TY - JOUR
T1 - 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)
AU - Zonana, Jonathan
AU - Elder, Melissa E.
AU - Schneider, Lynda C.
AU - Orlow, Seth J.
AU - Moss, Celia
AU - Golabi, Mahin
AU - Shapira, Stuart K.
AU - Farndon, Peter A.
AU - Wara, Diane W.
AU - Emmal, Stephanie A.
AU - Ferguson, Betsy M.
N1 - Funding Information:
This work was supported by National Institute of Dental and Craniofacial Research grant DE11311 (to J.Z.), a National Foundation for Ectodermal Dysplasias grant (to J.Z.), and National Institutes of Health grant M01 RR01271 (to the University of California, San Francisco, Pediatric Clinical Research Center). We would like to thank the families, as well as the physicians and dentists who assisted in gathering clinical information and samples. Specific thanks are due to Vicki Cox, and Barbara Pober, for their assistance in referring and evaluating the families.
PY - 2000
Y1 - 2000
N2 - 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.
AB - 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.
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U2 - 10.1086/316914
DO - 10.1086/316914
M3 - Article
C2 - 11047757
AN - SCOPUS:0033658369
SN - 0002-9297
VL - 67
SP - 1555
EP - 1562
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -