A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency

Courtois, G.; Smahi, Asma; Reichenbach, Janine; Döffinger, Rainer; Cancrini, Caterina; Bonnet, M; Puel, Anne; Chable‐Bessia, Christine; Shoji, Yasuhiro; Feinberg, Jacqueline; Dupuis‐Girod, Sophie; Bodemer, Christine; Livadiotti, Susanna; Novelli, Francesco; Rossi, Paolo; Fischer, Alain; Israël, Alain; Münnich, Arnold; Deist, Françoise Le; Casanova, Jean‐Laurent

doi:10.1172/jci200318714

Cited by 83 publications

(110 citation statements)

References 28 publications

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“…61,62 This new autosomal dominant form of EDA-ID shares many similarities with NEMO-related EDA-ID, but is also characterized by an unusual feature. It is associated with severely impaired T cell proliferation, something that is not observed with NEMO mutated patients.…”

Section: Eda-id (Autosomal Dominant Form)mentioning

confidence: 98%

NF-κB-related genetic diseases

Courtois

Smahi

2006

Cell Death Differ

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The recent identification of genetic diseases (incontinentia pigmenti, anhidrotic ectodermal dysplasia with immunodeficiency and cylindromatosis) resulting from mutations affecting components of the nuclear factor-jB (NF-jB) signaling pathway provides a unique opportunity to understand the function of NF-jB in vivo. Besides confirming the importance of NF-jB in innate and acquired immunity or bone mass control, analysis of these diseases has uncovered new critical roles played by this transcription factor in the development and homeostasis of the epidermis and the proper function of lymphatic vessels. In addition, the identified mutations will help understanding at the molecular level how NF-jB is activated in response to cell stimulation.

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Section: Eda-id (Autosomal Dominant Form)mentioning

confidence: 98%

NF-κB-related genetic diseases

Courtois

Smahi

2006

Cell Death Differ

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“…We and others discovered that boys with X-linked recessive EDA-ID carried hypomorphic mutations of NF-κB essential modulator (NEMO) that impaired NF-κB responses (95,96). Heterozygous gain-of-function mutations of the gene encoding the inhibitor IκBα were soon discovered in patients with an autosomal dominant form of EDA-ID (97). By spotlighting NF-κB immunity, these studies paved the way for investigations of children with IPD but without EDA.…”

Section: Invasive Pneumococcal Diseasementioning

confidence: 99%

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Casanova

2015

Proc. Natl. Acad. Sci. U.S.A.

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202

163

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This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

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“…The longest region of shared homozygosity, 42.4 MB on chromosome 14, harbors at least 435 genes, including NFKBIA, which is responsible for an autosomal dominant anhidrotic ectodermal dysplasia with T-cell immunodeficiency. 10 However, Sanger sequencing of genomic DNA from SO1-IV-1 for all coding exons of NFKBIA revealed normal sequence.…”

Section: Gene Discoverymentioning

confidence: 99%

Mutation of KREMEN1, a modulator of Wnt signaling, is responsible for ectodermal dysplasia including oligodontia in Palestinian families

et al. 2016

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Tooth development is controlled by the same processes that regulate formation of other ectodermal structures. Mutations in the genes underlying these processes may cause ectodermal dysplasia, including severe absence of primary or permanent teeth. Four consanguineous Palestinian families presented with oligodontia and hair and skin features of ectodermal dysplasia. Appearance of ectodermal dysplasia was consistent with autosomal recessive inheritance. Exome sequencing followed by genotyping of 56 informative relatives in the 4 families suggests that the phenotype is due to homozygosity for KREMEN1 p.F209S (c.626 T4C) on chromosome 22 at g.29,521,399 (hg19). The variant occurs in the highly conserved extracellular WSC domain of KREMEN1, which is known to be a high affinity receptor of Dickkopf-1, a component of the Dickkopf-Kremen-LRP6 complex, and a potent regulator of Wnt signaling. The Wnt signaling pathway is critical to development of ectodermal structures. Mutations in WNT10A, LRP6, EDA, and other genes in this pathway lead to tooth agenesis with or without other ectodermal anomalies. Our results implicate KREMEN1 for the first time in a human disorder and provide additional details on the role of the Wnt signaling in ectodermal and dental development.

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A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency

Cited by 83 publications

References 28 publications

NF-κB-related genetic diseases

NF-κB-related genetic diseases

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Mutation of KREMEN1, a modulator of Wnt signaling, is responsible for ectodermal dysplasia including oligodontia in Palestinian families

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