Identification and characterization of genes in patients with severe mental retardation caused by autosomal dominant trait.

• Project/Area Number: 13670158
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Institute for Developmental Research, Aichi Human Service Center
• Principal Investigator: WAKAMATSU Nobuaki Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Department Head., 遺伝学部, 部長 (60274198)
• Co-Investigator(Kenkyū-buntansha): YAMADA Kenichiro Dept Genetics, Inst Developmental Research, Aichi Human Service Center, Research Associate., 遺伝学部, 研究員 (30291173) ; YAMADA Yasukazu Dept Genetics, Inst Developmental Research, Aichi Human Service Center, Division Chief., 遺伝学部, 室長 (70191343)
• Project Period (FY): 2001 – 2002
• Project Status: Completed (Fiscal Year 2002)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000); Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: mental retardation / autosomal dominant / translocation / ZFHX1B / SIP1 / microcephaly / facial dysmorphism / congenital heart disease / agenesis of corpus callosum / nonsense mutation / frame shift mutation / 神経呈 / 脳発達障害

Research Abstract

Mental retardation (MR) is the most common cause of serious handicap in children and young adults. Defining features of MR include an IQ (intelligence quotient) of less than 70, together with associated functional deficits in adaptive behavior, which manifest themselves before 18 years of age. The molecular mechanisms underlying MR are quite heterogeneous and most of the genes responsible for MR are still unidentified. We have adopted the strategy of determining the chromosomal translocation breakpoints in two patients with profound mental retardation. Genes located at the translocation breakpoints should be candidates for MR and these conditions are likely caused by autosomal dominant traits. One patient (case 1 ) has a chromosomal translocation between 2q22 and 13q22 and the other (case 2) has 6q16 and 12p12. Case 1 has profound mental retardation, facial dysmorphism, microcephaly, delayed motor development, congenital heart disease and Hirschsprung disease, and was diagnosed as suffering from the Hirschsprung disease-Mental retardation (HSCR-MR) syndrome. The other patient has profound mental retardation and delayed motor development. We have identified ZFHX1B gene as a cause of the HSCR-MR syndrome, located at the 2q22 breakpoint. We also determined a translocation breakpoint on 6q16 from case 2. However our results suggest that the MR of case 2 is likely due to a defect in a gene located at 12p12.

Research Products

• [Publications] 東 雄二郎, 若松 延昭: "総説:zfhx1ファミリーとその欠損症"日本生化学会雑誌. 75. 27-36 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Yoneda M, Fujita T, Yamada Y, et al.(計13名): "Late infantile Hirschsprung disease-mental retardation syndrome with a 3-bp deletion in ZFHX1B"Neurology. 59. 1637-1640 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] 若松 延昭, 長屋 昌宏: "ヒルシュスプルング症侯群"ゲノム医学. 2. 41-46 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Yamada K^*, Yamada Y^*, Nomura N, et al.(計16名): "Nonsense and frameshift mutations in ZFHX1B, encoding Smad-interacting protein 1, cause a complex developmental disorder with a great variety of clinical features"Am J Hum Genet. 69. 1178-1185 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Yamada Y, Miura K, Kumagai T, et al.(計12名): "Molecular analysis of Japanese patients with Rett syndrome : Identification of five novel mutations and genotype-phenotype correlation"Hum Mutat. 18. 253(online#443) (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Wakamatsu N, Yamada Y, Yamada K, et al.(計13名): "Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease"Nature Genet. 27. 369-370 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Yoneda M, Fujita T, Yamada Y, Yamada K, Fujii A, Inagaki T, Nakagawa H, Shimada A, Kishikawa M, Nagaya M, Azuma T, Kuriyama M, Wakamatsu N: "Late infantile Hirschsprung disease-mental retardation syndrome with a 3-bp deletion in ZFHX1B"Neurology. 59(10). 1637-1640 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Nagaya M, Kato J, Niimi N, Tanaka S, Wakamatsu N.: "Clinical features of a form of Hirschsprung's disease caused by a novel genetic abnormality"J Pediatr Surg 2002. 37(8). 1117-1122 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yamada K, Yamada Y, Nomura N, Miura K, Wakako R, Hayakawa C, Matsumoto A, Kumagai T, Yoshimura I, Miyazaki S, Kato K, Sonta S, Ono H, Yamanaka T, Nagaya M, Wakamatsu N: "Nonsense and frameshift mutations in ZFHX1B, encoding Smad-interacting protein 1 , cause a complex developmental disorder with a great variety of clinical features"Am J Hum Genet. 69(6). 1178-1185 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yamada Y, Miura K, Kumagai T, Hayakawa C, Miyazaki S, Matsumoto A, Kurosawa K, Nomura N, Taniguchi H, Sonta S, Yamanaka T, Wakamatsu N: "Molecular analysis of Japanese patients with Rett syndrome : Identification of five novel mutations and genotype-phenotype correlation"Hum Mutat. 18(3). 253(Online#443) (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Wakamatsu N, Yamada Y, Yamada K, Ono T, Nomura N, Taniguchi H, Kitoh H, Mutoh N, Yamanaka T, Mushiake K, Kato K, Sonta S, Nagaya M: "Mutations in SIP1, encoding Smad interacting protein-1 , cause a form of Hirschsprung disease"Nature Genet. 27(4). 369-370 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 東 雄二郎, 若松 延昭: "総説:zfhx1ファミリーとその欠損症"日本生化学会雑誌. 75(1). 27-36 (2003)
• [Publications] Yoneda M, Fujita T, Yamada Y et al. (計13名): "Late infantile Hirschsprung disease-mental retardation syndrome with a 3-bp deletion in ZFHX1B"Neurology. 59(10). 1637-1640 (2002)
• [Publications] 若松 延昭, 長屋 昌宏: "ヒルシュスプルング症侯群"ゲノム医学. 2(3). 41-46 (2002)
• [Publications] Yamada K^*, Yamada Y^*, Nomura N. et al. (計16名): "Nonsense and frameshift mutations in ZFHX1B, encoding Smad-interacting protein 1, cause a complex developmental disorder with a great variety of clinical features"Am J Hum Genet. 69(6). 1178-1185 (2001)
• [Publications] Yamada Y, Miura K, Kumagai T et al. (計12名): "Molecular analysis of Japanese patients with Rett syndrome : Identification of five novel mutations and genotype-phenotype correlation"Hum Mutat. 18(3). 253(Online#443) (2001)
• [Publications] Wakamatsu N, Yamada Y, Yamada K. et al. (計13名): "Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease"Nature Genet. 27(4). 369-370 (2001)
• [Publications] Yamada K, et al.: "Nonsense and Frameshift Mutations in ZFHX1B, Encoding Smad-Interacting Protein 1, Cause a Complex Developmental Disorder with Great Variety of Clinical Features"Am J Hum Genet. 69(6). 1178-1185 (2001)
• [Publications] Yamada K, et al.: "Molecular analysis of Japanese patients with Rett syndrome : Identification of fire novel mutations and genotype-phenotypecarrelation"Hum Mutat. 18(3). 253-Online #443 (2001)
• [Publications] Wakamatsu N, et al.: "Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease"Nature Genet. 27(4). 369-270 (2001)
• [Publications] 若松 延昭: "てんかんと神経堤障害を呈する知的障害患者の病因遺伝子の同定"日本神経精神薬理学雑誌. 21. 63-67 (2001)
• [Publications] Yamada K, et al.: "A rare case of complete human eryhrocyte AMP deaminase deficiency due to two novel missorse mutations in AMPD3"Hum Mutat. 17(1). 78-Online #395 (2000)
• [Publications] Yamada K, et al.: "Novel genetic mutations responsible for the HPRT deficiency and the clinical phenotypes in Japanese"Adv Exp Med Biol. 486. 29-33 (2000)