A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO)

Jonathan Zonana, Melissa E. Elder, Lynda C. Schneider, Seth J. Orlow, Celia Moss, Mahin Golabi, Stuart K. Shapira, Peter A. Farndon, Diane W. Wara, Stephanie A. Emmal, Betsy M. Ferguson

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385 Scopus citations


Hypohidrotic ectodermal dysplasia (HED), a congenital disorder of teeth, hair, and eccrine sweat glands, is usually inherited as an X-linked recessive trait, although rarer autosomal dominant and recessive forms exist. We have studied males from four families with HED and immunodeficiency (HED-ID), in which the disorder segregates as an X-linked recessive trait. Affected males manifest dysgammaglobulinemia and, despite therapy, have significant morbidity and mortality from recurrent infections. Recently, mutations in IKK-gamma (NEMO) have been shown to cause familial incontinentia pigmenti (IP). Unlike HED-ID, IP affects females and, with few exceptions, causes male prenatal lethality. IKK-gamma is required for the activation of the transcription factor known as 'nuclear factor kappa B' and plays an important role in T and B cell function. We hypothesize that 'milder' mutations at this locus may cause HED-ID. In all four families, sequence analysis reveals exon 10 mutations affecting the carboxy-terminal end of the IKK-gamma protein, a domain believed to connect the IKK signalsome complex to upstream activators. The findings define a new X-linked recessive immunodeficiency syndrome, distinct from other types of HED and immunodeficiency syndromes. The data provide further evidence that the development of ectodermal appendages is mediated through a tumor necrosis factor/tumor necrosis factor receptor-like signaling pathway, with the IKK signalsome complex playing a significant role.

Original languageEnglish (US)
Pages (from-to)1555-1562
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number6
StatePublished - Jan 1 2000


ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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