Discovery of new causative genes for salt-losing nephropathy and elucidation of its pathological mechanism

• Project/Area Number: 19K17733
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Mori Takayasu 東京医科歯科大学, 医学部附属病院, 助教 (00735813)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 遺伝子解析研究 / 塩喪失性腎症 / 次世代シークエンサー / パネル遺伝子診断 / パネル遺伝子解析

Outline of Research at the Start

申請者は国内外の留学を経て次世代シークエンサー（NGS）の専門技術を習得し、これまで600名余りの様々な遺伝性腎疾患患者の網羅的遺伝子変異情報ならびに表現系情報を網羅したデータベース構築を経て、Gitelman症候群を含む塩喪失性腎症において共通の表現系を有する患者群の遺伝型を検討し、５家系に共通して新規のCaチャネル変異を、また他の独立した２家系ではオートファジーアダプター遺伝子に全く同一の超希少変異を同定し、これら２つの遺伝子は有望な候補責任遺伝子と考えられた。これらの変異意義検証を通じて新たな病態解明や、コモン病治療方策への展開を目指す。

Outline of Final Research Achievements

A comprehensive genetic analysis of 84 adult patients with salt-losing nephropathy represented by Gitelman syndrome (GS) was performed, and investigation of about half of the unsolved cases revealed that they have several clinical characteristics. We reported that these cases may be categorized into new disease groups (Mori T, HumMutat. 2021). Including this, a total of 18 original papers were published during the period of this research, confirming the importance of genetic analysis for kidney diseases. In addition, experimental approaches were conducted on the two candidate genes (CACNA1H and SQSTM1) that had been the focus of attention from the beginning of the application, but unfortunately no significant findings have been obtained so far, and further verification is required. Whole exome sequences on the unsolved cases have been completed, and we will continue to verify multiple promising candidates.

Academic Significance and Societal Importance of the Research Achievements

次世代シークエンシング技術（NGS）の登場により一度の解析で得られるゲノムデータ量は飛躍的に増加し、遺伝子検査は単なる個別疾患診断という枠組みを超え、大きな臨床的意義を持つようになった。今回Human Mutation誌に報告した塩喪失性疾患未解決群の臨床的特徴は、新しい疾患概念として再考される可能性があり、その病態解明は腎臓病学の発展に大きく寄与すると期待される。また塩喪失性腎症の新しい候補遺伝子探索は希少疾患の病態解明に止まらず、塩分摂取過多、飽食の時代における塩分感受性高血圧や臓器障害などのコモン病治療方策への展開としても、将来性を有すると期待される。

Research Products

• [Journal Article] A Novel Mutation in <i>LMX1B</i> (p.Pro219Ala) Causes Focal Segmental Glomerulosclerosis with Alport Syndrome-like Phenotype (2021)
  • Author(s): Oe Yuji、Mishima Eikan、Mori Takayasu、Okamoto Koji、Honkura Yohei、Nagasawa Tasuku、Yoshida Mai、Sato Hiroshi、Suzuki Jun、Ikeda Ryoukichi、Sohara Eisei、Uchida Shinichi、Katori Yukio、Miyazaki Mariko
  • Journal Title: Internal Medicine Volume: 60 Issue: 18 Pages: 2991-2996
  • DOI: 10.2169/internalmedicine.6987-20
  • NAID: 130008088274
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-09-15
  • Peer Reviewed
• [Journal Article] An infant with congenital nephrogenic diabetes insipidus presenting with hypercalcemia and hyperphosphatemia (2021)
  • Author(s): Tao Katsuo、Awazu Midori、Honda Misa、Shibata Hironori、Mori Takayasu、Uchida Shinichi、Hasegawa Tomonobu、Ishii Tomohiro
  • Journal Title: Endocrinology, Diabetes & Metabolism Case Reports Volume: 2021 Pages: 1-5
  • DOI: 10.1530/edm-20-0189
  • Peer Reviewed
• [Journal Article] Vasopressin Induces Urinary Uromodulin Secretion By Activating PKA (Protein Kinase A) (2021)
  • Author(s): Nanamatsu Azuma、Mori Takayasu、Ando Fumiaki、Furusho Taisuke、Mandai Shintaro、Susa Koichiro、Sohara Eisei、Rai Tatemitsu、Uchida Shinichi
  • Journal Title: Hypertension Volume: In press Issue: 6 Pages: 1953-1963
  • DOI: 10.1161/hypertensionaha.121.17127
  • Peer Reviewed
• [Journal Article] Osteomalacia caused by atypical renal tubular acidosis with vitamin D deficiency: a case report. (2021)
  • Author(s): Takedani K, Notsu M, Koike S, Yamauchi M, Mori T, Sohara E, Yamauchi A, Yoshikane K, Ito T, Kanasaki K.
  • Journal Title: CEN Case Rep Volume: 10 Issue: 2 Pages: 294-300
  • DOI: 10.1007/s13730-020-00561-y
  • Peer Reviewed / Open Access
• [Journal Article] Significance of kidney biopsy in autosomal dominant tubulointerstitial kidney disease-UMOD: is kidney biopsy truly nonspecific? (2021)
  • Author(s): Onoe Tamehito、Hara Satoshi、Yamada Kazunori、Zoshima Takeshi、Mizushima Ichiro、Ito Kiyoaki、Mori Takayasu、Daimon Shoichiro、Muramoto Hiroaki、Shimizu Maki、Iguchi Akira、Kuma Akihiro、Ubara Yoshifumi、Mitobe Michihiro、Tsuruta Hiroaki、Kishimoto Nao、Imura Junko、Konoshita Tadashi、Kawano Mitsuhiro
  • Journal Title: BMC Nephrology Volume: 22 Issue: 1 Pages: 1-1
  • DOI: 10.1186/s12882-020-02169-x
  • Peer Reviewed
• [Journal Article] Phenotypic differences of mutation‐negative cases in Gitelman syndrome clinically diagnosed in adulthood (2020)
  • Author(s): Mori Takayasu、Chiga Motoko、Fujimaru Takuya、Kawamoto Ryosuke、Mandai Shintaro、Nanamatsu Azuma、Nomura Naohiro、Ando Fumiaki、Susa Koichiro、Sohara Eisei、Rai Tatemitsu、Uchida Shinichi
  • Journal Title: Human Mutation Volume: 42 Issue: 3 Pages: 300-309
  • DOI: 10.1002/humu.24159
  • Peer Reviewed / Open Access
• [Journal Article] A family with Gitelman syndrome with asymptomatic phenotypes while carrying reported SLC12A3 mutations. (2020)
  • Author(s): Ishikawa M, Tada Y, Tanaka H, Morii W, Inaba M, Takada H, Mori T, Noguchi E
  • Journal Title: Case Rep Nephrol Dial Volume: 10 Issue: 2 Pages: 71-78
  • DOI: 10.1159/000507845
  • NAID: 120007180702
  • Peer Reviewed / Open Access
• [Journal Article] A patient with congenital nephrogenic diabetes insipidus due to AVPR2 mutation complicated by persisting polydipsia under hemodialysis treatment (2020)
  • Author(s): Iijima Takashi、Mori Takayasu、Sohara Eisei、Suwabe Tatsuya、Hoshino Junichi、Ubara Yoshifumi
  • Journal Title: CEN Case Reports Volume: 10 Issue: 2 Pages: 226-229
  • DOI: 10.1007/s13730-020-00549-8
  • Peer Reviewed
• [Journal Article] Genetics May Predict Effectiveness of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease (2020)
  • Author(s): Sekine Akinari、Hoshino Junichi、Fujimaru Takuya、Suwabe Tatsuya、Mizuno Hiroki、Kawada Masahiro、Hiramatsu Rikako、Hasegawa Eiko、Yamanouchi Masayuki、Hayami Noriko、Mandai Shintaro、Chiga Motoko、Kikuchi Hiroaki、Ando Fumiaki、Mori Takayasu、Sohara Eisei、Uchida Shinichi、Sawa Naoki、Takaichi Kenmei、Ubara Yoshifumi
  • Journal Title: American Journal of Nephrology Volume: 51 Issue: 9 Pages: 745-751
  • DOI: 10.1159/000509817
  • Peer Reviewed
• [Journal Article] Transplantation of a kidney with a heterozygous mutation in the SLC22A12 (URAT1) gene causing renal hypouricemia: a case report (2020)
  • Author(s): Tsuji Kiyokazu、Kitamura Mineaki、Muta Kumiko、Mochizuki Yasushi、Mori Takayasu、Sohara Eisei、Uchida Shinichi、Sakai Hideki、Mukae Hiroshi、Nishino Tomoya
  • Journal Title: BMC Nephrology Volume: 21 Issue: 1 Pages: 282-282
  • DOI: 10.1186/s12882-020-01940-4
  • Peer Reviewed / Open Access
• [Journal Article] Familial cases of pseudohypoaldosteronism type II harboring a novel mutation in the Cullin 3 gene (2020)
  • Author(s): Nakano Kiyoshi、Kubota Yasuo、Mori Takayuki、Chiga Motoko、Mori Takayasu、Sonoda Shyunya、Ueda Daisuke、Asakura Isao、Ikegaya Takeshi、Kagawa Jiro、Uchida Shinichi、Kubota Akira
  • Journal Title: Nephrology Volume: 25 Issue: 11 Pages: 818-821
  • DOI: 10.1111/nep.13752
  • Peer Reviewed
• [Journal Article] Bartter syndrome representing digenic-based salt-losing tubulopathies presumably accelerated by renal insufficiency (2020)
  • Author(s): Umene Ryusuke、Kitamura Mineaki、Arai Hideyuki、Matsumura Kazuki、Ishimaru Yuka、Maeda Kanenori、Uramatsu Tadashi、Obata Yoko、Mori Takayasu、Sohara Eisei、Uchida Shinichi、Nishino Tomoya
  • Journal Title: CEN Case Reports Volume: 9 Issue: 4 Pages: 375-379
  • DOI: 10.1007/s13730-020-00489-3
  • NAID: 120006988501
  • Peer Reviewed / Open Access
• [Journal Article] HPRT-related hyperuricemia with a novel p.V35M mutation in HPRT1 presenting familial juvenile gout. (2020)
  • Author(s): Mishima E, Mori T, Nakajima Y, Toyohara T, Kikuchi K, Oikawa Y, Matsuhashi T, Maeda Y, Suzuki T, Kudo M, Ito S, Sohara E, Uchida S, Abe T.
  • Journal Title: CEN Case Rep Volume: pub Issue: 3 Pages: 210-214
  • DOI: 10.1007/s13730-020-00459-9
  • Peer Reviewed / Open Access
• [Journal Article] A case of Gitelman syndrome: our experience with a patient treated in clinical practice on a local island (2019)
  • Author(s): Chinen Takashi、Saeki Eiji、Mori Takayasu、Sohara Eisei、Uchida Shinichi、Akimoto Tetsu
  • Journal Title: Journal of Rural Medicine Volume: 14 Issue: 2 Pages: 258-262
  • DOI: 10.2185/jrm.3014
  • NAID: 130007748822
  • ISSN: 1880-487X, 1880-4888
  • Peer Reviewed
• [Journal Article] Non-urate transporter 1, non-glucose transporter member 9-related renal hypouricemia and acute renal failure accompanied by hyperbilirubinemia after anaerobic exercise: a case report (2019)
  • Author(s): Furuto Yoshitaka、Kawamura Mariko、Namikawa Akio、Takahashi Hiroko、Shibuya Yuko、Mori Takayasu、Sohara Eisei
  • Journal Title: BMC Nephrology Volume: 20 Issue: 1 Pages: 433-433
  • DOI: 10.1186/s12882-019-1618-1
  • Peer Reviewed
• [Journal Article] A familial case of pseudohypoaldosteronism type II (PHA2) with a novel mutation (D564N) in the acidic motif in WNK4. (2019)
  • Author(s): Sakoh T, Sekine A, Mori T, Mizuno H, Kawada M, Hiramatsu R, Hasegawa E, Hayami N, Yamanouchi M, Suwabe T, Sawa N, Ubara Y, Fujimaru T, Sohara E, Shinichi U, Hoshino J, Takaichi K.
  • Journal Title: Mol Genet Genomic Med Volume: 1 Issue: 6
  • DOI: 10.1002/mgg3.705
  • Peer Reviewed
• [Journal Article] Complete clinical resolution of a Japanese family with renal pseudohypoaldosteronism type 1 due to a novel NR3C2 mutation. (2019)
  • Author(s): Tanaka T, Oki E, Mori T, Tsuruga K, Sohara E, Uchida S, Tanaka H.
  • Journal Title: Nephrology (Carlton) Volume: 24 Issue: 4 Pages: 489-490
  • DOI: 10.1111/nep.13391
  • Peer Reviewed
• [Journal Article] PKD1 mutation may epistatically ameliorate nephronophthisis progression in patients with NPHP1 deletion. (2019)
  • Author(s): Watanabe S, Ino J, Fujimaru T, Taneda S, Akihisa T, Makabe S, Kataoka H, Mori T, Sohara E, Uchida S, Nitta K, Mochizuki T.
  • Journal Title: Clin Case Rep Volume: 7 Issue: 2 Pages: 336-339
  • DOI: 10.1002/ccr3.1947
  • Peer Reviewed
• [Journal Article] Genotype-Clinical Correlations in Polycystic Kidney Disease with No Apparent Family History (2019)
  • Author(s): Sekine Akinari、Fujimaru Takuya、Hoshino Junichi、Suwabe Tatsuya、Oguro Masahiko、Mizuno Hiroki、Kawada Masahiro、Sumida Keiichi、Hiramatsu Rikako、Chiga Motoko、Kikuchi Hiroaki、Ando Fumiaki、Mori Takayasu、Sohara Eisei、Uchida Shinichi、Sawa Naoki、Takaichi Kenmei、Ubara Yoshifumi
  • Journal Title: American Journal of Nephrology Volume: 49 Issue: 3 Pages: 233-240
  • DOI: 10.1159/000497444
  • Peer Reviewed
• [Presentation] Gitelman 症候群と臨床診断された成人患者の遺伝的背景と変異陰性例における表現系の検討. (2020)
  • Author(s): 森崇寧，千賀宗子，藤丸拓也，萬代新太郎，蘇原映誠，頼建光，内田信一.
  • Organizer: 第63 回日本腎臓学会学術総会2020.08 横浜, web
• [Presentation] PKAはhepsinの活性に影響しuromodulinの細胞外分泌を促進する. (2020)
  • Author(s): 七松東, 森崇寧, 安藤史顕, 萬代新太郎, 磯部清志, 須佐紘一郎, 蘇原映誠, 頼建光, 内田信一.
  • Organizer: 第63回日本腎臓学会学術総会2020.08 横浜, web
• [Presentation] 腎生検にてネフロン癆が疑われた成人症例における臨床；病理所見と遺伝的背景の関係. (2020)
  • Author(s): 藤丸拓也, 蘇原映誠, 森崇寧, 萬代新太郎, 千賀宗子, 菊池寛昭, 安藤史顕, 森雄太郎, 岡戸丈和, 頼建光, 川西 邦夫, 長田道夫, 内田信一.
  • Organizer: 第63回日本腎臓学会学術総会2020.08 横浜, web
• [Presentation] More than half of patients clinically diagnosed as Gitelman syndrome in adulthood do not have causal mutations in known pathogenic genes. (2019)
  • Author(s): Mori T, Chiga M, Fujimaru T, Mandai S, Nanamatsu A, Sohara E, Rai T, Uchida S.
  • Organizer: ASN Kidney Week 2019.
• [Presentation] Tubular Basement Membrane Duplication and Cell Interposition Are Distinctive Histological Findings in the Adult Patients Genetically Diagnosed with Nephronophthisis-Related Ciliopathies. (2019)
  • Author(s): Fujimaru T, Mori T, Nagata M, Mandai S, Chiga M, Kikuchi H, Ando F, Mori Y, Susa K, Isobe K, Iimori S, Nomura N, Naito S, Okado T, Rai T, Uchida S, Sohara E.
  • Organizer: ASN Kidney Week 2019.
• [Presentation] 次世代シークエンサーによる腎臓病網羅的遺伝子診断パネルの構築 --網羅的遺伝子解析の重要性--. (2019)
  • Author(s): 森崇寧, 藤丸拓也, 蘇原映誠, 内田信一.
  • Organizer: 第62回日本腎臓学会学術総会.
  • Invited
• [Presentation] 網羅的遺伝子診断が腎臓病診断と治療にもたらすもの. (2019)
  • Author(s): 森崇寧.
  • Organizer: 第39回東部腎カンファランス.
  • Invited
• [Remarks] 東京医科歯科大学腎臓内科学
  • URL: https://tmd-kid.jp/
• [Remarks] 東京医科歯科大学腎臓内科学 研究活動
  • URL: https://tmd-kid.jp/