Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-09-29
2001-11-13
Myers, Carla J. (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C536S023200, C536S023500
Reexamination Certificate
active
06316188
ABSTRACT:
TECHNICAL FIELD
This invention relates to the association of histamine-N-methyltransferase gene variants with histaminergic diseases.
BACKGROUND OF THE INVENTION
Histamine plays a role in allergic responses, is involved in the regulation of gastric acid secretion and also is a neurotransmitter. Histamine is inactivated by oxidative deamination in a diamine oxidase catalyzed reaction or by N-methylation in a histamine N-methyltransferase (HNMT) catalyzed reaction. The product of the N-methylation, N-methylhistamine, is converted by monoamine oxidase to N-methyl imidazole acetic acid. HNMT is an S-adenosyl-L-methionine dependent cytosolic enzyme that contains 292 amino acids and has a relative molecular weight of 33 kDa.
N-methylation is the major process responsible for termination of the neurotransmitter actions of histamine in the brain as well as a major pathway for histamine metabolism in bronchial epithelium. HNMT also is expressed highly in the human kidney where a 6-fold interindividual variation in activity is observed. HNMT activity in human red blood cells varies as a result of a common genetic polymorphism. Scott, M. C. et al.,
Clin. Pharmacol. Ther
., 43:256-262 (1988); and Price, R. A. et al.,
Genet. Epidemiol
., 10:123-131 (1993). Approximately 70%-90% of the variance in activity is due to inheritance.
SUMMARY OF THE INVENTION
The invention is based on the discovery that polymorphisms within the HNMT gene are associated with histaminergic diseases. The methods described herein allow characterization of patients with histaminergic diseases, leading to a more accurate diagnosis and new avenues of therapy.
The invention features a method for characterizing a patient diagnosed with a histaminergic disease. The method includes determining if the patient has an HNMT gene variant associated with the histaminergic disease and characterizing the patient based on the determination. The histaminergic disease can be, for example, asthma, allergic asthma, allergy, schizophrenia and peptic ulcer disease. Characterizing the patient can include identifying a treatment regimen suitable for the patient based, at least in part, on the presence or absence of the variant in the patient. The HNMT gene variant can include, for example, a thymine at nucleotide 315 or a CA repeat polymorphism in intron 5.
The invention also features a method for determining a diagnosis or risk estimate of a histaminergic disease in a patient. The method includes detecting the presence or absence of an HNMT gene variant in the patient, and determining the diagnosis or risk estimate based, at least in part, on presence or absence of the variant in the patient.
The invention also features an isolated nucleic acid molecule including a HNMT intron sequence. The intron sequence includes a gene variant that is associated with a histaminergic disease and nucleotides flanking the gene variant. As used herein, “isolated nucleic acid” refers to a sequence corresponding to part or all of the HNMT gene, but free of sequences that normally flank one or both sides of the HNMT gene in a mammalian genome. The isolated nucleic acid molecule can be about 50 to about 120 nucleotides in length, about 54 to about 100 nucleotides in length, or about 70 to about 90 nucleotides in length. The gene variant can include a CA repeat, and in particular, can be located within intron 5 of the HNMT gene.
An oligonucleotide primer also is described. The oligonucleotide primer includes a nucleic acid molecule that causes elongation of a region of an HNMT intron having a gene variant. The gene variant is associated with a histaminergic disease. The primer can be about 14 to about 30 nucleotides in length. The nucleic acid primer can include the nucleotide sequence of SEQ ID NO:4 or SEQ ID NO:5. Kits containing oligonucleotide primers also are featured.
The invention also relates to an article of manufacture that includes packaging material and a nucleic acid molecule. The nucleic acid molecule specifically binds an HNMT gene variant, wherein the HNMT gene variant is associated with a histaminergic disease. The packaging material includes a label that indicates the nucleic acid molecule can be used for characterizing or diagnosing a histaminergic disease in the patient. The HNMT gene variant can include a thymine at nucleotide 315.
The invention also features a kit for characterizing or diagnosing a histaminergic disease in a patient. The kit includes an antibody that selectively binds an HNMT variant that is associated with the histaminergic disease.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
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Scott et al., “Pharmacogenetics of N-methylation: Heritability of human erythrocyte histamine N-methyltransferase activity”,Clin. Pharmacol. Ther., 1988, 43(3):256-262.
Price et al., “Genetic Segregation Analysis of Red Blood Cell (RBC) Histamine N-Methyltransferase (HNMT) Activity”,Genet. Epidemiol., 1993, 10(2):123-131.
Rose et al., “An Open-Label Study of the Therapeutic Efficacy of High-Dose Famotidine Adjuvant Pharmacotherapy in Schizophrenia: Preliminary Evidence for Treatment Efficacy”,Clin. Neuropharmacol., 1996, 19(4):341-348.
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Short Protocols in Molecular Biology, Chapter 8, Green Publishing Associates and John Wiley & Sons, Edited by Ausubel, F.M et al., 1992, 8-1—8-25.
Short Protocols in Molecular Biology, Chapter 11, Green Publi
Galinsky Raymond E.
Lachman Herb M.
Liggett Stephen
Weinshilboum Richard M.
Yan Lan
Fish & Richardson P.C.
Johannsen Diana
Mayo Foundation for Medical Education and Research
Myers Carla J.
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