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).

Abstract

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.

• Authors: J Zonana, M E Elder, L C Schneider, S J Orlow, C Moss, M Golabi, S K Shapira, P A Farndon, D W Wara, S A Emmal, B M Ferguson
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 67 Issue 6 Pg. 1555-62 (Dec 2000) ISSN: 0002-9297 [Print] United States
• PMID: 11047757 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• NF-kappa B
• Protein Serine-Threonine Kinases
• CHUK protein, human
• I-kappa B Kinase
• IKBKB protein, human
• IKBKE protein, human

Topics

• Adolescent
• Alleles
• Base Sequence
• Child
• Child, Preschool
• DNA Mutational Analysis
• Ectodermal Dysplasia (complications, genetics)
• Exons (genetics)
• Female
• Genes, Recessive (genetics)
• Genetic Linkage (genetics)
• Humans
• I-kappa B Kinase
• Immunologic Deficiency Syndromes (complications, genetics)
• Incontinentia Pigmenti (genetics)
• Infant
• Infant, Newborn
• Male
• Mutation (genetics)
• NF-kappa B (physiology)
• Pedigree
• Protein Serine-Threonine Kinases (chemistry, genetics)
• Protein Structure, Tertiary
• X Chromosome (genetics)