Atypical Forms of Incontinentia Pigmenti in Male Individuals Result from Mutations of a Cytosine Tract in Exon 10 of NEMO (IKK-γ)

Abstract

Familial incontinentia pigmenti (IP [MIM 308310]), or Bloch-Sulzberger syndrome, is an X-linked dominant and male-lethal disorder. We recently demonstrated that mutations in NEMO (IKK-gamma), which encodes a critical component of the NF-kappaB signaling pathway, were responsible for IP. Virtually all mutations eliminate the production of NEMO, causing the typical skewing of X inactivation in female individuals and lethality in male individuals, possibly through enhanced sensitivity to apoptosis. Most mutations also give rise to classic signs of IP, but, in this report, we describe two mutations in families with atypical phenotypes. Remarkably, each family included a male individual with unusual signs, including postnatal survival and either immune dysfunction or hematopoietic disturbance. We found two duplication mutations in these families, at a cytosine tract in exon 10 of NEMO, both of which remove the zinc (Zn) finger at the C-terminus of the protein. Two deletion mutations were also identified in the same tract in additional families. However, only the duplication mutations allowed male individuals to survive, and affected female individuals with duplication mutations demonstrated random or slight skewing of X inactivation. Similarly, NF-kappaB activation was diminished in the presence of duplication mutations and was completely absent in cells with deletion mutations. These results strongly indicate that male individuals can also suffer from IP caused by NEMO mutations, and we therefore urge a reevaluation of the diagnostic criteria.

Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations

“…A total of five alterations map in the C 7 and CNC 4_I segments (c.1167dupC, c.1167delC, c.1171G4T, c.1163_1175del, and c.1166_1178dup) and were found in 10 unrelated patients. c.1167delC was found in four unrelated patients [Aradhya et al, 2001b] (this report) and c.1167dupC in three [Zonana et al, 2000;Aradhya et al, 2001b] (Table 1). Similarly, exon 9 also contains C n stretches (Fig.…”

“…This disease is due to IKBKG hypomorphic mutations, often missense or small deletions/insertions, which mainly affect the zinc finger (ZF) domain of the protein. These mutations reduce but do not eliminate NF-kB activation, explaining why affected male patients survive [Zonana et al, 2000;Aradhya et al, 2001b;Doffinger et al, 2001]. Female patients carrying the same IKBKG mutations exhibit very mild signs of IP [Aradhya et al, 2001b].…”

Mutations in the NF-κB signaling pathway: implications for human disease

“…Mutations generating IP (red), EDA-ID) (blue) and immunodeficiencies without EDA (green) (Smahi et al, 2000;Zonana et al, 2000;Aradhya et al, 2001a;Aradhya et al, 2001b;Do¨ffinger et al, 2001;Jain et al, 2001;Fusco et al, 2004;Orange et al, 2004;FilipeSantos et al, 2006;Puel et al, 2006) (Zonana et al, 2000;Do¨ffinger et al, 2001;Jain et al, 2001;Aradhya et al, 2001a In contrast, the association of NEMO mutations with the EDA-ID defect in skin adnexes development is more puzzling. Because morphogenesis of all the affected appendages, such as hair, sweat glands and teeth, is dependent upon a specific interaction between the TNF-like ligand ectodysplasin A and its receptor EDAR (Mikkola and Thesleff, 2003), the analysis of EDA-ID pathology has revealed an unexpected link between ectodysplasin signaling and NF-kB activation, involving NEMO.…”

NF-κB-related genetic diseases

“…Most of them indeed carry mutations in NEMO but instead of leading to large truncations of the NEMO molecule as observed in IP, the mutations are mostly missense mutations or small deletions only affecting the ZF (Table 1). [30][31][32][33][34] Their molecular characterization is likely to provide valuable insights into NEMO function but for only few of them some specific defect has been identified.…”