A Mongolian patient with hypohidrotic ectodermal dysplasia with a novel P121S variant in EDARADD

Suda, Naoto; Bazar, A; Bold, O; Jigjid, B; Garidkhuu, Ariuntuul; Ganburged, Ganjargal; Moriyama, Keiji

doi:10.1111/j.1601-6343.2010.01484.x

Cited by 10 publications

(5 citation statements)

References 15 publications

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“…To date, four EDARADD mutations have been found in a subset of human HED, one leads to autosomal dominant inheritance (Leu112Arg) [26], while the others lead to autosomal recessive inheritance (Glu142Lys, Pro121Ser, and Thr135-Val136del) [6,28,29]. All of these mutations are located in the DD and functional analyses showed that they resulted in the failure of EDARADD to interact with EDAR and to activate NF-κB.…”

Section: Discussionmentioning

confidence: 99%

A rat model of hypohidrotic ectodermal dysplasia carries a missense mutation in the Edaradd gene

et al. 2011

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BackgroundHypohidrotic ectodermal dysplasia (HED) is a congenital disorder characterized by sparse hair, oligodontia, and inability to sweat. It is caused by mutations in any of three Eda pathway genes: ectodysplasin (Eda), Eda receptor (Edar), and Edar-associated death domain (Edaradd), which encode ligand, receptor, and intracellular adaptor molecule, respectively. The Eda signaling pathway activates NF-κB, which is central to ectodermal differentiation. Although the causative genes and the molecular pathway affecting HED have been identified, no curative treatment for HED has been established. Previously, we found a rat spontaneous mutation that caused defects in hair follicles and named it sparse-and-wavy (swh). Here, we have established the swh rat as the first rat model of HED and successfully identified the swh mutation.ResultsThe swh/swh rat showed sparse hair, abnormal morphology of teeth, and absence of sweat glands. The ectoderm-derived glands, meibomian, preputial, and tongue glands, were absent. We mapped the swh mutation to the most telomeric part of rat Chr 7 and found a Pro153Ser missense mutation in the Edaradd gene. This mutation was located in the death domain of EDARADD, which is crucial for signal transduction and resulted in failure to activate NF-κB.ConclusionsThese findings suggest that swh is a loss-of-function mutation in the rat Edaradd and indicate that the swh/swh rat would be an excellent animal model of HED that could be used to investigate the pathological basis of the disease and the development of new therapies.

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Section: Discussionmentioning

confidence: 99%

A rat model of hypohidrotic ectodermal dysplasia carries a missense mutation in the Edaradd gene

et al. 2011

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“…Our nomenclature of mutations refers to the longer transcript variant A (RefSeq NM_145861.2) [Yan et al, ]. To date, six different HED‐causing mutations in the gene EDARADD have been reported [Headon et al, ; Bal et al, ; Chassaing et al, ; Suda et al, ; Cluzeau et al, ; Koguchi‐Yoshioka et al, ]. In this study, we identified the causative mutation in members of a German, non‐consanguineous family with more than just the typical symptoms of HED.…”

Section: Introductionmentioning

confidence: 97%

A novel missense mutation in the gene EDARADD associated with an unusual phenotype of hypohidrotic ectodermal dysplasia

Wohlfart

Söder

Smahi

et al. 2015

American J of Med Genetics Pt A

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Hypohidrotic ectodermal dysplasia (HED) is a rare disorder characterized by deficient development of structures derived from the ectoderm including hair, nails, eccrine glands, and teeth. HED forms that are caused by mutations in the genes EDA, EDAR, or EDARADD may show almost identical phenotypes, explained by a common signaling pathway. Proper interaction of the proteins encoded by these three genes is important for the activation of the NF-κB signaling pathway and subsequent transcription of the target genes. Mutations in the gene EDARADD are most rarely implicated in HED. Here we describe a novel missense mutation, c.367G>A (p.Asp123Asn), in this gene which did not appear to influence the interaction between EDAR and EDARADD proteins, but led to an impaired ability to activate NF-κB signaling. Female members of the affected family showed either unilateral or bilateral amazia. In addition, an affected girl developed bilateral ovarian teratomas, possibly associated with her genetic condition.

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“…To date, ten different mutations in EDARADD have been associated with HED, with only three of these being deletion or insertion [ 4 , 5 , 7 , 8 , 15 – 19 ], and different possible molecular pathogenic mechanisms have been hypothesized (disruption of the interaction with EDAR; impairment of the wild-type EDARADD ability to activate NF-kB, disturbance of the multimerization of EDARADD). Additionally, a homozygous gross deletion c.131-?_189+?del was reported with a loss-of-function mechanism.…”

Section: Discussionmentioning

confidence: 99%

Novel homozygous frameshift insertion variant in the last exon of the EDARADD causing hypohidrotic ectodermal dysplasia in two siblings: case report and review of the literature

Kablan,

Tasdelen

2024

Ital J Pediatr

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Background Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that results in the abnormal development of structures derived from ectodermal tissue. This rare condition predominantly affects the hair, nails, eccrine glands, and teeth. While HED can be caused by various genes, the EDA, EDAR, EDARADD, and WNT10A genes account for approximately 90% of cases. Notably, HED forms associated with variants in the EDA, EDAR, or EDARADD genes may exhibit similar phenotypes due to defects in a common signaling pathway. Proper interaction among the products of these genes is crucial for the activation of the nuclear factor (NF-κB) signaling pathway, which subsequently regulates the transcription of targeted genes. The EDARADD gene, in particular, harbors one of the rarest reported variants associated with HED. Case presentation Five-and two-years-old brothers born into consanguineous parents were examined at our outpatient medical genetics clinic at Sanliurfa Training and Research Hospital, Turkey. Both displayed the same classical phenotypic features of HED. The elder had a very sparse dark and brittle hair, sparse eyebrows and eyelashes, conical upper and lower premolar teeth with hypodontia, widely spaced teeth, very dry skin, mildly prominent forehead, and periorbital wrinkles. The younger one showed the same, but less severe, clinical features. After thorough examination and patient history evaluation, targeted next-generation sequencing analysis yielded the novel homozygous insertion variant c.322_323insCGGGC p.(Arg108ProfsTer7) in EDARADD. The mutation has not been reported to date in the literature. Conclusions In this report, we present two siblings exhibiting classical HED symptoms and a novel insertion variant of the EDARADD gene, which leads to a frameshift introducing a stop codon. Both brothers inherited such mutation from their parents, who were heterozygous carriers of the same variant. The present study may shed light about the pathogenic mechanisms underlying HED, and expand the spectrum of EDARADD gene variants associated with this condition.

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A Mongolian patient with hypohidrotic ectodermal dysplasia with a novel P121S variant in EDARADD

Abstract: This study reports an individual affected with hypohidrotic ectodermal dysplasia with a novel heterozygous P121S variant in the death domain of EDARADD.

Cited by 10 publications

References 15 publications

A rat model of hypohidrotic ectodermal dysplasia carries a missense mutation in the Edaradd gene

A rat model of hypohidrotic ectodermal dysplasia carries a missense mutation in the Edaradd gene

A novel missense mutation in the gene EDARADD associated with an unusual phenotype of hypohidrotic ectodermal dysplasia

Novel homozygous frameshift insertion variant in the last exon of the EDARADD causing hypohidrotic ectodermal dysplasia in two siblings: case report and review of the literature

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