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.

Figure 1

Pedigrees of families with HED-ID. Black squares denote affected males; circles containing dots denote carrier females. (−) = Mutant allele; (+) = wild-type allele.

Figure 2

Affected males from each family: HED-ID 1 (a), HED-ID 2 (b), HED-ID 3 (c), and HED-ID 4 (d). Note the hypodontia and conical-shaped teeth and the periorbital wrinkling and darkening in panels a and c. Scalp hair of the affected individuals is variable, with a normal appearance in panels a and b, mild thinning in panel c, and sparse thin hair in panel d.

Figure 3

Relevant mutant (upper graphs) and wild-type (lower graphs) genomic sequence from each family. Note that affected hemizygous males appear to be heterozygous, because of a highly homologous IKK-gamma pseudogene.