A novel nonsense mutation in the STS gene in a Pakistani family with X-linked recessive ichthyosis: including a very rare case of two homozygous female patients

Abstract

Background: X-linked ichthyosis (XLI; OMIM# 308100) is a recessive keratinization disorder characterized by the presence of dark brown, polygonal, adherent scales on different parts of the body surface. It almost exclusively affects males and the estimated prevalence ranges from 1:2000-6000 in males worldwide. Extracutaneous manifestations are frequent including corneal opacities, cryptorchidism, neuropsychiatric symptoms or others. Up to 90% of XLI cases are caused by recurrent hemizygous microdeletion encompassing entire STS gene on chromosome Xp22.3, while only a minority of patients shows partial deletions or loss of function point mutations in STS. Larger deletions also involving contiguous genes are identified in syndromic patients.

Methods: Here, we report clinical and genetic findings of a large Pakistani family having 16 affected individuals including 2 females with XLI. Molecular karyotyping and direct DNA sequencing of coding region of the STS gene was performed.

Results: The clinical manifestations in affected individuals involved generalized dryness and scaling of the skin with polygonal, dark scales of the skin on scalp, trunk, limbs, and neck while sparing face, palms and soles. There were no associated extra-cutaneous features such as short stature, cryptorchidism, photophobia, corneal opacities, male baldness, and behavioral, cognitive, or neurological phenotypes including intellectual disability, autism or attention deficit hyperactivity disorder. Molecular karyotyping was normal and no copy number variation was found. Sanger sequencing identified a novel hemizygous nonsense mutation (c.287G > A; p.W96*), in exon 4 of STS gene in all affected male individuals. In addition, two XLI affected females in the family were found to be homozygous for the identified variant.

Conclusions: This study is useful for understanding the genetic basis of XLI in the patients studied, for extending the known mutational spectrum of STS, diagnosis of female carriers and for further application of mutation screening in the genetic counseling of this family.

Keywords: Affected females; P,W96*; Pakistan; STS gene; Steroid sulfatase; X-linked ichthyosis.

Fig. 1

Identification of a novel nonsense mutation in STS gene (A) Pedigree of the family with X-linked ichthyosis. The proband (IV:23) is noted with an arrow. ■, affected male; ●, affected female; ◻, healthy male; ○, healthy female. (B) Sequencing chromatogram showing the wild type normal control hemizygous affected male and heterozygous female carrier, with mutation position marked by an arrow. (C) Schematic representation of exon-intron structure of STS gene; exons are designated as boxes E (1–10). DNA and protein sequence of the exon 4 where the mutation c.287G > A (p.W96*) resides is shown expanded. Nucleotide and amino acid numbering correspond to NM_000351 for the cDNA and NP_000342.2 for the protein. Nucleotides were numbered using A of the ATG translation initiation codon as + 1 nucleotide of the coding sequence. (D) A ribbon diagram showing the secondary and tertiary structures of the wild type STS enzyme. Sheets are drawn in yellow, helices in red and loop regions in green. (a) showing β-sheets, α-helices and coils. The structure (b) denotes the potential truncated polypeptide (STS enzyme) due to p.W96* mutation (Swiss-Model). (E) Schematic illustration of the domain graph of the encoded STS protein (Uniprot identifier: P08842), and the genetic variants. A full-length wild type STS protein is shown, with its N-terminus and C-terminus. Novel variant identified in our study is boxed in red alongside previously reported point mutations and a splice- site variant underlying XLI phenotype in The Human Gene Mutation Database (HGMD®; http://www.hgmd.cf.ac.uk)

Fig. 2

Clinical findings of XLI patients. Photographs of skin showing thick, large, polygonal, dark-brown scales involving the trunk front and back, neck, arm and ear