Novel mutation inNIPAL4in a Romanian family with autosomal recessive congenital ichthyosis

Abstract

Autosomal recessive congenital ichthyosis (ARCI), a severe and highly clinically heterogeneous group of mendelian disorders of cornification, is the result of mutations in at least nine genes regulating the epidermal barrier functionality. NIPAL4 is the second most frequently mutated ARCI gene. We report two adult patients from a nonconsanguineous family of Romanian origin, who had lamellar ichthyosis. A positive in situ transglutaminase 1 activity assay excluded a putative TGM1 mutation. NIPAL4 sequencing revealed in both patients a new homozygous missense mutation, c.403A>C, affecting a highly conserved amino acid (p. Ser135Arg) and predicted to be deleterious according to in silico analysis. In addition to the ARCI features, the patients had caries and partial edentation. Although delay in dental treatment led to caries progression and extraction of secondary teeth, this finding raises the possibility of a deficiency in enamel mineralization due to NIPAL4 dysfunction as an Mg(2+) transporter. Evaluating new patients with ARCI provides fruitful clinical and molecular findings.

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

“…An interesting aspect in NIPAL4 mutated ARCI patients is the oral involvement, which we described in the 2 patients previously reported (11). Extensive teeth destruction and caries were present in the 3 patients from the current study, with subsequent partial edentation, possibly due to the implication of NIPAL4 in the regulation of magnesium levels in enamel, an interesting hypothesis for future studies (20).…”

“…The 3 patients presented here were also part of a study on TGase1 deficiency that included 18 Romanian ARCI patients (24), of which we previously reported 2 other patients with a different new NIPAL4 mutation (11). Thus the total number of cases identified with NIPAL4 mutations was 5 out of 18; furthermore, only 3 cases of TGM1 mutations were found.…”

“…A large study found NIPAL4 mutations in 16% of ARCI patients, second only to TGM1 defects (8), with 10 different NIPAL4 mutations described in 39 families of various origins worldwide: c.403C>A, c.425G>T, c.433C>T, c.464-1G>A, c.527C>A, c.623C>T, c.688G>A, c.709C>G, c.772+1G>A and c.889G>A (5,(9)(10)(11)(12)(13).…”

A Defect in NIPAL4 Is Associated with Autosomal Recessive Congenital Ichthyosis in American Bulldogs

“…This protein, with nine predicted transmembrane domains, is thought to be a Mg 2+ transporter and plays a role in lipid metabolism during the epidermal development, but specific understanding of its function remains unknown [2, 4, 9]. To date, ten unique variants in NIPAL4 have been associated with various forms of ichthyosis in human patients, consisting of seven missense variants in exons 4, 5, and 6 [9–11], one nonsense variant in exon 2 [9], and two consensus splice site variants affecting splicing of introns 2 and 5 [10]. The nonsense and splice site variations seen in human patients, all of which are predicted to cause the production of a truncated protein, are most likely to cause a similar phenotype to the frameshift variant of the ABD.…”

Identification of a novel missense mutation in NIPAL4 gene: First 3D model construction predicted its pathogenicity

“…The NIPAL4/ichthyin is the second most frequently mutated ARCI gene (Maier, Mazereeuw-Hautier, & Tilinca, 2016). It is located on chromosome 5q33.3 and composed of 6 exons (GenBankNM_001099287) (Vahlquist, Fischer, & Törmä, 2018).…”