Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1997-02-07
1999-09-28
Guzo, David
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
536 235, 536 2431, C12Q 168, C07H 2104
Patent
active
059586850
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP95/00906, filed May 12, 1995.
1. Technical Field
This invention relates to abnormalities in the insulin receptor structure gene in non-insulin-dependent diabetes mellitus (hereinafter referred to simply as NIDDM). More particularly, it relates to mutant human insulin receptor DNAs having mutations at specific sites and fragments thereof.
2. Background Art
NIDDM, which is a genetic disease with one of the highest incidence in mankind today, is induced by several gene abnormalities combined with environmental factors such as obesity, stress and aging. In Japan, the number of patients with NIDDM is estimated to be about 5,000,000. NIDDM has been recently designated as one of the four most serious diseases following cancer, cerebral stroke and heart infarction. Thus there has been an urgent need to establish an effective countermeasure for NIDDM. In general, the symptoms of NIDDM can be frequently ameliorated by diet therapy and kinesitherapy. Therefore, if possible, it is best to diagnose NIDDM at an early stage. Presently, in order to diagnose NIDDM at an early stage, troublesome examinations, such as OGTT, must be conducted. OGTT comprises orally administering 75 g of glucose to a patient in a fasting state, collecting the blood at intervals of 30 minutes and measuring the blood sugar level at two hour intervals. Therefore, a more convenient and reliable diagnostic method is needed for early detection and prevention of NIDDM.
Although no gene has been found to be responsible for the onset of NIDDM, it is assumed that genes of insulin function mechanism-relating factors or genes of insulin secretion-relating factors may be candidate genes for NIDDM. It is known that the factors relating to insulin function involve insulin receptor, insulin receptor substrate (IRS-1), glucose transporter type 4, etc., while the factors relating to insulin secretion involve glucose transporter type 2, glucokinase, chondriogene, etc. Although attempts were made to detect abnormalities in the latter two genes in association with NIDDM, the abnormality ratio was only around 1% in each case (Interim Report in 1993, Onset Mechanism Group, Research and Study Project on Diabetes, Ministry of Health and Welfare).
Insulin acts upon the target cell by binding to the insulin receptor located on the cell membranae. Insulin resistance is often observed in the early stages of NIDDM (Taylor, S. I. Diabetes 41:1473-1490, 1992). Based on these facts, it has been speculated that the insulin receptor might be the gene responsible for the onset of NIDDM. Abnormalities in the insulin receptor would result in a high insulin resistance and thus induce severe diabetes accompanied by hyperinsulinemia. However, such a phenomenon is scarcely observed in NIDDM cases. Thus, abnormalities in the insulin receptor have not been related to NIDDM.
In recent years, a number of insulin receptor abnormalities have been discovered by others including the present inventors. It has been found that the examination data and symptoms of patients vary widely depending on the mutation type (M. Taira et al., Science 245:63-66, 1989; F. Shimada et al., Lancet 335:1179-1181, 1990). Thus, it is quite possible that insulin receptor gene abnormalities may partially participate in the onset of NIDDM. However, no attempt has been made so far to systematically detect the insulin receptor gene abnormalities on a large scale in association with NIDDM. In addition, the particular locations of the gene abnormalities are still unknown.
Under these circumstances, the present inventors have prepared chromosomal DNAs from the blood of typical NIDDM Japanese patients and studied the base sequences of insulin receptor DNAs in order to reveal the relationship between human insulin receptor gene abnormalities and NIDDM. As a result, they have found out that a quantitative abnormality is observed at a significant frequency in the patients with NIDDM, thus completing the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an electrophorogram whi
REFERENCES:
patent: 5260200 (1993-11-01), Kahn et al.
patent: 5621075 (1997-04-01), Kahn et al.
Krook et al., "Rapid and simultanoues detection of multiple mutations by pooled . . ." Hum. Molec. Gene. 1(6):391-395 (1992).
Makino et al., Mini Review Insulin Receptor Gene Mutation: A Molecular Genetical and Functional Analysis Cell. Sign. 4(4):351-363 (1992).
Kan et al., "Frequency of Mutations of Insulin Receptor Gene in Japanese Patients with NIDDM" Diabetes 44:1081-1086 (1995).
Ebina Yousuke
Guzo David
Otsuka Pharmaceutical Co. Ltd.
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