Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or...
Reexamination Certificate
2001-05-22
2004-11-30
Wehbé, Anne Marie S. (Department: 1632)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
C435S005000, C435S006120, C435S007800, C536S023100
Reexamination Certificate
active
06824972
ABSTRACT:
FIELD OF THE INVENTION
This invention generally relates to defective NF-&kgr;B activation through loss of functional NF-&kgr;B Essential Modulator (NEMO). More specifically, the invention relates to diagnosis and treatment in organisms with medical conditions related to defective NF-&kgr;B Essential Modulator.
BACKGROUND OF THE INVENTION
Incontinentia Pigmenti (IP), or Bloch-Sulzberger Syndrome, is an X-linked dominant, male-lethal disorder with four classic cutaneous stages that begin in the neonatal period: 1) blisters and vesicles on an erythematous base; 2) raised pustular and verrucous cutaneous patches; 3) hyperpigmentation in a distinctive pattern assumed to represent lines of cell migration (lines of Blaschko); and 4) scarred dermal hypopigmentation and atrophy with absence of the hair follicles and sweat glands. The early inflammatory stages are accompanied by eosinophilia both in the peripheral blood and in the skin lesions. Streaks and whorls of hyperpigmentation give the condition its name and result from release of melanin from cells of the epidermis into the dermis, generally by 6 months of age, particularly in the axillae and groin. This “marble cake” hyperpigmentation fades, typically by the third decade, leaving superficially scarred, hairless, pale tissue as the subtle dermatologic sign in adulthood. IP is often associated with developmental abnormalities of the teeth, eyes, hair, and the central nervous system (reviewed in Carney, 1976; Landy, 1993; Francis, 1997). Dental abnormalities, typically anodontia and hypodontia, conical pegging, delayed eruption, and malformed crowns with soft enamel, affect about 80% of cases (Garcia-Bravo, 1986; Optiz, 1981). Ophthalmologic anomalies, particularly dysplasia of retinal vessels, cicatrization and retinal folds, and tractional retinal detachment, affect about one-third of cases (Rosenfeld, 1985; Goldberg, 1993). Approximately 10-30% also manifest permanent neurological defects, such as intracranial vascular occlusions, neuronal remodeling or migration defects, mental retardation, hypotonia, spasticity, epilepsy, and microcephaly (Landy, 1993). IP females may also have partial or patchy alopecia even on the scalp, mild dystrophic changes in the nails, or supernumerary nipples or hypoplasia or aplasia of the breast, and show periungual keratotic tumours of the hands (Adeniran, 1993; Baran, 1998).
At birth, the ratio of female:male offspring from known affected females is consistent with lethality in utero among male conceptuses (Carney, 1976). The reasons for spontaneous male abortion (usually in the second and occasionally the third trimester) are unclear, although post mortem examination of a few cases has revealed infiltration of immune cells into tissues, indicating that IP may involve an immune response (Roberts, 1998). IP females exhibit severely skewed (>98%) X-inactivation in white blood cells and fibroblasts resulting from loss of cells expressing the mutated X (Parrish, 1996). Elimination of defective cells is likely to occur close to or immediately after birth rather than in utero in these tissues, since cell populations expressing both X-chromosomes can be derived from cord blood or from neonatal skin (Parrish, 1996). This selective mechanism may explain both the difference in morbidity between hemizygous males and heterozygous females and the gradual resolution of many of the skin signs in affected females. The cause of cell loss is unknown, although it coincides with the early inflammatory skin lesions.
Linkage of the IP locus to markers in distal Xq28 (DXS52-tel) was established with close linkage to the gene for factor VIII (Sefiani, 1989; Smahi, 1994; Parrish, 1996; Jouet, 1997) Many genes from this region have been excluded by extensive mutation screening (Heiss, 1999; Aradhya, 2000; Woffendin, 2000; Das, 1994). Recently, a gene intimately involved in inflammatory responses, NEMO/IKK&ggr;, has been mapped 200 kb proximal to the factor VIII locus (Jin, 1999). NEMO is central to the activation of the ubiquitous transcription factor NF-&kgr;B (Yamaoka, 1998; Rudolph, 2000). The NF-&kgr;B/Rel family of transcription factors plays a particularly important role in inflammatory and immune responses, in cellular stress, and in regulating apoptosis (Ghosh, 1998; Baldwin, 1996). Their activity is induced by a variety of different stimuli including pro-inflammatory cytokines such as interleukin-1 (IL-1) and Tumour Necrosis Factor (TNF). The immediate responsiveness required of such a key regulator is effected by an unique mechanism whereby NF-&kgr;B homo- or heterodimers are sequestered in the cytoplasm through interaction with an inhibitory molecule of the IKB family (three different species exist in cells: I&kgr;B&agr;, I&kgr;B&bgr; and I&kgr;B&egr;). Upon cytokine stimulation the I&kgr;B molecules are phosphorylated on two Ser residues, then polyubiquitinated and degraded through the ubiquitin-proteasome pathway. NF-&kgr;B is therefore free to translocate to the nucleus and to activate its target genes. This phosphorylation event is carried out by a high molecular weight, multiprotein kinase complex containing two subunits with kinase activity (IKK1/&agr; and IKK2/&bgr;) (Zandi, 1999; Mercurio, 1999). A third component of this complex is a 48 kDa protein with no apparent catalytic activity, called NEMO (NF-&kgr;B Essential Modulator), IKK&ggr;, or IKKAP (Yamaoka, 1998; Rothwarf, 1998; Mercurio, 1999). NEMO directly interacts with the kinase subunits and is required for activation of the kinase complex in response to extracellular (or intracellular) stimuli: its absence results in a complete inhibition of NF-&kgr;B activation.
Enhanced apoptosis might explain the selection against cells expressing the IP mutation in affected females (Smahi et al.). In support of this notion, patient-derived cell lines exhibit a high sensitivity to TNF-induced cell death. Based on these observations and the chromosomal localization of the gene in Xq28, a possible role of NEMO in IP was investigated.
REFERENCES:
Baldwin et al. (1996) Annu. Rev. Immunol., vol. 14:649-681.*
Mutations in Brief, Human Mutation vol. 12, No. 5, (Oct. 7, 1998), pp. 361-363.
Rothnie, Helen, M. et al.; Polyadenylation in Rice Tungro Bacilliform Virus: cis-Acting Signals and Regulation, Journal of Virology (May 2001), vol. 75, No. 9, pp. 4184-4194.
McQueen, Karina L., et al.; Functional analysis of 5′ and 3′ regions of the closely related Ly49c and j genes, Immunogenetics (2001) vol. 52, pp. 212-223.
Graber, Joel H., et al.; In silico detection of control signals: mRNA 3′ -end-processing sequences in diverse species, PNAS (Nov. 23, 1999), vol. 96, No. 24, pp. 14055-14060.
Xu, Zhi-Li, et al.; Optimization of transcriptional regulatory elements for constructing plasmid vectors, Int'l Journal of Genes and Genomes, (2001), vol. 272, pp. 149-156.
Shamsher, Monee K., et al.; Identification of an intronic regulatory element in the human protein C (PROC) gene, Human Genetics (2000), vol. 107, pp. 458-465.
Ionasescu, V.V., et al.; Mutations of the noncoding region of the connexin32 gene in X-linked dominant Charcot-Marie-Tooth neuropathy, American Academy of Neurology (1996), vol. 47, pp. 541-544.
Harland, Mark, et al.; Mutation Screening of the CKDKN2A Promoter in Melanoma Families, Genes, Chromosomes & Cancer (2000) vol. 28, pp. 45-57.
Pyne, Michael T., et al.; The BRCA2 genetic variant IVS7+ 2T—G is a mutation, J. Hum. Genetics (2000), vol. 45, pp. 351-357.
Jannssen R.J., et al.; A branch site mutation leading to aberrant splicing of the human tyrosine hydroxylase gene in a child with a severe extrapyramidal movement disorder, Am. Hum. Genet. (2000), vol. 64, pp. 375-382.
Hobson, G.M., et al.; Mutations in noncoding regions of the protelolipid protein gene in pelizaeous—Merzbacher disease, Neurology (2000), vol. 55, pp. 1089-1096.
Aradhya, Swaroop, et al.; Multiple pathogenic and benign genomic rearrangments occur at a 35 kb duplication involving the NEMO and LAGE2 genes, Hum. Mol. Genet. (2001), vol. 10, No. 22, pp. 2557-2567
Aradhya Swaroop
D'Urso Michele
Heiss Nina
Israel Alain
Kenwrick Sue J.
Baylor College of Medicine
Fulbright & Jaworski LLP
S. Wehbé Anne Marie
LandOfFree
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