Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NEMO (NFkappaB essential modulator) is a non-catalytic subunit of the cytokine-dependent IkappaB kinase complex that is involved in activation of the transcription factor NFkappaB. The human NEMO gene maps to Xq28 and is arranged head to head with the proximal G6PD gene. Mutations in NEMO have recently been associated with Incontinentia Pigmenti (Smahi et al., Nature 405 (2000) 466), an X-linked dominant disorder. Three alternative transcripts with different non-coding 5' exons (1a, 1b and 1c) of NEMO have been described. In order to identify regulatory elements that control alternative transcription we have established the complete genomic sequence of the murine orthologs Nemo and G6pdx. Sequence comparison suggests the presence of two alternative promoters for NEMO/Nemo. First, a CpG island is shared by both genes driving expression of the NEMO/Nemo transcripts containing exons 1b and 1c in one direction and the housekeeping gene G6PD/G6pdx in the opposite direction. In contrast to human, an additional variant of exon 1c, named 1c+, was identified in several tissues of the mouse. This larger exon utilizes an alternative donor site located 1594 bp within intron 1c. The putative second promoter for NEMO/Nemo transcripts starting with exon 1a is unidirectional, and not associated with a CpG island. Surprisingly, this promoter is located in the second intron of G6PD/G6pdx. It shows very low basal activity and may be involved in stress/time- and/or tissue-dependent expression of NEMO. To our knowledge, an overlapping gene order similar to the G6PD/NEMO complex has not been described before.
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PMID:Human-mouse comparative sequence analysis of the NEMO gene reveals an alternative promoter within the neighboring G6PD gene. 1141 Mar 70

Incontinentia Pigmenti is a rare, X-linked, dominant disorder in which affected female infants develop characteristic abnormalities of the skin, central nervous system, hair, teeth, and eyes. Ocular abnormalities occur in about 35% of patients and consist of proliferative vitreoretinopathy, retinal detachment, strabismus, cataract, microphthalmia, optic nerve atrophy, and iris hypoplasia. Retinal vascular abnormalities, ranging from peripheral retinal avascularity to neovascular and fibrous proliferation with traction retinal detachment, are the primary cause of severe visual dysfunction in patients. Therapeutic intervention with laser photocoagulation and cryotherapy for the proliferative vitreoretinopathy of incontinentia pigmenti has met with variable success. We report a case in which laser photocoagulation was used at the onset of retinopathy with subsequent resolution of the vasculopathy.
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PMID:Laser photocoagulation in preproliferative retinopathy of incontinentia pigmenti. 1150 87

Incontinentia pigmenti (IP) is an X-linked dominant disorder characterized by abnormal skin pigmentation, retinal detachment, anodontia, alopecia, nail dystrophy and central nervous system defects. This disorder segregates as a male lethal disorder and causes skewed X-inactivation in female patients. IP is caused by mutations in a gene called NEMO, which encodes a regulatory component of the IkappaB kinase complex required to activate the NF-kappaB pathway. Here we report the identification of 277 mutations in 357 unrelated IP patients. An identical genomic deletion within NEMO accounted for 90% of the identified mutations. The remaining mutations were small duplications, substitutions and deletions. Nearly all NEMO mutations caused frameshift and premature protein truncation, which are predicted to eliminate NEMO function and cause cell lethality. Examination of families transmitting the recurrent deletion revealed that the rearrangement occurred in the paternal germline in most cases, indicating that it arises predominantly by intrachromosomal misalignment during meiosis. Expression analysis of human and mouse NEMO/Nemo showed that the gene becomes active early during embryogenesis and is expressed ubiquitously. These data confirm the involvement of NEMO in IP and will help elucidate the mechanism underlying the manifestation of this disorder and the in vivo function of NEMO. Based on these and other recent findings, we propose a model to explain the pathogenesis of this complex disorder.
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PMID:A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations. 1159 Jan 34

Incontinentia pigmenti (IP), or "Bloch-Sulzberger syndrome," is an X-linked dominant disorder characterized by abnormalities of skin, teeth, hair, and eyes; skewed X-inactivation; and recurrent miscarriages of male fetuses. IP results from mutations in the gene for NF-kappaB essential modulator (NEMO), with deletion of exons 4-10 of NEMO accounting for >80% of new mutations. Male fetuses inheriting this mutation and other "null" mutations of NEMO usually die in utero. Less deleterious mutations can result in survival of males subjects, but with ectodermal dysplasia and immunodeficiency. Male patients with skin, dental, and ocular abnormalities typical of those seen in female patients with IP (without immunodeficiency) are rare. We investigated four male patients with clinical hallmarks of IP. All four were found to carry the deletion normally associated with male lethality in utero. Survival in one patient is explained by a 47,XXY karyotype and skewed X inactivation. Three other patients possess a normal 46,XY karyotype. We demonstrate that these patients have both wild-type and deleted copies of the NEMO gene and are therefore mosaic for the common mutation. Therefore, the repeat-mediated rearrangement leading to the common deletion does not require meiotic division. Hypomorphic alleles, a 47,XXY karyotype, and somatic mosaicism therefore represent three mechanisms for survival of males carrying a NEMO mutation.
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PMID:Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome. 1167 21

The X-linked dominant and male-lethal disorder incontinentia pigmenti (IP) is caused by mutations in a gene called NEMO (IKK-gamma). We recently reported the structure of NEMO and demonstrated that most IP patients carry an identical deletion that arises due to misalignment between repeats. Affected male abortuses with the IP deletion had provided clues that a second, incomplete copy of NEMO was present in the genome. We have now identified clones containing this truncated copy (Delta NEMO) and incorporated them into a previously constructed physical contig in distal Xq28. Delta NEMO maps 22 kb distal to NEMO and only contains exons 3-10, confirming our proposed model. A sequence of 26 kb 3' of the NEMO coding sequence is also present in the same position relative to the Delta NEMO locus, bringing the total length of the duplication to 35.5 kb. The LAGE2 gene is also located within this duplicated region, and a similar but unique LAGE1 gene is located just distal to the duplicated loci. Mapping and sequence information indicated that the duplicated regions are in opposite orientation. Analysis of the great apes suggested that the NEMO/LAGE2 duplication occurred after divergence of the lineage leading to present day humans, chimpanzees and gorillas, approximately 10-15 million years ago. Intriguingly, despite this substantial evolutionary history, only 22 single nucleotide differences exist between the two copies over the entire 35.5 kb, making the duplications >99% identical. This high sequence identity and the inverted orientations of the two copies, along with duplications of smaller internal sections within each copy, predispose this region to various genomic alterations. We detected four rearrangements that involved NEMO, Delta NEMO or LAGE1 and LAGE2. The high sequence similarity between the two NEMO/LAGE2 copies may be due to frequent gene conversion, as we have detected evidence of sequence transfer between them. Together, these data describe an unusual and complex genomic region that is susceptible to various types of pathogenic and polymorphic rearrangements, including the recurrent lethal deletion associated with IP.
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PMID:Multiple pathogenic and benign genomic rearrangements occur at a 35 kb duplication involving the NEMO and LAGE2 genes. 1170 43

In two neonate girls with vesicular skin lesions, incontinentia pigmenti (Bloch-Sulzberger syndrome) was diagnosed. This rare X-linked dominant ectodermal disease can cause abnormalities in several organ systems. Most prominent are the dermatological abnormalities, developing in 4 stages: the vesicular stage, the verrucous stage, the hyperpigmentation phase, and the atrophic phase. In addition to the cutaneous manifestations, many patients have anomalies of nails, hair and teeth. Serious related abnormalities of the eyes (intraocular vasculopathy) and central nervous system (convulsions, mental retardation) may occur. In 1989 the locus for the incontinentia pigmenti mutation was shown to be present on Xq28. Recently it was shown that the causative mutation is located on the NEMO ('NF-kappa B essential modulator') gene. A NEMO knock-out mouse model shows a dermatopathy of a transient nature, resembling the skin lesions in patients with incontinentia pigmenti.
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PMID:[Two neonates with vesicular skin lesions due to incontinentia pigmenti]. 1172 18

Incontinentia pigmenti (IP) is an X-linked dominant genodermatosis primarily affecting female children. The initial vesiculobullous stage of IP is characterized clinically by inflammatory papules, blisters, and pustules, and histopathologically by acanthosis, keratinocyte necrosis, epidermal spongiosis and massive epidermal eosinophil infiltration. The cause of this multisystem disease is attributed to the mutations of an X-linked regulatory gene, termed nuclear factor-kappaB essential modulator (NEMO). The exact mechanism of epidermal eosinophil accumulation has not yet been determined. We explored the possible role of an eosinophil-selective, nuclear factor-kappaB-activated chemokine, eotaxin, in the accumulation of eosinophils in the initial stage of the disease. Monoclonal antibody (6H9) specific for human eotaxin strongly labelled the suprabasal epidermis of IP skin, paralleling the upper epidermal accumulation of eosinophils, but did not label the epidermis of normal skin or lesional skin from patients with other inflammatory skin diseases not characterized by prominent eosinophil accumulation, namely dermatitis herpetiformis and selected cases of atopic dermatitis lacking significant numbers of eosinophils. In addition, endothelial cells in lesional skin of IP also exhibited strong expression of eotaxin, which correlated with perivascular and intravascular eosinophil infiltration. We also examined the in vitro effects on epidermally derived eotaxin of several cytokines that were nuclear factor-kappaB-activated and/or known to induce eotaxin expression. In normal human keratinocytes, proinflammatory cytokines either independently (IL-1alpha) or synergistically (tumour necrosis factor-alpha (TNF-alpha)/ interferon-gamma (IFN-gamma) and TNF-alpha/IL-4) up-regulated eotaxin expression. These studies suggest that release of cytokines during the initial inflammatory stage of IP induces epidermal expression of eotaxin, which may play a role in the epidermal accumulation of eosinophils.
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PMID:Expression of eotaxin, an eosinophil-selective chemokine, parallels eosinophil accumulation in the vesiculobullous stage of incontinentia pigmenti. 1196 63

Incontinentia pigmenti, also known as Bloch-Sulzberger syndrome, is a rare multi-systemic disorder. The disease is characterised by abnormalities in ectodermal tissues including the skin, eyes, central nervous system and dentition. It is inherited as an X-linked dominant trait and is usually fatal for male fetuses. Thirty-eight Swedish patients from 16 families were identified. Thirty patients were examined clinically and their DNA were analysed for deletions in the NEMO-gene. The disease showed a large clinical variability even within families and the common deletion in the NEMO-gene was found present in 70% of the families.
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PMID:[Incontinentia pigmenti. A rare disease with many symptoms]. 1199 69

A child with X-linked osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency (OL-EDA-ID) was recently reported. We report the clinical features of a second boy with this novel syndrome and his mother, who presented with signs of incontinentia pigmenti (IP). The child had mild osteopetrosis without neurosensory complications, unilateral lymphedema of the left leg, and characteristic features of anhidrotic ectodermal dysplasia with sparse hair, facial dysmorphy, delayed eruption of teeth, and sweat gland abnormalities. He died at 18 months of severe immunodeficiency with multiple infections caused by Gram-negative (Salmonella enteritidis) and Gram-positive (Streptococcus pneumoniae) bacteria, nontuberculous mycobacteria (Mycobacterium kansasii), and fungi (Pneumocystis carinii). His 30-year-old mother's medical history, together with residual cutaneous lesions, was highly suggestive of IP without neurologic impairment. In this patient with OL-EDA-ID, we detected the same NF-kappaB essential modulator stop codon hypomorphic mutation identified in the previous patient. The occurrence of the same clinical features in 2 unrelated patients with the same genotype demonstrates that OL-EDA-ID is a genuine clinical syndrome. The clinical and biological descriptions of the proband and his mother further corroborate the relationship between IP and EDA. Both syndromes are allelic and are associated with mutations in NF-kappaB essential modulator, with a genotype-phenotype correlation in hemizygous males. In contrast, loss-of-function mutations and hypomorphic mutations may cause IP in females.
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PMID:Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pigmenti in his mother. 1204 91

IkappaB kinase gamma (IKKgamma) (also known as NEMO, Fip-3, and IKKAP-1) is the essential regulatory component of the IKK complex; it is required for NF-kappaB activation by various stimuli, including tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1), phorbol esters, lipopolysaccharides, and double-stranded RNA. IKKgamma is encoded by an X-linked gene, deficiencies in which may result in two human genetic disorders, incontinentia pigmenti (IP) and hypohidrotic ectodermal dysplasia with severe immunodeficiency. Subsequent to the linkage of IKKgamma deficiency to IP, we biochemically characterized the effects of a mutation occurring in an IP-affected family on IKK activity and NF-kappaB signaling. This particular mutation results in premature termination, such that the variant IKKgamma protein lacks its putative C-terminal Zn finger and, due to decreased mRNA stability, is underexpressed. Correspondingly, IKK and NF-kappaB activation by TNF-alpha and, to a lesser extent, IL-1 are reduced. Mutagenesis of the C-terminal region of IKKgamma was performed in an attempt to define the role of the putative Zn finger and other potential functional motifs in this region. The mutants were expressed in IKKgamma-deficient murine embryonic fibroblasts (MEFs) at levels comparable to those of endogenous IKKgamma in wild-type MEFs and were able to associate with IKKalpha and IKKbeta. Substitution of two leucines within a C-terminal leucine zipper motif markedly reduced IKK activation by TNF-alpha and IL-1. Another point mutation resulting in a cysteine-to-serine substitution within the putative Zn finger motif affected IKK activation by TNF-alpha but not by IL-1. These results may explain why cells that express these or similar mutant alleles are sensitive to TNF-alpha-induced apoptosis despite being able to activate NF-kappaB in response to other stimuli.
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PMID:The carboxyl-terminal region of IkappaB kinase gamma (IKKgamma) is required for full IKK activation. 1219 55


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