Functional analysis of Homeobox gene responsible for congenital hereditary ptosis and isolation of its associated protein

• Project/Area Number: 15590291
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human genetics
• Research Institution: Nagasaki University
• Principal Investigator: YOSHIURA Koh-ichiro Nagasaki University, Graduate School of Biomedical Sciences, Associate Professor, 大学院・医歯薬学総合研究科, 助教授 (00304931)
• Co-Investigator(Kenkyū-buntansha): AKTTA Sadanori Nagasaki University Hospital, Research Associate, 医学部・歯学部附属病院, 助手 (90315250)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2003: ¥2,700,000 (Direct Cost: ¥2,700,000)
• Keywords: Congenital hereditary ptosis / DMBX1 gene / linkage analysis / chromosome 1 / chromosome 14 / incomplete penetrance / 眼瞼下垂 / MBX1遺伝子 / OARドメイン / 連座解析 / MBX遺伝子 / OTX3遺伝子 / 遺伝子変異

Research Abstract

We firstly thought DMBX1 is strong candidate which is located 2.6 Mb telomeric side of D1S2733. The STRP marker, D1S2733,is distal marker Engle et al., defined the cadidate locus. We found missnese mutation in one patient with congenital hereditary ptosis(CHP). We also found, however, this missense mutaiton in non-affected father and younger brother of the patients, DMBX1 gene would not likely to be causative gene for CHP.
We changed our research aim to do linkage analysis in one large family to fined new locus for CHP. We used ABI Prism Linkage Mapping Set-MD10 in 15 members including 4 affected individuals. LOD score calculation was performed with MLINK software in FASTLINK ver.4.1P or Genehunter software. Six markers, D1S2697 (1p)、D1S255 (1p)、D1S484 (1q), D5S630 (5p), D7S669 (7q), and D14S276 (14q) showed relatively high LOD score indication possible linkage. We set another STRP markers around these markers to perform haplotype analysis. We found two regions, 1p35.3-36.1 and 14q21.1-23.2,are possible candidate loci, but we could not define to one region. Some members have possible mutant haplotype without CHP phenotype and suggest incomplete penetrance in this family. We would re-evaluate phnotypes of members in this family and perform linkage analysis of new family to confirm the candidate locus for CHP.

Research Products

• [Journal Article] Large deletion involving the 5'-UTR in the spastin gene caused mild phenotype of autosomal dominant hereditary spastic paraplegia. (2005)
  • Author(s): lwanaga H et al.
  • Journal Title: Am J Med Genet A. 133 Pages: 13-17
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Large deletion involving the 5'-UTR in the spastin gene caused mild phenotype of autosomal dominant hereditary spastic paraplegia. (2005)
  • Author(s): Iwanaga H, Tsujino A, Shirabe S, Eguchi H, Fukushima N, Niikawa N, Yoshiura K, Eguchi K.
  • Journal Title: Am J Med Genet A.Feb 133(1) Pages: 13-17
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Interferon regulatory factor 6 (IRF6) gene variants confer risk for isolated cleft Lip and palate. (2004)
  • Author(s): Zucchero TM et al.
  • Journal Title: New Engl J Med 351 Pages: 769-780
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Interferon regulatory factor 6(IRF6) gene variants confer risk for isolated cleft Lip and palate. (2004)
  • Author(s): Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, Caprau D, Christensen K, Suzuki Y, Machida J, Natsume N, Yoshiura K, Vieira AR, Orioli IM, Castilla EE, Moreno L, Arcos-Burgos M, Lidra! AC, Field LL, Liu Y, Ray A, Goldstein TH, Schultz RE, Shi M, Johnson MK, Kondo S, Schutte BC, Marazita, ML, Murray JC
  • Journal Title: New Engl J Med 351 Pages: 769-780
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Interferon regulatory factor 6(IRF6)gene variants confer risk for isolated cleft Lio and palate. (2004)
  • Author(s): Zucchero TM. et al.
  • Journal Title: New Engl J Med 351 Pages: 769-780
• [Journal Article] Phenotype-genotype correlation in two patients with 12 proximal deletion. (2004)
  • Author(s): Miyake N. et al.
  • Journal Title: J Hum Genet 49 Pages: 282-281
• [Journal Article] An isolated congenital anosmia locus maps to 18p11.23-q12.2. (2004)
  • Author(s): Ghadami M. et al.
  • Journal Title: J Med Genet 41 Pages: 299-303
• [Publications] Matsuzawa N: "A T25G mutation in the IRF6 gene in a Japanese family with Van der Woude syndrome"Oral Surg, Oral Med. Oral Pathol_Oral Radiol, Endodont. (In press).
• [Publications] Kinoshita A: "TGFB1 mutations in four new families with Camurati-Engelmann disease : Confirmation of independently arising LAP-domain-specific mutations"Am J Med Genet. (In press).