Identification of novel SNPs to localize a susceptibility locus within a candidate region of pemphigus

• Project/Area Number: 16591111
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Dermatology
• Research Institution: Nara Medical University
• Principal Investigator: MIYAGAWA Sachiko Nara Medical University, School of Medicine, Professor, 医学部, 教授 (30094626)
• Co-Investigator(Kenkyū-buntansha): ASADA Hideo Nara Medical University, School of Medicine, Associate Professor, 医学部, 助教授 (60252681) ; NIIZEKI Hironori Nara Medical University, School of Medicine, Assistant Professor, 医学部, 講師 (10228124) ; INOKO Hidetoshi Tokai University, School of Medicine, Professor, 医学部・基礎医学系・分子生命科学, 教授 (10101932)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: Pemphigus / Gene polymorphism / HLA / Desmoglein / Genome wide scan

Research Abstract

There is a consensus that HLA-DRB1 and -DQB1 are susceptible genes associated with the development of pemphigus. However, it is suggested that there might be numerous candidate genes in the disease. The purpose of this study is to discover novel single nucleotide polymorphisms (SNPs) to localize a susceptible locus within a particular candidate region. We studied desmoglein (DSG) cluster in chromosome 18q12 as a candidate region that encodes pemphigus-specific autoantigens.
To identify novel SNPs in the DSG1,DSG4, and DSG3 genes, we sequenced all exons including the flanking intronic sequence using direct sequencing. Genomic DNA extracted from peripheral blood was subjected from 8 patients with pemphigus vulgaris (PV) and 8 healthy controls.
We identified 14 SNPs in the DSG1 gene, 4 SNPs in the DSG4 gene, and 21 SNPs in the DSG3 gene. Several SNPs were identified in exon 1 and 16 (identical to exon 15 in the DSG1 gene) among all 3 genes. Exon 11 in the DSG1 and DSG3 gene includes a nonsynonymous SNP. Only one synonymous SNP in exon 7 in the DSG1 gene was found. This SNP was located in exon 2 to 10 to encode T cell epitopes in an extracellular domain of the desmoglein protein. It has been reported that this SNP (T809C) was associated with pemphigus foliaceus in the French and Tunisian populations. We identified the T809C SNP both in the patient and control group among Japanese in this study. Moreover, we also identified the PV-associated haplotype that includes 5 SNPs in the DSG3 gene reported by Capon, et al.
Haplotype association analysis using a large sample (N>160) we have already collected so far and functional analysis of these variants would enable us to provide evidence that the DSG genes are involved in the development of pemphigus through functional genetic polymorphisms.

Research Products

• [Journal Article] High-throughput DNA typing of HLA-A, -B, -C, and -DRB1 loci by a PCR-SSOP-Luminex method in the Japanese population. (2005)
  • Author(s): Itoh Y, Mizuki N, Shimada T, Azuma F, Itakura M, Kashiwase K, Kikkawa E, Kulski JK, Satake M, Inoko H.
  • Journal Title: Immunogenetics 57(10) Pages: 717-729
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Intravascular histiocytosis associated with rheumatoid arthritis : report of a case with lymphatic endothelial proliferation (2005)
  • Author(s): Okazaki A, Asada H, Niizeki H, Nonomura A, Miyagawa S
  • Journal Title: Br J Dermatol 152(6) Pages: 1385-1387
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Neonatal lupus erythematosus : a review of the racial differences and similarities in clinical, serological and immunogenetic features of Japanese versus Caucasian patients. (2005)
  • Author(s): Miyagawa S
  • Journal Title: J Dermatol 32(7) Pages: 514-522
  • NAID: 10020418945
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mosquito salivary gland extracts induce EBV-infected NK cell oncogenesis via CD4 T cells in patients with hypersensitivity to mosquito bites (2005)
  • Author(s): Asada H, Saito-Katsuragi M, Niizeki H, Yoshioka A, Suguri S, Isonokami M, Aoki T, Ishihara S, Tokura Y, Iwatsuki K, Miyagawa S
  • Journal Title: J Invest Dermatol 125(5) Pages: 956-961
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] High-throughput DNA typing of HLA-A,-B,-C, and -DRB1 loci by a PCR-SSOP-Luminex method in the Japanese population. (2005)
  • Author(s): Itoh Y, Mizuki N, Shimada T, Azuma F, Itakura M, Kashiwase K, Kikkawa E, Kulski JK, Satake M, Inoko H
  • Journal Title: Immunogenetics 57(10) Pages: 717-729
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Intravascular histiocytosis associated with rheumatoid arthritis case with lymphatic endothelial proliferation (2005)
  • Author(s): Okazaki A, Asada H, Niizeki H, Nonomura A, Miyagawa S
  • Journal Title: Br J Dermatol 152(6) Pages: 1385-1387
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mosquito salivary gland extracts induce EBV-infected NK cell oncogenesis via CD4 T cells in patients with hypersensitivity to mosquito bites. (2005)
  • Author(s): Asada H, Saito-Katsuragi M, Niizeki H, Yoshioka A, Suguri S, Isonokami M, Aoki T, Ishihara S, Tokura Y, Iwatsuki K, Miyagawa S
  • Journal Title: J Invest Dermatol 125(5) Pages: 956-961
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ampicillin-induced cutaneous eruption associated with Epstein-Barr virus reactivation (2005)
  • Author(s): Saito-Katsuragi M, Asada H, Yokoi S, Niizeki H, Miyagawa S
  • Journal Title: J Am Acad Dermatol 52(Suppl 1)
• [Journal Article] Intravascular histiocytosis associated with rheumatoid arthritis: report on with lymphatic endothelial proliferation (2005)
  • Author(s): Okazaki A, Asada H, Niizeki H, Nonomura A, Miyagawa S
  • Journal Title: Br J Dermatol 152(6) Pages: 1385-1387
• [Journal Article] Neonatal lupus erythematosus: a review of the racial differences and similarities in clinical, serological and immunogenetic features of Japanese versus Caucasian patients. (2005)
  • Author(s): Miyagawa S
  • Journal Title: J Dermatol 32(7) Pages: 514-522
  • NAID: 10020418945
• [Journal Article] Mosquito salivary gland extracts induce EBV-infected NK cell oncogem CD4 T cells in patients with hypersensitivity to mosquito bites (2005)
  • Author(s): Asada H, Saito-Katsuragi M, Niizeki H, Yoshioka A, Suguri S, Isonokami M, Aoki T, Ishihara S, Tokura Y, Iwatsuki K, Miyagawa S
  • Journal Title: J Invest Dermatol 125(5) Pages: 956-961
• [Journal Article] Exclusion of the TAP1 and TAP2 genes within the HLA class II region as candidate susceptibility genes to pemphigus in the Japanese population (2004)
  • Author(s): Niizeki H, Asada H, Miyagawa S, et al.
  • Journal Title: J Dermatol Sci 36(2) Pages: 122-124
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Exclusion of the TAP1 and TAP2 genes within the HLA class II region as candidate susceptibility genes to pemphigus in the Japanese population. (2004)
  • Author(s): Niizeki H, Kumagai S, Kanagawa S, Amagai M, Yamashina Y, Asada H, Nishikawa T, Miyagawa S
  • Journal Title: J Dermatol Sci 36(2) Pages: 122-124
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Exclusion of the TAP1 and TAP2 genes within the HLA class II region as candidate susceptibility genes to pemphigus in the Japanese population (2004)
  • Author(s): Niizeki H, Asada H, Miyagawa S, et al.
  • Journal Title: J Dermatol Sci 36・2 Pages: 122-124
• [Journal Article] The MICA5.1 allele is not associated with susceptibility to effects of ultraviolet-B radiation on induction of contact hypersensitivity. (2004)
  • Author(s): Niizeki H, Inoko H, et al.
  • Journal Title: J Dermatol Sci 35・3 Pages: 221-223
  • NAID: 10016184929
• [Journal Article] Childhood epidermolysis bullosa acquisita with auto-antibodies against all 3 structural domains of type VII collagen. (2004)
  • Author(s): Fukumoto T, Asada H, Miyagawa S, et al.
  • Journal Title: J Am Acad Dermatol 50・3 Pages: 480-482
• [Journal Article] Novel algorithm for automated genotyping of microsatellites. (2004)
  • Author(s): Matsumoto T, Inoko H, Tamiya G, Gojobori T, et al.
  • Journal Title: Nucleic Acids Res 32・20 Pages: 2069-2077
• [Journal Article] Autoimmune thyroid disease in anti-Ro/SSA positive children with annular erythema : report of two cases. (2004)
  • Author(s): Miyagawa S, Asada H, et al.
  • Journal Title: Br J Dermatol 150・5 Pages: 1005-1008
• [Journal Article] Intravascular histiocytosis associated with rheumatoid arthritis : a report of a case with lymphatic endothelial proliferation.
  • Author(s): Okazaki A, Asada h, Niizeki H, Miyagawa S, et al.
  • Journal Title: Br J Dermatol (印刷中)
• [Book] 24皮膚疾患 先天性表皮水痘症、「今日の小児治療指針」第14版 (2006)
  • Author(s): 新関寛徳
  • Total Pages: 1
  • Publisher: 医学書院
• [Book] 24.皮膚疾患 先天性表皮水疱症、「今日の小児治療指針」第14版
  • Author(s): 新関寛徳
  • Total Pages: 1
  • Publisher: 医学書院(印刷中)
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Epidermolysis bullosa, Today's therapy in 2006
  • Author(s): Niizeki H
  • Publisher: Igaku Shoin (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 「今日の小児治療指針」第14版
  • Author(s): 新関寛徳
  • Publisher: 医学書院(印刷中)