title: 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.affiliation: Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland, OR 97221, USA. zonanaj@ohsu.edu
authors.forename: J
authors.initials: J
authors.lastname: Zonana
authors.forename: M E
authors.initials: ME
authors.lastname: Elder
authors.forename: L C
authors.initials: LC
authors.lastname: Schneider
authors.forename: S J
authors.initials: SJ
authors.lastname: Orlow
authors.forename: C
authors.initials: C
authors.lastname: Moss
authors.forename: M
authors.initials: M
authors.lastname: Golabi
authors.forename: S K
authors.initials: SK
authors.lastname: Shapira
authors.forename: P A
authors.initials: PA
authors.lastname: Farndon
authors.forename: D W
authors.initials: DW
authors.lastname: Wara
authors.forename: S A
authors.initials: SA
authors.lastname: Emmal
authors.forename: B M
authors.initials: BM
authors.lastname: Ferguson
mesh_terms: D000293:Adolescent; D000483:Alleles; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004476:Ectodermal Dysplasia / Q000150:complications / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D051550:I-kappa B Kinase; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000235:genetics*; D007184:Incontinentia Pigmenti / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D016328:NF-kappa B / Q000502:physiology; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics*; D017434:Protein Structure, Tertiary; D014960:X Chromosome / Q000235:genetics*
chemical_list: D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human