Down syndrome critical region 1-like proteins

Details Down syndrome critical region 1-like proteins Down syndrome critical region 1-like proteins

2000-07-11

2003-02-25

Kunz, Gary (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, C435S006120, C435S007100, C536S023100

Reexamination Certificate

active

06524819

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to nucleic acid molecules and amino acid sequences of a new mammalian protein and to their use in the characterization, diagnosis, and treatment of conditions such as Alzheimer's disease, Down syndrome and other forms of dementia.
BACKGROUND OF THE INVENTION
Alzheimer's disease is a progressive neurodegenerative disorder that is characterized by the formation of senile plaques and neurofibrillary tangles containing amyloid beta peptide. These plaques are found in limbic and association cortices of the brain, including hippocampus, temporal cortices, cingulate cortex, amygdala, nucleus basalis and locus caeruleus. Early in Alzheimer's pathology, physiological changes are visible in the cingulate cortex (Minoshima et al. (1997) Annals of Neurology 42:85-94). In subjects with advanced Alzheimer's disease, accumulating plaques damage the neuronal architecture in limbic areas and eventually cripple the memory process.
Approximately twenty million people worldwide suffer with dementia that results from Alzheimer's disease. The disease can be early onset affecting individuals as young as 30 years of age, or it can be familial or sporadic. Familial Alzheimer's disease was once thought to be inherited strictly as an autosomal dominant trait; however, this view is changing as more genetic determinants are isolated. For example, some normal allelic variants of apolipoprotein E (ApoE), which is found in senile plaques, can either protect against or increase the risk of developing the disease (Strittmatter et al. (1993) Proc Natl Acad Sci 90:1977-1981).
Mutations in four genes are known to predispose an individual to Alzheimer's disease: ApoE, amyloid precursor protein (APP), presenilin-1, and presenilin-2 (Selkoe (1999) Nature 399:A23-A31). The e4 allele of the ApoE gene confers increased risk for late onset Alzheimer's disease. &bgr;-amyloid protein (A&bgr;) is the major component of senile plaques, and it is normally formed when &bgr;- and &ggr;-secretases cleave APP. In Alzheimer's disease patients, large quantities of A&bgr; are generated and accumulate extracelluarly in these neuropathological plaques.
Associations between Alzheimer's disease and many other genes and proteins have been reported. Fetal Alzheimer antigen an synuclein a are found in brain plaques and tangles. Inheritance of some gene polymorphisms is also linked to increased risk of developing the disease. For example, a polymorphism in the gene encoding &bgr;2-macroglobulin, a protein that can act as a protease inhibitor, is associated with increased risk for developing a late-onset form of Alzheimer's disease.
Experiments using microarray technology have provided additional evidence for changes in expression of specific genes in tissues from subjects with Alzheimer's disease. One such gene, Down syndrome critical region 1-like 1 (Mazowiecki et al. (1996) J Biol Chem 271:14567-14571) also named DSCR1L1 (g1435040), was found to be down-regulated more than two-fold in Alzheimer's tissue. DSCR1L1 encodes a thyroid hormone responsive protein and is a member of a gene family that includes DSCR1 (g7657042) and DSCR1L2 (g6017918). The first member of the family cloned, DSCR1, was named based on its proximity to the Down syndrome region of chromosome 21, but the function of the encoded protein and its role in Down syndrome, if any, remains unclear. The defining motifs of this family of proteins include an N-terminal RNA-binding domain, which is similar to those found in many RNA-binding proteins and in some single-stranded DNA-binding proteins, and a central short, unique serine-proline motif that includes an ISPPXSPP box that may be a target for phosphorylation (Fuentes et al. (1995) Hum Mol Genet 4:1935-1944).
Based on general features of the amino acid sequences, these DSCR1 genes likely encode proteins involved in transcriptional regulation and signal transduction (Strippoli et al. (2000) Genomics 64:252-263). The three genes appear to be differentially expressed: DSCR1 is highly expressed in fetal brain and heart, DSCR1L1 is evident in heart, brain, liver and skeletal muscle, and DSCR1L2 is expressed in most tissues including blood.
There are several connections between Alzheimer's disease and Down syndrome, such as the appearance of enhanced &bgr;-amyloid deposits in middle-aged Down syndrome patients. The thyroid hormone responsive properties of DSCR1L1 may be relevant to the role for this gene in Alzheimer's disease and/or Down syndrome: both Alzheimer's and Down's patients have been shown to have disturbances in thyroid hormone metabolism including elevated antithyroglobulin antibodies and reduced levels of prealbumin in the cerebrospinal fluid of Alzheimer's patients and pronounced subclinical hypothyroidism in Down's patients who have clinical manifestations of Alzheimer's disease (Sutherland et al. (1992) Neurobiol Aging 13:301-312). Conversely, hypothyroid patients display some of the same neurologic symptoms seen in Alzheimer's patients and a history of thyroid dysfunction is considered to be a risk factor for developing Alzheimer's disease. One possible connection is the discovery that thyroid hormone negatively regulates the transcriptional activity of the APP gene (Belandia et al. (1998) J Biol Chem 273:30366-30371); overexpression of APP has been hypothesized to cause neuronal degeneration by a mechanism involving increased production of &bgr;-amyloid protein. The down-regulation of the thyroid responsive DSCR1L1 gene and possibly other DSCR1 genes in Alzheimer's patients also provides a link between Alzheimer's and thyroid hormone function.
The discovery of additional mammalian nucleic acid molecules encoding members of the DSCR1 protein family may be used for the diagnosis, prognosis or treatment of Alzheimer's disease, Down syndrome and other forms of dementia.
SUMMARY OF THE INVENTION
The invention is based on the discovery of a substantially purified mammalian nucleic acid molecule encoding mammalian DSCR1L1&agr; protein, which satisfies a need in the art by providing compositions useful in the characterization, diagnosis, and treatment of conditions such as Alzheimer's disease, Down syndrome and other forms of dementia.
The invention provides an isolated mammalian cDNA or a fragment thereof encoding a mammalian protein or a portion thereof selected from the group consisting of an amino acid sequence of SEQ ID NO:2, a variant having at least 95% identity to the amino acid sequence of SEQ ID NO:2, and an antigenic epitope of SEQ ID NO:2. The invention also provides an isolated mammalian cDNA or the complement thereof selected from the group consisting of a nucleic acid sequence of SEQ ID NO:1, a variant having at least 85% identity to the nucleic acid sequence of SEQ ID NO:1, and a fragment of SEQ ID NO:1. The invention additionally provides a composition, a substrate, and a probe comprising the cDNA, or the complement of the cDNA, encoding DSCR1L1&agr;. The invention further provides a vector containing the cDNA, a host cell containing the vector and a method for using the cDNA to make DSCR1L1&agr;. The invention still further provides a transgenic cell line or organism comprising the vector containing the cDNA encoding DSCR1L1&agr;. The invention additionally provides a mammalian fragment or the complement thereof selected from the group consisting of SEQ ID NOs:3-9. In one aspect, the invention provides a substrate containing at least one of these fragments. In a second aspect, the invention provides a probe comprising the fragment which can be used in methods of detection, screening, and purification. In a further aspect, the probe is a single stranded complementary RNA or DNA molecule.
The invention provides a method for using a cDNA to detect the differential expression of a nucleic acid in a sample comprising hybridizing a probe to the nucleic acids, thereby forming hybridization complexes and comparing hybridization complex

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