Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-06-08
2004-12-07
Woitach, Joe (Department: 1632)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S024330, C536S024310
Reexamination Certificate
active
06828430
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to PAB II gene, and its uses thereof for the diagnosis, prognosis and treatment of a disease related with protein accumulation in nucleus, such as oculopharyngeal muscular dystrophy.
2. Description of Prior Art
Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease with a world-wide distribution. It usually presents itself in the sixth decade with progressive swallowing difficulties (dysphagia), eye lid drooping (ptosis) and and proximal limb weakness. Unique nuclear filament inclusions in skeletal muscle fibers are its pathological hallmark (Tome, F.M.S. & Fardeau, Acta Neuropath. 49, 85-87 (1980)). Using the full power of linkage analysis in eleven French Canadian families, the oculopharyngeal muscular dystrophy gene was fine mapped on human chromosome 14 (Brais et al., 1997, Neuromuscular Disorders 7 (Suppl.1):S70-74). A region of 0.75 cM was thereby identified as a region containing the potential and unknown OMPD gene (Brais et al., 1997, supra). Unfortunately, the OMPD gene has yet to be isolated and its nucleic acid or protein sequence have yet to be described.
It would be highly desirable to be provided with a tool for the diagnosis, prognosis and treatment of a disease related with polyalanine accumulation in the nucleus, such as observed in oculopharyngeal muscular dystrophy.
SUMMARY OF THE INVENTION
One aim of the present invention is to provide a tool for the diagnosis, prognosis and treatment of a disease related with polyalanine accumulation in nucleus, such as oculopharyngeal muscular dystrophy.
Herein, the poly(A) binding protein II (PAB II) gene was isolated from a 217 kb candidate interval in chromosome 14q11. A (GCG)6 repeat encoding a polyalanine tract located at the N-terminus of the protein was expanded to (GCG)8-13 in the 144 OPMD families screened. More severe phenotypes were observed in compound heterozygotes for the (GCG)9 mutation and a (GCG)7 allele found in 2% of the population, whereas homozygosity for the (GCG)7 allele leads to autosomal recessive OPMD. Thus the (GCG)7 allele is an example of a polymorphism which can act as either a modifier of a dominant phenotype or as a recessive mutation. Pathological expansions of the polyalanine tract may cause mutated PAB II oligomers to accumulate as filament inclusions in nuclei.
In accordance with the present invention there is provided a human PAB II gene containing a transcribed polymorphic GCG repeat, which comprises a sequence as set forth in
FIG. 4
, which includes introns and flanking genomic sequence.
The allelic variants of GCG repeat of the human PAB II gene are associated with a disease related with protein accumulation in the nucleus, such as polyalanine accumulation, or with a disease related with swallowing difficulties, such as oculopharyngeal muscular dystrophy.
In accordance with the present invention there is also provided a method for the diagnosis of a disease associated with protein accumulation in the nucleus, which comprises the steps of:
a) obtaining a nucleic acid sample of said patient; and
b) determining allelic variants of a GCG repeat of the human PAB II gene; whereby long allelic variants are indicative of a disease related with protein accumulation in the nucleus, such as polyalanine accumulation and oculopharyngeal muscular dystrophy.
The long allelic variants have from about 245 to about 263 bp in length.
In accordance with the present invention there is also provided a non-human mammal model for the human PAB II gene, whose germ cells and somatic cells are modified to express at least one allelic variant of the PAB II gene and wherein said allelic variant of the PAB II is being introduced into the mammal, or an ancestor of the mammal, at an embryonic stage.
In accordance with the present invention there is also provided a method for the screening of therapeutic agents for the prevention and/or treatment of oculopharyngeal muscular dystrophy, which comprises the steps of:
a) administering the therapeutic agents to the non-human animal of the present invention or oculopharyngeal muscular dystrophy patients; and
b) evaluating the prevention and/or treatment of development of oculopharyngeal muscular dystrophy in this animal (such as a mammal) or in patients.
In accordance with the present invention there is also provided a method to identify genes, products thereof, or part thereof, which interact with a biochemical pathway affected by the PAB II gene, which comprises the steps of:
a) designing probes and/or primers using the PAB II gene and screening oculopharyngeal muscular dystrophy patients samples with said probes and/or primers; and
b) evaluating the role of the identified gene in oculopharyngeal muscular dystrophy patients.
REFERENCES:
patent: WO98/31800 (1998-07-01), None
patent: WO99/29896 (1999-06-01), None
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Brais Bernard
Rouleau Guy A.
Hamilton, Brook, Smith & Reylonds, P.C.
McGill University
Woitach Joe
LandOfFree
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