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 (original) (raw)
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Journal of the European Academy of Dermatology and Venereology, 2010
Background Recessive X-linked ichthyosis (RXLI) (OMIM 308100) is a genodermatosis characterized by polygonal, dark, adherent and mild-to-moderate scales that normally improve during summer. RXLI is caused by a deficiency in steroid sulphatase (STS), whose gene has been located on the X chromosome (locus Xp22.3). Up to 90% of the mutations described in this gene are complete deletions. Objectives Previous reports of partial deletion of STS gene in cases of RXLI prompted us to determine the incidence of these abnormalities in a Spanish population. Methods We have studied exons 1, 5 and 10 of the STS gene by polymerase chain reaction in 40 patients with clinical features of RXLI. Results Our results revealed that 30 patients presented complete deletions (75%) while 10 patients had partial deletions (25%) a rate higher than that reported in the previous studies. Conclusions Amplification of exons 1, 5 and 10 is reliable in screening RXLI in the population studied here. No correlation was found between phenotype and the extent of the deletions.
Annals of Dermatology
Dear Editor: Inherited ichthyoses comprise a large group of cornification maladies characterized by dry, rough and scaly appearance of most or all the integument. Ichthyoses have a heterogenous genetic background with ＞50 associated genes segregating in autosomal recessive/dominant and Xlinked inheritance pattern. Its subtypes can be distinguished based on the pattern of hyperkeratosis/scaling, mode of inheritance, onset and alterations over time, manifestations in other organs, and family history. Yet, the phenotypic heterogeneity occasionally necessitates laboratory investigations and genetic analysis for proper diagnosis 1 .
Introduction: X-linked recessive ichthyosis (XLI) is a genodermatosis, caused by a deficiency of the steroid sulphatase enzyme encoded by the STS gene (OMIM # 300747). Adopted XLI molecular diagnosis approaches differ from one laboratory to another depending on available technical facilities. Our work aims to figure out a sound diagnostic strategy for XLI.Patients and Methods: We collected 8 patients with XLI, all males, from 3 unrelated Tunisian families from central Tunisia. Genetic diagnosis was conducted through a large panel of genetic techniques including: Sanger Sequencing, haplotype analysis of STR markers, MLPA analysis, FISH and array CGH.Results: Direct Sanger sequencing of the STS gene showed the same deletion of 13 base pairs within the exon 4 in all patients resulting in a premature stop codon. However, all patients’ mothers were not carriers of this variant and no common haplotype flanking STS gene was shared between affected patients. Sequence alignment with referenc...
Most "Sporadic" Cases of X-linked Ichthyosis are not De Novo Mutations
Acta Dermato-Venereologica, 1999
X-linked ichthyosis is an inherited disease with dark, regular and adherent scales as clinical characteristics. It is caused by a de¢ciency of the steroid sulphatase enzyme. Steroid sulphatase assay is a relative easy tool that enables correct diagnosis of X-linked ichthyosis patients and carriers. A large number of X-linked ichthyosis patients correspond to non-familial cases that seem to represent de novo mutations. In this study, we examined the X-linked ichthyosis carrier state of the mothers of 42 non-familial cases to determine whether their children corresponded to de novo mutations. To classify patients and carriers, a steroid sulphatase assay was performed in leukocytes using 7-[ 3 H]-dehydroepiandrosterone sulphate as substrate. In 36 mothers (85%) we found steroid sulphatase activity compatible with the carrier state of Xlinked ichthyosis. This data suggest that most of the mothers of these patients present the primary gene defect, excluding de novo mutations in the patients.
Molecular Genetics of Keratinization Disorders – What’s New About Ichthyosis
Acta Dermato Venereologica
Patients with ichthyosis manifest with dry and scaly skin, with considerable phenotypic variability. The heritable forms of ichthyosis are associated with mutations in over 60 different genes which encode proteins critical for normal physiological function of the skin. This overview highlights some of the new findings in the genetics of heritable forms of ichthyosis and emphasizes the connection of skin findings to extracutaneous manifestations, in some forms of the syndromic ichthyosis. The presentation also emphasizes the importance of determining the specific mutations in the underlying genes, which allows subclassification of the patients into distinct categories, with the capability to prognosticate the severity and the overall outcome of the disease in general terms. The knowledge of mutations in specific genes is also required for application of allele-specific therapies being developed for this group of disorders currently without specific treatments. The heritable forms of keratinization disorders, including various forms of ichthyosis and keratodermas, comprise a phenotypically heterogeneous group of diseases which can be divided into syndromic and nonsyndromic forms. In the non-syndromic forms, the clinical manifestations are limited to the cutaneous structures while the syndromic ones are associated with a spectrum of extracutaneous manifestations. The inheritance in different families can be autosomal dominant, autosomal recessive or either X-linked dominant or recessive. Currently at least 67 distinct genes have been associated with different forms of ichthyosis. These genes can be grouped on the basis of their physiological involvement, including genes encoding structural components of epidermis, those involved in epidermal lipid metabolism, or those critical for cell-cell adhesion, and keratinocyte differentiation. This overview highlights some of the recent progress made in understanding the molecular genetics of keratinization disorders, and presents selected, recently characterized cases as representative of different forms of heritable ichthyosis.
Human Mutation, 2018
Autosomal recessive congenital ichthyosis (ARCI), a phenotypically heterogeneous group of nonsyndromic Mendelian disorders of keratinization, is caused by mutations in as many as 13 distinct genes. We examined a cohort of 125 consanguineous families with ARCI for underlying genetic mutations. The patients' DNA was analyzed with a gene-targeted next generation sequencing panel comprising 38 ichthyosis associated genes. The interpretations of results of genomic data was assisted by genome-wide homozygosity mapping and transcriptome sequencing. Sequence data analysis identified biallelic mutations in 106 families out of a total of 125 (85%), most of them (102, 96.2%) being homozygous, reflecting consanguinity in these families. Among the 85 distinct mutations in 10 different genes, 45 (53%) were previously unreported. Phenotype-genotype correlations allowed assignment of specific genes in the majority of the families to a specific subtype of ARCI, lamellar ichthyosis (LI) vs. congenital ichthyosiform erythroderma (CIE). Interestingly, mutations in several genes could give rise to an overlapped phenotype consistent with either LI or CIE. Also, this is the third report for SDR9C7, SULT2B1 and fourth report for CERS3 mutations. Direct comparison of our results with previously published regional cohorts highlights the global mutation landscape of ARCI, however, population specific differences were noted.
X-linked ichthyosis without STS deficiency: Clinical, genetical, and molecular studies
American Journal of Medical Genetics, 1995
We report on a Sardinian pedigree with congenital ichthyosis associated with normal levels of steroid sulfatase and a normal molecular pattern, as detectable with a cDNA probe for the steroid sulfatase (STS) gene. Though the pattern of transmission of the disease is consistent with X-linked recessive inheritance, this form of ichthyosis was found to segregate independently of genetic polymorphisms detected by probes of the region Xp22.3, where the STS locus has been mapped. The search for close genetic linkages with other polymorphic markers scattered along the entire X chromosome has so far been fruitless. For the time being, the main conclusion derived from these data is that STS deficiency is not a sine qua non for X-linked ichthyosis which may also result from a mutational event at an X-chromoso-ma1 site genetically unlinked to the STS locus. 0 1995 Wiley-Liss, Inc.
Genetics of Inherited Ichthyoses and Related Diseases
Acta Dermato Venereologica, 2020
This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Acta Derm Venereol 2020; 100: adv00096 Centenary theme section: GENODERMATOSES SIGNIFICANCE Knowledge of the molecular genetic causes and mechanisms of hereditary ichthyoses has increased hugely since the 1990s due to the ubiquitous application of modern sequencing technologies. It is important for doctors and scientists that this new knowledge is clinically and genetically correctly classified, in order to make diagnosis and differential diagnosis easier. This article provides an overview of the genetic background and clinical features of ichthyoses and related cornification disorders. Inherited ichthyoses are classified as Mendelian disorders of cornification (MEDOC), which are defined on the basis of clinical and genetic features and are mainly divided into non-syndromic and syndromic ichthyoses. Numerous genes, which encode for corresponding proteins, are involved in the normal differentiation of keratinocytes (cornification) and participate in the formation of a functional epidermal barrier. To date, mutations in more than 50 genes are known to result in various types of ichthyoses. Thanks to modern genetic diagnostic methods based on targeted next generation sequencing (NGS), approximately 80-90% of cases can be resolved at present. Further sequencing methods covering the whole exome (WES) or whole genome (WGS) will obviously elucidate another portion of the remaining unknown ichthyoses in the future.