Tunisian consanguineous family carry a homozygous NIPAL4 mutation [ 13 ]. The first symptoms in the older sister in this study appeared at the age of 5 months.…”

“…In ARCI, three major phenotypes have been described: lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE), and harlequin ichthyosis (HI). EKV-like phenotypes have only been described in isolated cases with ARCI, including patients with mutations in NIPAL4 [ 13 ] and ABCA12 [ 14 ]. Here, we present a larger cohort, including seven patients with initially suspected EKV, in which we found biallelic mutations in ABCA12 , including four novel mutations and other known mutations previously described in patients with ARCI.…”

Insulin docking within the open hemichannel of connexin 43 may reduce risk of amyotrophic lateral sclerosis

“…We assume that insulin docks identically within hexameric Cx31 and hexameric Cx43, but this may not be the case. Cx31 abnormalities are associated with erythrokeratoderma, a rare skin condition [19].…”

Insulin Docking Within the Open Hemichannel of Connexin 43 May Reduce Risk of Amyotrophic Lateral Sclerosis

“…We assume that insulin docks identically within hexameric Cx31 and hexameric Cx43, but this may not be the case. Cx31 abnormalities are associated with erythrokeratoderma, a rare skin condition (22).…”