Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
2001-06-29
2004-08-31
Kemmerer, Elizabeth (Department: 1647)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S252300, C435S320100, C435S325000, C536S023100, C530S350000, C530S300000
Reexamination Certificate
active
06783955
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a human presenilin variant, its encoding cDNA and to the use of these molecules in the diagnosis, prognosis, treatment and evaluation of therapies for cancers and neurodegenerative and immune disorders, particularly early onset Alzheimer's disease.
BACKGROUND OF THE INVENTION
Phylogenetic relationships among organisms have been demonstrated many times, and studies from a diversity of prokaryotic and eukaryotic organisms suggest a more or less gradual evolution of molecules, biochemical and physiological mechanisms, and metabolic pathways. Despite different evolutionary pressures, the proteins of nematode, fly, rat, and man have common chemical and structural features and generally perform the same cellular function. Comparisons of the nucleic acid and protein sequences from organisms where structure and/or function are known accelerate the investigation of human sequences and allow the development of model systems for testing diagnostic and therapeutic agents for human conditions, diseases, and disorders.
Cancer and immune response as a complication of cancer are characterized by continuous cell proliferation, inflammation, and cell death. Several molecular pathways have been linked to these activities, their development and progression. In addition, the analysis of the differential expression of key genes in any of these pathways may be diagnostically or prognostically important. For example, the analysis of cytokine levels is known to be useful as a prognostic indicator for distinguishing between various histologically-similar melanomas (Porter et al. (2001) Ann Surg Oncol 8:116-122).
Alzheimer's disease (AD) is a degenerative disorder of the central nervous system which causes progressive memory loss and cognitive decline during mid to late adult life and is accompanied by a wide range of neuropathologic features including amyloid deposits and intra-neuronal neurofibrillary tangles. Although the pathogenic pathway leading to neurodegeneration and AD is not well understood, at least three genetic loci that confer genetic susceptibility to the disease have been identified. (Schellenberg, G. D. (1995) Proc. Natl. Acad. Sci. 92:8552-8559; Sherrington, R. et al. (1995) Nature 375:754-760.)
The &egr;4 allele (C112 to R) of the apolipoprotein E gene is associated with AD in a significant proportion of late-onset (>60 years) cases. Mutations in the gene for the &bgr;-amyloid precursor protein (&bgr;APP) have been found in a small number of families (<3% of cases) with disease onset before 56 years of age. A third locus (AD3) has been mapped by genetic linkage studies to chromosome 14q24.3 and may account for up to 70% of early-onset autosomal-dominant AD. (Sherrington et al. supra.) Although early-onset AD is less common than late-onset AD, the AD3 locus is associated with the most aggressive form of the disease.
Initial studies of known genes on chromosome 14q resulted in their exclusion from the AD3 locus. However, additional studies conducted in a collection of 21 pedigrees segregating AD as a putative autosomal dominant trait resulted in the selection of more than 18 genetic markers associated with the AD3 locus, and the isolation of at least 19 transcripts encoded within this region. (Sherrington et al. supra.) One of these transcripts (S182) was found to encode presenilin-I (PS-1 or 1-467) containing multiple transmembrane domains and resembling an integral membrane protein. A similar gene product (presenilin-II, PS-2) was also identified in association with chromosome 1 in a separate lineage of AD subjects. (Levy-Lahad, E. et al. (1995) Science 269:973-977.) In both PS-1 and PS-2, missense mutations were found that cosegregated with early-onset familial AD in the respective pedigrees. The fact that mutations occurred in conserved domains of the gene and were not found in normal, asymptomatic family members indicates that the mutations are pathogenic for this form of AD. (Sherrington et al. supra; Levy-Lahad et al. supra.) In all cases, the mutations were found in the putative open reading frame of the nucleotide and would be predicted to change the encoded amino acid at that position. Variants of normal human presenilin (PS; 1467, 1463, and 1374) have also been reported. These variants result from either nucleotide deletions or alternative splicing, are ubiquitously expressed, and are associated with intracellular membranes. (Sahara, N. et al. (1996) FEBS Lett. 26:7-11.)
The normal cellular function of PS and, more particularly, the effects of these mutations on cellular function in AD individuals is not yet known. However, the general topology of PS suggests that it is an integral membrane protein such as a receptor, channel protein, or structural membrane protein. In addition, similarities between PS and the
Caenorhabditis elegans
proteins, SPE-4 and SEL-12, suggest that they may have similar functions. SPE-4 appears to be involved in the transport and storage of soluble and membrane-bound polypeptides during membrane budding and fusion events in
C. elegans
. (Sherrington et al. supra.) In humans, PS could be involved in similar vesicle transport processes, perhaps in moving &bgr;APP. If so, mutations in PS could alter intracellular trafficking of &bgr;APP and ultimately lead to altered &bgr;APP processing. (Levy-Lahad et al. supra.) Studies using PS-1 and PS-2 and their AD-linked mutations to rescue the effects of a sel-12 mutant in
C. elegans
demonstrated that mutant human presenilins had reduced ability to rescue the sel-12 mutation relative to PS-1 and PS-2. (Levitan, D et al. (1996) Proc. Natl. Acad. Sci. 93:14940-14944.) The results indicated that the mutant PSs have reduced activity relative to normal PS-1 and PS-2 and that this may be a contributing factor in the development of AD. It was also noted by Levy-Lahad (supra) that several of the amino acid mutations occurring in AD-associated PS were found at or near the beginning of transmembrane domains, and that the mutations may adversely effect the insertion or anchoring of these proteins in the membrane.
The discovery of a human presenilin variant and its encoding cDNA satisfies a need in the art by providing new compositions which are useful in the diagnosis, prognosis, treatment and evaluation of therapies for cancers and neurodegenerative and immune disorders, particularly early onset Alzheimer's disease.
SUMMARY OF THE INVENTION
The present invention is based on the discovery of a human presenilin variant and its encoding cDNA that are differentially expressed in human disorders. The cDNA, protein and an antibody which specifically binds the protein are useful in the diagnosis, prognosis, treatment and evaluation of therapies for cancers and neurodegenerative and immune disorders, particularly early onset Alzheimer's disease.
The invention provides an isolated cDNA comprising a nucleic acid sequence encoding a protein having the amino acid sequence of SEQ ID NO:1. The invention also provides an isolated cDNA selected from a nucleic acid sequence of SEQ ID NO:2, a fragment of SEQ ID NO:2 selected from SEQ ID NOs:3-7, and a variant selected from SEQ ID NOs:8-11 which has from about 85% to about 91% sequence identity with SEQ ID NO:2, and complements of SEQ ID NOs:2-11. The invention additionally provides compositions, a substrate, and a probe comprising the cDNA or the complement of the cDNA. The invention further provides a vector containing the cDNA, a host cell containing the vector and a method for using the cDNA to make the human presenilin variant. The invention still further provides a transgenic cell line or organism comprising the vector containing a cDNA selected from SEQ ID NO:2-11. The invention additionally provides a fragment, a variant, or the complement of a cDNA selected from SEQ ID NOs:2-11. In one aspect, the invention provides a substrate containing at least one cDNA selected from SEQ ID NOs:2-11 or a complement thereof. In a second aspect, the invention provides a cDNA or the complement thereof which can be used
Arvizu Chandra
Kaser Matthew R.
Murry Lynn E.
Incyte Corporation
Incyte Corporation
Kemmerer Elizabeth
Turner Sharon
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