molecular basis and a new genetic cause of primary aderenal insufficiency

• Project/Area Number: 16K09998
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Keio University
• Principal Investigator: Amano Naoko 慶應義塾大学, 医学部(信濃町), 共同研究員 (70348689)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 副腎機能低下症 / 発生分化 / 副腎 / 副腎低形成症 / 副腎皮質 / 発生 / 遺伝子 / 小児内分泌学

Outline of Final Research Achievements

We enrolled 63 Japanese children (59 families) with biochemically uncharacterized PAI, and sequenced 12 PAI-associated genes. We calculated the proportion of mutation-carrying patients according to demographic characteristics. We identified genetic defects in 50 (85%) families: STAR in 19, NR0B1 in 18, SAMD9 in seven, AAAS in two, NNT in two, MC2R in one and CDKN1C in one. This work was published in the peer-reviewed academic journal‘European journal of endocrinology.’
We identified submicroscopic deletions in the gene A in three patients with adrenal hypoplasia. The in vitro study using the HEK293 cells having stable expression of gene A revealed that β-catenin producing-capacity would decrease in the identified gene A-deleted cells.

Academic Significance and Societal Importance of the Research Achievements

本邦おける「生化学診断が困難な原発性副腎皮質機能低下症」の分子基盤および各単一遺伝子疾患の臨床的特徴を明らかとした。さらに先天性副腎低形成症の新規責任遺伝子を発見し、その分子機構がWnt-βカテニンシグナル系の低下であることを明らかにする。最終的にはヒトの副腎発生分化におけるWnt-βカテニンシグナル系の意義を解明することが目標である。

Research Products

• [Journal Article] Pubertal Development and Pregnancy Outcomes in 46,XX Patients with Nonclassic Lipoid Congenital Adrenal Hyperplasia. (2018)
  • Author(s): Hatabu N, Amano N, Mori J, Hasegawa Y, Matsuura H, Sumitomo N, Nishizawa K, Suzuki M, Katakura S, Kanamoto N, Kamimaki T, Ishii T, Hasegawa T
  • Journal Title: J Clin Endocrinol Metab Volume: ePub ahead Issue: 5 Pages: 1866-1870
  • DOI: 10.1210/jc.2018-01752
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comment on: Acquired monosomy 7 myelodysplastic syndrome in a child with clinical features of dyskeratosis congenita and IMAGe association. (2018)
  • Author(s): Wilson DB, Bessler M, Ferkol TW, Shenoy S, Amano N, Ishii T, Shima H, Narumi S.
  • Journal Title: Pediatric Blood and Cancer Volume: 65 Issue: 1
  • DOI: 10.1002/pbc.26747
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic Defects in Pediatric-onset Adrenal Insufficiency in Japan (2017)
  • Author(s): Amano N, Narumi S, Hayashi M, Takagi M, Imai K, Nakamura T, Hachiya R, Sasaki G, Homma K, Ishii T, Hasegawa T
  • Journal Title: Eur J Endocrinol Volume: 177 Issue: 2 Pages: 187-194
  • DOI: 10.1530/eje-17-0027
  • Peer Reviewed
• [Journal Article] A novel case of somatic KCNJ5 mutation in pediatric-onset aldosterone- producing adenoma (2017)
  • Author(s): Uchida N, Amano N, Yamaoka Y, Uematsu A, Sekine Y, Suzuki M, Watanabe J, Nishimoto K, Mukai K, Fukuzawa R, Hasegawa T, Ishii T
  • Journal Title: J Endocrine Soc Volume: 1 Issue: 8 Pages: 1056-1061
  • DOI: 10.1210/js.2017-00210
  • Peer Reviewed / Open Access
• [Presentation] 小児期発症原発性副腎皮質機能低下症63例における遺伝子異常：STAR変異例の遺伝子型と臨床的特徴 (2017)
  • Author(s): 天野直子、鳴海覚志、林美恵、蜂屋瑠見、高木優樹、佐々木悟郎、本間桂子、石井智弘、長谷川奉延
  • Organizer: 第51回日本小児内分泌学会学術集会