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...

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Autores principales:	Cherine Charfeddine, Nadia Laroussi, Rahma Mkaouar, Raja Jouini, Olfa Khayat, Aladin Redissi, Amor Mosbah, Hamza Dallali, Achraf Chedly Debbiche, Anissa Zaouak, Sami Fenniche, Sonia Abdelhak, Houda Hammami-Ghorbel
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/09f5de1e44634ec2bcdc6744e8287381
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spelling	oai:doaj.org-article:09f5de1e44634ec2bcdc6744e82873812021-12-02T20:16:45ZExpanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis-Like Autosomal Recessive Congenital Ichthyosis.1932-620310.1371/journal.pone.0258777https://doaj.org/article/09f5de1e44634ec2bcdc6744e82873812021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0258777https://doaj.org/toc/1932-6203Erythrokeratodermia 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.Cherine CharfeddineNadia LaroussiRahma MkaouarRaja JouiniOlfa KhayatAladin RedissiAmor MosbahHamza DallaliAchraf Chedly DebbicheAnissa ZaouakSami FennicheSonia AbdelhakHouda Hammami-GhorbelPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 10, p e0258777 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cherine Charfeddine Nadia Laroussi Rahma Mkaouar Raja Jouini Olfa Khayat Aladin Redissi Amor Mosbah Hamza Dallali Achraf Chedly Debbiche Anissa Zaouak Sami Fenniche Sonia Abdelhak Houda Hammami-Ghorbel Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis-Like Autosomal Recessive Congenital Ichthyosis.
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 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.
format	article
author	Cherine Charfeddine Nadia Laroussi Rahma Mkaouar Raja Jouini Olfa Khayat Aladin Redissi Amor Mosbah Hamza Dallali Achraf Chedly Debbiche Anissa Zaouak Sami Fenniche Sonia Abdelhak Houda Hammami-Ghorbel
author_facet	Cherine Charfeddine Nadia Laroussi Rahma Mkaouar Raja Jouini Olfa Khayat Aladin Redissi Amor Mosbah Hamza Dallali Achraf Chedly Debbiche Anissa Zaouak Sami Fenniche Sonia Abdelhak Houda Hammami-Ghorbel
author_sort	Cherine Charfeddine
title	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_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_sort	expanding the clinical phenotype associated with nipal4 mutation: study of a tunisian consanguineous family with erythrokeratodermia variabilis-like autosomal recessive congenital ichthyosis.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/09f5de1e44634ec2bcdc6744e8287381
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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.

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