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Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis—Like Autosomal Recessive Congenital Ichthyosis
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 consanguineo...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528321/ https://www.ncbi.nlm.nih.gov/pubmed/34669720 http://dx.doi.org/10.1371/journal.pone.0258777 |
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author | Charfeddine, Cherine Laroussi, Nadia Mkaouar, Rahma Jouini, Raja Khayat, Olfa Redissi, Aladin Mosbah, Amor Dallali, Hamza Chedly Debbiche, Achraf Zaouak, Anissa Fenniche, Sami Abdelhak, Sonia Hammami-Ghorbel, Houda |
author_facet | Charfeddine, Cherine Laroussi, Nadia Mkaouar, Rahma Jouini, Raja Khayat, Olfa Redissi, Aladin Mosbah, Amor Dallali, Hamza Chedly Debbiche, Achraf Zaouak, Anissa Fenniche, Sami Abdelhak, Sonia Hammami-Ghorbel, Houda |
author_sort | Charfeddine, Cherine |
collection | PubMed |
description | 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 Mg(2+) 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. |
format | Online Article Text |
id | pubmed-8528321 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-85283212021-10-21 Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis—Like Autosomal Recessive Congenital Ichthyosis Charfeddine, Cherine Laroussi, Nadia Mkaouar, Rahma Jouini, Raja Khayat, Olfa Redissi, Aladin Mosbah, Amor Dallali, Hamza Chedly Debbiche, Achraf Zaouak, Anissa Fenniche, Sami Abdelhak, Sonia Hammami-Ghorbel, Houda PLoS One Research Article 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 Mg(2+) 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. Public Library of Science 2021-10-20 /pmc/articles/PMC8528321/ /pubmed/34669720 http://dx.doi.org/10.1371/journal.pone.0258777 Text en © 2021 Charfeddine et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Charfeddine, Cherine Laroussi, Nadia Mkaouar, Rahma Jouini, Raja Khayat, Olfa Redissi, Aladin Mosbah, Amor Dallali, Hamza Chedly Debbiche, Achraf Zaouak, Anissa Fenniche, Sami Abdelhak, Sonia Hammami-Ghorbel, Houda Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis—Like Autosomal Recessive Congenital Ichthyosis |
title | Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis—Like Autosomal Recessive Congenital Ichthyosis |
title_full | Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis—Like Autosomal Recessive Congenital Ichthyosis |
title_fullStr | Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis—Like Autosomal Recessive Congenital Ichthyosis |
title_full_unstemmed | Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis—Like Autosomal Recessive Congenital Ichthyosis |
title_short | Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis—Like Autosomal Recessive Congenital Ichthyosis |
title_sort | expanding the clinical phenotype associated with nipal4 mutation: study of a tunisian consanguineous family with erythrokeratodermia variabilis—like autosomal recessive congenital ichthyosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528321/ https://www.ncbi.nlm.nih.gov/pubmed/34669720 http://dx.doi.org/10.1371/journal.pone.0258777 |
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