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

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258777
Author(s):  
Cherine Charfeddine ◽  
Nadia Laroussi ◽  
Rahma Mkaouar ◽  
Raja Jouini ◽  
Olfa Khayat ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Mutational Analysis ◽  
Clinical Phenotype ◽  
Homozygous Mutation ◽  
Congenital Ichthyosis ◽  
Whole Exome ◽  
Genes Encoding ◽  
Autosomal Recessive Congenital Ichthyosis ◽  
Connexin Genes ◽  
Disorder Of Cornification

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.

scholarly journals Variants in the PNPLA1 Gene in Families with Autosomal Recessive Congenital Ichthyosis Reveal Clinical Significance

2021 ◽  
pp. 1-11
Author(s):  
Farooq Ahmad ◽  
Ishtiaq Ahmed ◽  
Qamre Alam ◽  
Tanveer Ahmad ◽  
Ammara Khan ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
Genetic Disorders ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Sequence Variant ◽  
Phenotype Correlation ◽  
Congenital Ichthyosis ◽  
Whole Exome ◽  
Autosomal Recessive Congenital Ichthyosis

The term autosomal recessive congenital ichthyosis (ARCI) is the subgroup of ichthyosis, which describes a highly heterogeneous group of genetic disorders of the skin characterized by cornification and defective keratinocytes differentiation associated with mutations in at least 14 genes including <i>PNPLA1</i>. To study the molecular basis of the Pakistani kindreds (A and B) affected by ARCI, whole-exome sequencing (WES) in the DNA samples of affected members was performed followed by Sanger sequencing of the candidate gene to hunt down the disease-causing sequence variant/s. WES data analysis led to the identification of a novel nonsense sequence variant (c.892C&#x3e;T; p.Arg298*, family A) and a recurrent missense variant (c.102C&#x3e;A; p.Asp34Glu, family B) in <i>PNPLA1</i> mapped to the ARCI locus in chromosome 6p21.31. Validation and cosegregation analysis of the variants in the remaining family members of the respective families were confirmed by Sanger sequencing. The current investigation expands the spectrum of <i>PNPLA1</i> mutations and helps establish the proper clinico-genetic diagnosis and correct genotype-phenotype correlation.

scholarly journals NIPAL4 mutation c.527C˃A identified in Romanian patients with autosomal recessive congenital ichthyosis

2016 ◽  
Vol 24 (4) ◽  
pp. 387-398
Author(s):  
Dalila Maier ◽  
Adrian Florea ◽  
Mariana Cornelia Tilinca ◽  
Ancuța Zazgyva ◽  
Rodica Cosgarea
Keyword(s):  
Autosomal Recessive ◽  
Direct Sequencing ◽  
Case Series ◽  
Skin Condition ◽  
Current Data ◽  
Homozygous Mutation ◽  
Congenital Ichthyosis ◽  
Transglutaminase 1 ◽  
Autosomal Recessive Congenital Ichthyosis

Abstract Introduction: Autosomal recessive congenital ichthyosis is a non-syndromic ichthyosis, with a genetic background of mutations in 9 genes. This case series presents clinical and paraclinical particularities of 3 Romanian ARCI patients with NIPAL4 mutation c.527C>A. Material and methods: Three Caucasian patients were investigated, two sisters and an unrelated female patient, aged 47, 49, and 42 respectively. Skin anomalies were recorded and documented photographically; peripheral blood samples were harvested for DNA extraction and gene analysis. Skin biopsies were used for histological assessment, electron microscopy, and evaluation of in situ transglutaminase 1 activity. Results: All patients presented with generalized ichthyosis, palmoplantar keratoderma, normal hair shafts, and significant oral manifestations. Natural evolution was relatively stable in all cases, without phenotype changing. Medical treatment with retinoids in patients 1 and 2 resulted in normalisation of the skin condition. Histological samples showed hyperkeratosis, acanthosisand perivascular inflammatory infiltrates in the dermis. Positive findings of transglutaminase 1 in situ activity excluded TGM1 deficiency. Direct sequencing of amplicons revealed one homozygous mutation in exon 4, a c.527C>A missense mutation. Conclusions: This is the first report of the hotspot mutation NIPAL4 c.527C>A in Romanian autosomal recessive congenital ichthyosis patients. The phenotype was similar to that reported in the literature, while transglutaminase 1 activity in situ assay detected differences in enzyme distribution between patients bearing the same mutation but different phenotypes. Based on the current data, NIPAL4 mutations are more frequent than TGM1 mutations in Romanian patients with autosomal recessive congenital ichthyosis.

scholarly journals Autosomal Recessive Congenital Ichthyosis and Steroid-Resistant Nephrotic Syndrome due to Homozygous Mutation in the ALOX12B gene: A Novel Association with Review of Literature

2020 ◽  
Author(s):  
Lesa Dawman ◽  
Anit Kaur ◽  
Ritambhra Nada ◽  
Soumalya Chakraborty ◽  
Sanjeev Handa ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Autosomal Recessive ◽  
Skin Lesions ◽  
Homozygous Mutation ◽  
Steroid Resistant ◽  
Congenital Ichthyosis ◽  
Autosomal Recessive Congenital Ichthyosis ◽  
Novel Association ◽  
History Of

AbstractNephrotic syndrome (NS) associated with autosomal recessive congenital ichthyosis (ARCI) is a rare association. We describe a 4-year-old boy with steroid-resistant NS (SRNS) who had a history of ichthyotic skin lesions since birth. Renal biopsy revealed focal segmental glomerulosclerosis (tip variant). The skin biopsy was consistent with the findings of ichthyosis. Next-generation sequencing revealed a homozygous pathogenic variant (c.1625_1626del) in the exon 12 of the ALOX12B gene, confirming the diagnosis of ARCI2. The ALOX12B gene belongs to the lipoxygenase family and has a pivotal role in the formation of lipid layers in the epidermis. Leukotrienes have a counter-regulatory effect within the inflamed glomeruli, which influences the vascular tone and glomerular basement membrane permeability, that can be implicated in the pathogenesis of the NS. This child is currently in remission, on tacrolimus and low-dose prednisolone, with emollients and is on regular follow-up. SRNS associated with congenital ichthyosis secondary to a mutation in the ALOX12B gene has never been reported so far. The knowledge regarding this novel association will help the treating physicians in diagnosing this condition early, which will enable proper genetic counseling and prognostication of the disease to the family.

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