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)

• Published in: American journal of human genetics 2000-12, Vol.67 (6), p.1555-1562
• Main Authors: Zonana, Jonathan, Elder, Melissa E., Schneider, Lynda C., Orlow, Seth J., Moss, Celia, Golabi, Mahin, Shapira, Stuart K., Farndon, Peter A., Wara, Diane W., Emmal, Stephanie A., Ferguson, Betsy M.
• Format: Article
• Language: English
• Subjects: Adolescent; Alleles; Base Sequence; Biological and medical sciences; Child; Child, Preschool; Complex syndromes; DNA Mutational Analysis; Ectodermal Dysplasia - complications; Ectodermal Dysplasia - genetics; Exons - genetics; Female; Genes, Recessive - genetics; Genetic Linkage - genetics; Humans; I-kappa B Kinase; Immunologic Deficiency Syndromes - complications; Immunologic Deficiency Syndromes - genetics; Incontinentia Pigmenti - genetics; Infant; Infant, Newborn; Male; Medical genetics; Medical sciences; Mutation - genetics; NF-kappa B - physiology; Pedigree; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases - chemistry; Protein-Serine-Threonine Kinases - genetics; X Chromosome - genetics
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/316914

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.