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Gene causative of Rothmund-Thomson syndrome and gene product

a technology of rothmund-thomson syndrome and gene product, which is applied in the field of Causative gene of rothmund-thomson syndrome, can solve problems such as genetic instability, and achieve the effect of facilitating and efficiently diagnosing

Inactive Publication Date: 2006-10-26
AGENE RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] Further, from this fact, they have found that it is possible to diagnose Rothmund-Thomson syndrome by detecting mutations in the RecQ4 helicase gene; moreover, it is possible to treat the disease by compensating for the mutations.
[0068] Then, oligonucleotides A and X are annealed with the above-mentioned product of polymerase chain reaction to ligate oligonucleotides A and X with each other. When a mutation of interest is present in the sample DNA, the 3′-end of oligonucleotide A can form a base pair with the mutated base and as a result oligonucleotide A can be connected to oligonucleotide X; and this allows the production of oligonucleotides with labels at both ends (for example, biotin and digoxigenin).
[0077] A number of cases have been discovered where a protein, which has a truncation at the C terminus of the normal RecQ4 helicase, is presumed to be produced by frame shift or a newly generated termination codon due to mutations in the RecQ4 helicase gene in patients with Rothmund-Thomson syndrome (see Examples). Accordingly, it is possible to carry out easily and efficiently the diagnosis of Rothmund-Thomson syndrome by using antibody recognizing the C terminus of RecQ4 helicase (see Japanese Patent Application No. Hei 10-311284).

Problems solved by technology

This suggested that the mutations in the RecQ4 gene result in genetic instability and are the cause of Rothmund-Thomson syndrome.

Method used

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  • Gene causative of Rothmund-Thomson syndrome and gene product
  • Gene causative of Rothmund-Thomson syndrome and gene product
  • Gene causative of Rothmund-Thomson syndrome and gene product

Examples

Experimental program
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Effect test

example 1

Genomic DNA Cloning of the RecQ4 Helicase Gene

[0101] The genomic DNA of the human RecQ4 helicase gene was obtained by screening a P1 / PAC library. The P1 / PAC library used was obtained from Genome Systems, and the preparation method is described in the Smoller et al. reference (Smoller, et al., Chromosoma, 1991, vol. 100, pp487-pp494). The screening was carried out by PCR using a sense primer, Q4P (5′-CGC TTC TGG AGA AAA TAC CTG CAC-3′ / SEQ ID NO: 9), and an antisense primer, Q4Q (5′-TTG GAG CCT CCT CGT TCC CAC ACC-3′ / SEQ ID NO: 10), corresponding to the base sequence segments in exon 21 of the RecQ4 gene. The screening was carried out in Genome Systems Co. The isolation and purification of DNA from P1 clone #13447 obtained in the screening was performed by the method as descried in the reference (Smoller, et al., Chromosoma, 1991, vol. 100, pp487-pp494). The genomic base sequence of the RecQ4 gene was determined by using the purified P1 DNA as the template. The determined base sequen...

example 2

Cloning of the Promoter Region of the RecQ4 Helicase Gene

[0103] DNA from P1 clone #13447, containing the genomic DNA of the human RecQ4 helicase gene, was digested with restriction enzymes BamHI and BglII (TaKaRa Shuzo), and the plasmid vector pBluescriptII KS+ was digested with BamHI. The resulting digested DNAs were mixed with each other and then T4 DNA ligase (TaKaRa Shuzo) was added thereto for ligation reaction. E. coli competent cells, DH5α (Toyobo), were transformed with the reaction product and the resulting E. coli colonies were screened by PCR to determine whether or not the DNA from each colony contained a 5′ upstream region of human genomic DNA of RecQ4. The screening for clones containing the 5′ upstream region was carried out by using a sense primer, Q4 S (5′-TCA CAA CTT CTG ATC CCT GGT GAG-3′ / SEQ ID NO: 5), and an antisense primer, Q4 R (5′-GAG GGT CTT CCT CAA CTG CTA CAG-3′ / SEQ ID NO: 6), for amplifying a 247-bp segment of genomic DNA of RecQ4 sequence (residue 1399...

example 3

Detection of Mutations in the RecQ4 Helicase Gene in Patients with Rothmund-Thomson Syndrome

[0104] The inventors had previously cloned and analyzed two novel human helicase genes, RecQ4 and RecQ5, belonging to the RecQ helicase gene family (see Japanese Patent Application No. Hei 9-200387; Japanese Patent Application No. Hei 10-81492; and Kitao, S. et al., Genomics, 1998, vol. 54, pp443-pp452). Together, with these two novel genes, there are 5 members belonging to the human RecQ helicase gene family, including RecQ1 (M. Seki et al., Nucleic Acids Res. 22:4566 (1994); K. L. Puranam et al., J. Biol. Chem. 269:29838 (1994)), BLM (N. A. Ellis et al., Cell 83:655 (1995)), WRN(C.-E. Yu et al., Science 272:258 (1996)), RecQ4 and RecQ5.

[0105] Northern blot analysis for these five RecQ helicase genes revealed that, RecQ5, like RecQ1, was observed to be ubiquitously expressed through all the tissues and organs, while markedly high level expression was observed in the thymus and testis and h...

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Abstract

The RecQ4 helicase gene, belonging to the RecQ helicase gene family, is revealed herein to be the causative gene of Rothmund-Thomson syndrome. The present inventors found out that it is possible to diagnose Rothmund-Thomson syndrome by detecting mutation of this gene. Further, they uncovered that it is possible to treat patients of Rothmund-Thomson syndrome by utilizing normal RecQ4 helicase gene or proteins thereof.

Description

TECHNICAL FIELD [0001] The present invention relates to a causative gene of Rothmund-Thomson syndrome, methods for the diagnosis of the disease, and diagnostic agents and therapeutic agents for the disease. BACKGROUND ART [0002] Rothmund-Thomson syndrome ((RTS); poikiloderma congenital) is a rare autosomal recessive hereditary disease, the pathophysiology and causative gene of which remain unrevealed. In 1868, a German ophthalmologist, August Rothmund, reported for the first time, 10 patients from an isolated village in Bayern showing crisis of poikiloderma at their youth and exhibiting at a high frequency juvenile cataracts (A. Rothmund, Arch. Ophthalmol. 4:159 (1887)). In 1936, an English ophthalmologist, Sidney Thomson, reported 3 patients with very similar poikiloderma (M. S. Thomson, Br. J. Dermatol. 48:221 (1936)). Two of the three had bone abnormality. Today, these two similar clinical cases are recognized as Rothmund-Thomson syndrome (RTS). Many cases in children of a variet...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/68G01N33/574C07H21/04C12P21/06C12N9/22C07K16/40C12N1/21C12N9/90C12Q1/6883G01N33/573
CPCC12N9/90C12Q1/6883C12Q2600/156G01N33/573G01N2333/99
Inventor KITAO, SAORISHIMAMOTO, AKIRAFURUICHI, YASUHIRO
Owner AGENE RES INST
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