A disease-causing novel missense mutation in the ST14 gene underlies autosomal recessive ichthyosis with hypotrichosis syndrome in a consanguineous family

Abstract

Autosomal recessive ichthyosis with hypotrichosis (ARIH; MIM 602400) syndrome is characterized by diffused congenital ichthyosis and generalized non-scarring hypotrichosis. The underlying genetic cause of ARIH syndrome has been associated with sequence variants of the gene ST14, encoding type II transmembrane serine protease matriptase, which maps to chromosome 11q24.3. The current report aimed to investigate the clinical features and genetic cause of ARIH syndrome in a large consanguineous family of Pakistani origin. The technique of homozygosity mapping with highly polymorphic microsatellite markers was employed to establish linkage within the family. Sanger sequencing of exons and intron-exon boundaries of ST14 was performed to identify the potential pathogenic sequence variants, followed by structural analysis of the mutated protein. Linkage was established to chromosome 11q24.3, comprising the gene ST14. Sequence analysis led to the identification of a novel homozygous missense variant (c.1315G>A, p.Gly439Ser) in the ST14 gene that co-segregated with the disease phenotype in all affected members. Homology modelling and molecular docking analysis of ST14 with wild-type TMEFF1 protein was performed which revealed that glycine at position 439 is crucial for maintaining normal structural confirmation and interaction with the EGF domain of TMEFF1 protein. Taken together, the data strongly advocate this ST14 variant as the underlying genetic cause of ARIH syndrome in this first reported affected family from Pakistan. Moreover, the present study adds to the spectrum of mutations in the ST14 gene, implicating them in the pathogenesis of ARIH syndrome.

Keywords: ST14 gene; autosomal recessive ichthyosis with hypotrichosis syndrome; novel missense variant.

Figure 1.

A) Pedigree of the five-generation consanguineous Pakistani family, displaying the features of autosomal recessive ichthyosis with hypotrichosis (ARIH) syndrome. Consanguineous unions are represented by double lines. Males are represented by squares and females by circles. Filled symbols indicate affected family members and unaffected individuals are represented by clear symbols. A diagonal line indicates a deceased individual. B, C, D, E, F) The clinical appearance of affected individuals with the features of ARIH syndrome. B) Hypotrichosis; scalp hairs appear light-brown, woolly, curly, and lustreless with receding frontal hair line and sparse eyebrows and eyelashes. C) Chest area with diffuse and dry scales. D) Facial area showing sparse eyebrows and eyelashes, dry facial skin, with mild and diffuse scales. (E) Lower back area, severely affected with dark brown scales. F) Neck area, severely affected by dry and diffuse scales.

Figure 2.

Sequence analysis of the ST14 gene revealing the mutation c.1315G>A (p.Gly439Ser). Upper panel (A) represents the nucleotide sequence of an affected individual, middle panel (B) a heterozygous carrier, and lower panel (C) a homozygous normal individual. The arrow indicates the missense mutation.

Figure 3.

Upper panel: schematic representation of the coding region of the ST14 gene alongside known protein structural and functional domains (intronic regions are not drawn to scale). The location of all mutations known to date is also indicated. The novel missense mutation c.1315G>A (p.Gly439Ser), identified in the present report, is indicated in red; this affects the second CUB domain of the mature ST14 protein. Lower panel: Sequence comparison of the ST14 gene across different species, highlighting homology and the conserved glycine residue at position 439.

Figure 4.

(A) Representation of predicted structure of the CUB domain of human ST14 protein, with beta sheet in red, alpha helices in cyan, and loop in pink. Close-up view showing (B) the wild-type domain with Gly439 and (C) the mutant domain with Ser439; in the latter, a hydrogen bond is depicted (green dotted line) between Ser439 and Ser353.

Figure 5.

Visualization of optimal docking for the ST14 (CUB domain)-TMEFF1 complex. A) Detailed structure and (B) surface view of wild-type ST14 interacting with TMEFF1; C) detailed structure and (D) surface view of mutated ST14 interacting with TMEFF1 (ST14 is depicted in cyan and TMEFF1 in green). Interacting residues are shown in stick representation and hydrogen bonds are highlighted by a black dotted line.