A Novel Nonsense Mutation in the EDA Gene Causing X-Linked Hypohidrotic Ectodermal Dysplasia
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2019, Vol 12, Issue 3
Abstract
X-linked hypohidrotic ectodermal dysplasia (XLHED) can be characterized by hypohidrosis, sparse hair, hypodontia, and characteristic facial features and usually caused by mutations of ectodysplasin A (EDA) gene located on the X chromosome. In this study, we examined a HED pedigree and carried out molecular biological experiments of the disease. A novel nonsense mutation was revealed by direct sequencing analysis in the EDA exons (c.526 G>T). The function of the mutant EDA gene was subsequently confirmed by in vitro study in human embryonic kidney 293T cells transfected with mutant or wild isoforms of EDA. The mutant-type EDA1 sequence showed total loss of the capability of protein producing compared with wild-type EDA1. This novel nonsense EDA mutation was considered to be the cause of HED in the pedigree reported here. Our findings, combined with those reported elsewhere, provide an improved understanding of the pathogenic mechanism of HED as well as important information for a genetic diagnosis. Full-Text HTML Abstract Full-Text PDF Full-Text XML How to Cite Research Article A Novel Nonsense Mutation in the EDA Gene Causing X-Linked Hypohidrotic Ectodermal Dysplasia Liu Guannan1,2, Wang Xin1, Qin Man1, Sun Lisha3 and Zhu Junxia*1 Author Affiliations Received: December 08, 2018 | Published: December 19, 2018 Corresponding author:Zhu Junxia, Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, China DOI: 10.26717/BJSTR.2018.12.002249 Abstract X-linked hypohidrotic ectodermal dysplasia (XLHED) can be characterized by hypohidrosis, sparse hair, hypodontia, and characteristic facial features and usually caused by mutations of ectodysplasin A (EDA) gene located on the X chromosome. In this study, we examined a HED pedigree and carried out molecular biological experiments of the disease. A novel nonsense mutation was revealed by direct sequencing analysis in the EDA exons (c.526 G>T). The function of the mutant EDA gene was subsequently confirmed by in vitro study in human embryonic kidney 293T cells transfected with mutant or wild isoforms of EDA. The mutant-type EDA1 sequence showed total loss of the capability of protein producing compared with wild-type EDA1. This novel nonsense EDA mutation was considered to be the cause of HED in the pedigree reported here. Our findings, combined with those reported elsewhere, provide an improved understanding of the pathogenic mechanism of HED as well as important information for a genetic diagnosis. Keywords: Etodysplasin A; Hypohidrotic Ectodermal Dysplasia; Mutation; Nonsense Abbreviations:XLHED: X-Linked Hypohidrotic Ectodermal Dysplasia; EDA: Ectodysplasin A; HED: Hypohidrotic Ectodermal Dysplasia; SNP: Single Nucleotide Polymorphisms; TNF: Tumor Necrosis Factor; PCR: Polymerase Chain Reaction; PTC: Premature Termination Codon Introduction Ectodermal dysplasia (ED) contains a group more than 170 types of congenital disorders resulting from abnormal development of ectoderm-derived structures [1,2]. The most common type of ED, hypohidrotic ectodermal dysplasia (HED), occurs in 1 in 10,000–100,000 births [3,4]. HED is characterized by hypohidrosis, hypotrichosis, hypodontia, and characteristic facial features. The common clinical signs include dry skin, sparse hair, deformity teeth, diminishing or absence of eccrine function and characteristic facial features including frontal bossing, chin prominence, saddle nose, maxillary hypoplasia, low-set ears, wrinkles, and periorbital hyperpigmentation. Three inheritance patterns of HED are known: X-linked recessive, autosomal recessive, and autosomal dominant, corresponding to the main causative genes (EDA, EDAR and EDARADD). The X-linked HED (XLHED) is caused by mutations of ectodysplasin A (EDA) gene (Genbank accession number: NM 001399) located within the X q12-q13.1 region, causing an X-linked recessive pattern of inheritance [5,6]. The hemizygous males are often most severely affected, showing the “classic” clinical features, while heterozygous females generally show normal or moderately affected features [3-7]. The EDA-A1 protein which contains 391 amino acids, is the most common and also the largest product of the EDA gene [8]. It is a trimeric type II transmembrane protein composed of a transmembrane domain, a furin protease recognition site, a 19 repeat Gly-X-Y collagenous domain as well as a tumor necrosis factor (TNF) homology C-terminal domain [9]. To date, more than 300 mutations of the EDA gene have been reported [10], including missense, nonsense and splice mutations as well as small deletions [11,12]. 11 of the 16 nonsense mutations reported in the database of single nucleotide polymorphisms (SNP) of the National Center for Biotechnology. Information (NCBI) are described as “pathogenic”, although none has been validated in functional studies. In this study, we describe the clinical features and molecular characterization of a novel nonsense mutation identified in a Chinese family with XLHED. We also performed in vitro functional experiments to elucidate the molecular mechanisms underlying the effects of this mutation.
Authors and Affiliations
Guannan Liu, Wang Xin, Qin Man, Sun Lisha, Zhu Junxia
Keywords
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- EP ID EP586994
- DOI 10.26717/BJSTR.2018.12.002249
- Views 186
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