Clarification of genetic mechanisms leading to the whole phenotype in Turner syndrome

• Project/Area Number: 15591150
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: National Research Institute for Child Health and Development
• Principal Investigator: OGATA Tsutomu National Research Institute for Child Health and Development, Director, 部長 (40169173)
• Co-Investigator(Kenkyū-buntansha): SATO Naoko National Research Institute for Child Health and Development, Research Fellow, 研究員 (10383069) ; FUKAMI MAKI National Research Institute for Child Health and Development, Research Fellow, 研究員 (40265872)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000); Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: Turner syndrome / Sex choromosome / SHOX / Haploinsufficiency / Enhancer sequence / Gonadal function / Lymphogenic gene / Genotype-phenotype correlation

Research Abstract

The main results obtained in the research period is two-folds.
<Identification of the enhancer region for the SHOX expression>
We have previously studied more than 40 patienst with Leri-Weill syndrome, and identified SHOX deletion or mutation in 33 patients. In this research period, we found microdeltions at the 3' region of the SHOX gene in four patients with no demonstrable SHOX mutation. The smallest overlapping deleted region was determined as 39 kb, and in silico analysis disclosed 6 evolutionally conserved sequences within the 39 kb critical region. Thus, we performed luciferase assay with the evolutionally conserved sequences, and identified that a roughly 800 bp sequence has the transactivation function for the SHOX expression. The results suggest for the first time that the enhancer sequence for SHOX is present in the 800 bp region, and support the presence of an enhancer disorder. Furthermore, the identification of the molecule regulating the enhancer will permit to clarify the molecular network underlying the SHOX deficiency disorders.
<Localization of a lymphogenic gene>
We have previously proposed that the characteristic soft tissue and visceral features in Turner syndrome is explained as the malformation sequence initiated by lymphatic hypoplasia, suggesting the presence of an Xp-Yp homologous lymphogenic gene. In this research period, we performed genotype-phenotype correlation in 47 patients with partial Xp deletions and in 18 patients with partial Yp deletions, and localized the putative lymphogenic gene to a roughly 9 Mb region between MAOA and DMD on Xp and to an approximatedly 4 Mb region between PABY and DYS255 on Yp. Furthermore, we have identified three ESTs that may be regarded as the candidates for the lymphogenic gene,.

Research Products

• [Journal Article] Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients. (2005)
  • Author(s): Fukami, M., Horikawa, R., Nagai, T., Tanaka, T., Naiki, Y., Sato, N., Okuyama, T., Nakai, H., Soneda, S., Tachibana, K., Matsuo, N., Sato, S., Homma, K., Nishimura, G., Hasegawa, T., Ogata, T.
  • Journal Title: Journal of Clinical Endocrinology and Metabolism 90 Pages: 414-426
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] PTPNll mutation analysis and clinical assessment in 45 patients with Noonan syndrome. (2004)
  • Author(s): Yoshida R, Ogata T, et al.
  • Journal Title: Journal of Clinical Endocrinology and Metabolism 89(7) Pages: 3359-3364
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Statural growth in 31 Japanese patients with SHOX haploinsufficiency : support for a disadvantageous effect of gonadal estrogens (2004)
  • Author(s): Fukami M, Ogata T, et al.
  • Journal Title: Endocrine Journal 51(2) Pages: 197-200
  • NAID: 10012888213
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Clinical features in SHOX haploinsufficiency : diagnostic and therapeutic implications (2004)
  • Author(s): Ogata T, Fukami M
  • Journal Title: Growth, Genetics & Hormones 20(2) Pages: 17-23
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Statural growth in 31 Japanese patients with SHOX haploinsufficiency: support for a disadvantageous effect of gonadal estrogens. (2004)
  • Author(s): Fukami, M., Nishi, Y., Hasegawa, Y., Miyoshi, Y., Okabe, T., Haga, N., Nagai, T., Tanaka, T., Ogata, T.
  • Journal Title: Endocrine Journal 51(2) Pages: 197-200
  • NAID: 10012888213
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Premature ovarian failure in a female with proximal symphalangism and NOG mutation. (2004)
  • Author(s): Kosaki, K., Sato, S., Hasegawa, T., Matsuo, N., Suzuki, T., Ogata, T.
  • Journal Title: Fertility and Sterility 81(4) Pages: 1137-1139
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A 3 bp deletion mutation of PTPN11 in an infant with severe Noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia. (2004)
  • Author(s): Yoshida, R., Miyata, M., Nagai, T., Yamazaki, T., Ogata, T.
  • Journal Title: American Journal of Medical Genetics 128A(1) Pages: 63-66
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Protein tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome. (2004)
  • Author(s): Yoshida, R., Hasegawa, T., Hasegawa, Y., Nagai, T., Kinoshita, E., Tanaka, Y., Kanegane, H., Ohyama, K., Onishi, T., Hanew, K., Okuyama, T., Horikawa, R., Tanaka, T., Ogata, T.
  • Journal Title: Journal of Clinical Endocrinology and Metabolism 89(7) Pages: 3359-3364
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clinical features in SHOX haploinsufficiency: diagnostic and therapeutic implications. (2004)
  • Author(s): Ogata, T., Fukami, M.
  • Journal Title: Growth, Genetics & Hormones 20(2) Pages: 17-23
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome. (2004)
  • Author(s): Yoshida, R., Nagai, T., Hasegawa, T., Kinoshita, E., Tanaka, T., Ogata, T.
  • Journal Title: American Journal of Medical Genetics 130A(4) Pages: 432-434
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A 3 bp deletion mutation of PTPN11 in an infant with severe Noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia (2004)
  • Author(s): Ogata T, Yoshida R, et al.
  • Journal Title: American Journal of Medical Genetics 128A(1) Pages: 63-66
• [Journal Article] PTPN11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome. (2004)
  • Author(s): Yoshida R, Ogata T, et al.
  • Journal Title: Journal of Clinical Endocrinology and Metabolism 89(7) Pages: 3359-3364
• [Journal Article] Longitudinal auxological study in a female with SHOX haploinsuf ficiency and normal ovarian function (2003)
  • Author(s): Fukami M, Ogata T, et al.
  • Journal Title: European Journal of Endocrinology 149(4) Pages: 337-341
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mental retardation in a boy with congenital adrenal hypoplasia: a clue to contiguous gene syndrome involving DAX-1 and IL1RAPL. (2003)
  • Author(s): Sasaki, R., Inamo, Y., Saitoh, M., Hasegawa, T., Kinoshita, E., Ogata, T.
  • Journal Title: Endocrine Journal 50(3) Pages: 303-307
  • NAID: 50000262998
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Lymphstasis in a boy with Noonan syndrome: implication for the development of skeletal features. (2003)
  • Author(s): Ogata, T., Sato, S., Hasegawa, T., Kosaki, K.
  • Journal Title: Endocrine Journal 50(3) Pages: 319-324
  • NAID: 130004443046
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Longitudinal auxological study in a female with SHOX haploinsufficiency and normal ovarian function. (2003)
  • Author(s): Fukami, M., Matsuo, N., Hasegawa, T., Sato, S., Ogata, T.
  • Journal Title: European Journal of Endocrinology 149(4) Pages: 337-341
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] PTPNll mutations and genotype-phenotype correlations in Noonan and LEOARD syndromes
  • Author(s): Ogata T, Yoshida R
  • Journal Title: Pediatric Endocrinology Reviews In press
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Langer mesomelic dysplasia in a 45,X/46,X, r(X) infant with loss of SHOX from the ring X Chromosome and a microdeletion in the SHOX 3' region of the cytogenetically normal X chromosome.
  • Author(s): Fukami M, Ogata T, et al.
  • Journal Title: American Journal of Medical Genetics In press
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Langer mesomelic dysplasia in a 45,X/46,X, r(X) infant with loss of SHOX from the ring X Chromosome and a microdeletion in the SHOX 3' region of the cytogenetically normal X chromosome.
  • Author(s): Fukami, M., Okuyama, T., Yamamori, S., Nishimura, G., Ogata, T.
  • Journal Title: American Journal of Medical Genetics. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes.
  • Author(s): Ogata, T., Yoshida, R.
  • Journal Title: Pediatric Endocrinology Reviews. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Langer mesomelic dysplasia in a 45,X/46,X r(X) infant with loss of SHOX from the ring X Chromosome and a microdeletion in the SHOX 3' region of the cytogenetically normal X chromosome.
  • Author(s): Fukami M, Ogata T, et al.
  • Journal Title: American Journal of Medical Genetics (In press)
• [Journal Article] PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes
  • Author(s): Ogata T, Yoshida R
  • Journal Title: Pediatric Endocrinology Reviews (In press)
• [Book] ターナー症候群の遺伝学(単行本) (2003)
  • Author(s): 緒方 勤
  • Total Pages: 205
  • Publisher: メディカルレビュー社
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Ogata T, Fukami M: "Clinical features in SHOX haploinsufficiency : diagnostic and therapeutic implications"Growth, Genetics & Hormones. In press.
• [Publications] Yoshida R, Ogata T, et al.: "PTPN11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome."Journal of Clinical Endocrinology and Metabolism. In press.
• [Publications] Fukami M, Ogata T, et al.: "Statural growth in 31 Japanese patients with SHOX haploinsufficiency : support for a disadvantageous effect of gonadal estrogens"Endocrine Journal. In press.
• [Publications] Yoshida R, Ogata T, et al.: "A 3 by deletion mutation of PTPN11 in an infant with severe Noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia."American Journal of Medical Genetics. In press.
• [Publications] Sato N, Fukami M, Ogata T, et al.: "Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients"Journal of Clinical Endocrinology and Metabolism. 89(3). 1079-1088 (2004)
• [Publications] Fukami M, Ogata T, et al.: "Longitudinal auxological study in a female with SHOX haploinsufficiency and normal ovarian function"European Journal of Endocrinology. 149(4). 337-341 (2003)
• [Publications] 緒方 勤: "ターナー症候群の遺伝学(単行本)"メディカルレビュー社. 205 (2003)