新規ＣＡＫＵＴ原因遺伝子の発現・機能解析と包括的遺伝子診断システムの構築

2013 年度 研究成果報告書

• 研究課題/領域番号: 23591192
• 研究種目: 基盤研究(C)
• 配分区分: 基金
• 応募区分: 一般
• 研究分野: 腎臓内科学
• 研究機関: 神戸大学
• 研究代表者: 飯島 一誠 神戸大学, 医学(系)研究科(研究院), 教授 (00240854)
• 研究分担者: 長田 道夫 筑波大学, 人間総合科学研究科, 教授 (10192238)
• 研究期間 (年度): 2011 – 2013
• キーワード: 腎尿路奇形 / 原因遺伝子

研究概要

既知のCAKUT原因遺伝子シークエンスにて変異を検出できなかった症例に対して、ゲノムワイドCGH アレイや次世代シークエンサーを用いて解析を行ったところ、特に腎尿路奇形以外の奇形や異常を合併する症候性CAKUTで、その原因と思われる遺伝子コピー数の変化や新規原因遺伝子と思われる遺伝子変異を複数検出した。CAKUTの原因として、1q21.1, 16q12.1q12.2, 16q12.1q13及び 8q12.1q12.3領域の欠失やUPK3A及びEP300の遺伝子変異を同定し、CAKUTの包括的遺伝子診断システムを確立した。

研究成果

• [雑誌論文] Natural history of genetically proven autosomal recessive Alport syndrome (2014)
  • 著者名/発表者名: Oka M, Nozu K, Kaito H, Fu XJ, Nakanishi K, Hashimura Y, Morisada N, Yan K, Matsuo M, Yoshikawa N, Vorechovsky I, Iijima K
  • 雑誌名: Pediatr Nephrol 巻: (Epub ahead of print)
• [雑誌論文] Rituximab treatment combined with methylprednisolone pulse therapy and immunosuppressants for childhood steroid-resistant nephrotic syndrome (2014)
  • 著者名/発表者名: Kamei K, Okada M, Sato M, Fujimaru T, Ogura M, Nakayama M, Kaito H, Iijima K, Ito S
  • 雑誌名: Pediatr Nephrol 巻: 29(7) ページ: 1181-7
• [雑誌論文] The problem of transition from pediatric to adult healthcare in patients with steroid-sensitive nephrotic syndrome (SSNS): a survey of the experts (2014)
  • 著者名/発表者名: Honda M, Iijima K, Ishikura K, Kaneko K
  • 雑誌名: Clin Exp Nephrol 巻: (Epub ahead of print)
• [雑誌論文] Milder clinical aspects of X-linked Alport syndrome in men positive for the collagen IVα5 chain (2014)
  • 著者名/発表者名: Hashimura Y, Nozu K, Kaito H, Nakanishi K, Fu XJ, Ohtsubo H, Hashimoto F, Oka M, Ninchoji T, Ishimori S, Morisada N, Matsunoshita N, Kamiyoshi N, Yoshikawa N, Iijima K
  • 雑誌名: Kidney Int. 巻: 85(5) ページ: 1208-13
• [雑誌論文] Cyclosporine C2 monitoring for the treatment of frequently relapsing nephrotic syndrome in children : a multicenter randomized phase II trial (2014)
  • 著者名/発表者名: Iijima K, Sako M, Oba MS, Ito S, Hataya H, Tanaka R, Ohwada Y, Kamei K, Ishikura K, Yata N, Nozu K, Honda M, Nakamura H, Nagata M, Ohashi Y, Nakanishi K, Yoshikawa N; Japanese Study Group of Kidney Disease in Children
  • 雑誌名: Clin J Am Soc Nephrol 巻: 9(2) ページ: 271-8
• [雑誌論文] Acute kidney injury after acute gastroenteritis in an infant with hereditary hypouricemia (2014)
  • 著者名/発表者名: Kamei K, Ogura M, Ishimori S, Kaito H, Iijima K, Ito S
  • 雑誌名: Eur JPediatr 巻: 173(2) ページ: 247-913
• [雑誌論文] Diffuse glomerular nodular lesions in diabetic pigs carrying a dominant-negative mutant hepatocyte nuclear factor 1-alpha, an inheritant diabetic gene in humans (2014)
  • 著者名/発表者名: Hara S, Umeyama K, Yokoo T, Nagashima H, Nagata M
  • 雑誌名: PLoS One 巻: 9(3) ページ: e92219
• [雑誌論文] Molecular background of urate transporter genes in patients with exercise-induced acute kidney injury (2013)
  • 著者名/発表者名: Kaito H, Ishimori S, Nozu K, Shima Y, Nakanishi K, Yoshikawa N, Iijima K
  • 雑誌名: Am J Nephrol 巻: 38(4) ページ: 316-20
• [雑誌論文] SLC26A3 gene analysis in patients with Bartter and Gitelman syndromes and the clinical characteristics of patients with unidentified mutations (2013)
  • 著者名/発表者名: Ishimori S, Kaito H, Matsunoshita N, Otsubo H, Hashimoto F, Ninchoji T, Nozu K, Morisada N, Iijima K
  • 雑誌名: Kobe J Med Sci. 巻: 59(2) ページ: E36-43
• [雑誌論文] Different phenotypes of HNF1ß deletion mutants in familial multicystic dysplastic kidneys (2013)
  • 著者名/発表者名: Hasui M, Kaneko K, Tsuji S, Isozaki Y, Kimata T, Nozu Y, Nozu K, Iijima K
  • 雑誌名: Clin Nephrol 巻: 79(6)(PubMed PMID : 23725647) ページ: 484-7
• [雑誌論文] First Japanese case of Pierson syndrome with mutations in LAMB2 (2013)
  • 著者名/発表者名: Togawa H, Nakanishi K, Mukaiyama H, Hama T, Shima Y, Nakano M, Fujita N, Iijima K, Yoshikawa N
  • 雑誌名: Pediatr Int. 巻: 55(2) ページ: 229-31
• [雑誌論文] Reference ranges for serum cystatin C measurements in Japanese children by using 4 automated assays (2013)
  • 著者名/発表者名: Yata N, Uemura O, Honda M, Matsuyama T, Ishikura K, Hataya H, Nagai T, Ikezumi Y, Fujita N, Ito S, Iijima K, Saito M, Keneko T, Kitagawa T
  • 雑誌名: Clin Exp Nephrol 巻: 17(6) ページ: 872-6
• [雑誌論文] Two-year outcome of the ISKDC regimen and frequent-relapsing risk in children with idiopathic nephrotic syndrome (2013)
  • 著者名/発表者名: Nakanishi K, Iijima K, Ishikura K, Hataya H, Nakazato H, Sasaki S, Honda M, Yoshikawa N; Japanese Study Group of Renal Disease in Children
  • 雑誌名: Clin J Am Soc Nephrol 巻: 8(5) ページ: 756-62
• [雑誌論文] Endoplasmic reticulum stress with low-dose cyclosporine in frequently relapsing nephrotic syndrome (2013)
  • 著者名/発表者名: Hama T, Nakanishi K, Mukaiyama H, Shima Y, Togawa H, Sako M, Nozu K, Iijima K, Yoshikawa N
  • 雑誌名: Pediatr Nephrol 巻: 28(6) ページ: 903-9
• [雑誌論文] Prospective 5-year follow-up of cyclosporine treatment in children with steroid-resistant nephrosis (2013)
  • 著者名/発表者名: Hamasaki Y, Yoshikawa N, Nakazato H, Sasaki S, Iijima K, Nakanishi K, Matsuyama T, Ishikura K, Ito S, Kaneko T, Honda M; for Japanese Study Group of Renal Disease in Children
  • 雑誌名: Pediatr Nephrol 巻: 28(5) ページ: 765-71
• [雑誌論文] Survey of rituximab treatment for childhood-onset refractory nephrotic syndrome (2013)
  • 著者名/発表者名: Ito S, Kamei K, Ogura M, Udagawa T, Fujinaga S, Saito M, Sako M, Iijima K
  • 雑誌名: Pediatr Nephrol 巻: 28(2) ページ: 257-64
• [雑誌論文] Spontaneous remission in children with IgA nephropathy (2013)
  • 著者名/発表者名: Shima Y, Nakanishi K, Hama T, Mukaiyama H, Togawa H, Sako M, Kaito H, Nozu K, Tanaka R, Iijima K, Yoshikawa N
  • 雑誌名: Pediatr Nephrol 巻: 28(1) ページ: 71-6
• [雑誌論文] Establishment of a normal reference value for serumβ2 microglobulin in Japanese children : reevaluation of its clinical usefulness (2013)
  • 著者名/発表者名: Ikezumi Y, Honda M, Matsuyama T, Ishikura K, Hataya H, Yata N, Nagai T, Fujita N, Ito S, Iijima K, Kaneko T, Uemura O
  • 雑誌名: Clin Exp Nephrol 巻: 17(1) ページ: 99-105
• [雑誌論文] Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss (2013)
  • 著者名/発表者名: Ueno T, Kobayashi N, Nakayama M, Takashima Y, Uesugi N, Pastan D, Pippin J, Shankland S, Matsusaka Nagata M
  • 雑誌名: Kidney Int 巻: 83(6) ページ: 1065-75
• [雑誌論文] A Novel Case of Nephrotic Syndrome Caused by Immune-Mediated Acquired LCAT Deficiency (2013)
  • 著者名/発表者名: Takahashi S, Hiromura K, Tsukida M, Ohishi Y, Hamatani H, Sakurai N, Sakairi T, Ikeuchi H, Kaneko Y, Maeshima A, Kuroiwa T, Yokoo H, Nagata M, Nojima Y
  • 雑誌名: J Am Soc Nephrol 巻: 24(8) ページ: 1305-12
• [雑誌論文] Henoch-Schönlein purpura nephritis in a patient with IgG4-related disease : a possible association (2013)
  • 著者名/発表者名: Ito K, Yamada K, Mizushima I, Aizu M, Fujii H, Mizutomi K, Matsumura M, Hayashi K, Yamagishi M, Umehara H, Yamaguchi Y, Nagata M, Kawano M
  • 雑誌名: Clin Nephrol 巻: 79(3) ページ: 246-52
• [雑誌論文] The direction and role of phenotypic transition between podocytes and parietal epithelial cells in focal segmental glomerulosclerosis (2013)
  • 著者名/発表者名: Sakamoto K, Ueno T, Kobayashi N, Hara S, Takashima Y, Pastan I, Matsusaka T, Nagata M
  • 雑誌名: Am J Physiol Renal Physiol
• [雑誌論文] Two-year follow-up of a prospective clinical trial of cyclosporine for frequently relapsing nephrotic syndrome in children (2012)
  • 著者名/発表者名: Ishikura K, Yoshikawa N, Nakazato H, Sasaki S, Iijima K, Nakanishi K, Matsuyama T, Ito S, Yata N, Ando T, Honda M; Japanese Study Group of Renal Disease in Children
  • 雑誌名: Clin J Am Soc Nephrol 巻: 7(10) ページ: 1576-83
• [雑誌論文] Is the new Schwartz equation derived from serum creatinine and body length suitable for evaluation of renal function in Japanese children? (2012)
  • 著者名/発表者名: Uemura O, Honda M, Matsuyama T, Ishikura K, Hataya H, Nagai T, Ikezumi Y, Fujita N, Ito S, Iijima K; Japanese Society for Pediatric Nephrology, the Committee of Measures for Pediatric CKD
  • 雑誌名: Eur J Pediatr 巻: 171(9) ページ: 1401-4
• [雑誌論文] Focal segmental glomerulosclerosis in patients with complete deletion of one WT1 allele (2012)
  • 著者名/発表者名: Iijima K, Someya T, Ito S, Nozu K, Nakanishi K, Matsuoka K, Ohashi H, Nagata M, Kamei K, Sasaki S
  • 雑誌名: Pediatrics 巻: 129(6) ページ: e1621-5
• [雑誌論文] Renal biopsy criterion in children with asymptomatic constant isolated proteinuria (2012)
  • 著者名/発表者名: Hama T, Nakanishi K, Shima Y, Mukaiyama H, Togawa H, Tanaka R, Hamahira K, Kaito H, Iijima K, Yoshikawa N
  • 雑誌名: Nephrol Dial Transplant 巻: 27(8) ページ: 3186-90
• [雑誌論文] Validity of the Oxford classification of IgA nephropathy in children (2012)
  • 著者名/発表者名: Shima Y, Nakanishi K, Hama T, Mukaiyama H, Togawa H, Hashimura Y, Kaito H, Sako M, Iijima K, Yoshikawa N
  • 雑誌名: Pediatr Nephrol 巻: 27(5) ページ: 783-92
• [雑誌論文] Remission of proteinuria in renal amyloidosis secondary to rheumatoid arthritis (2012)
  • 著者名/発表者名: Ueno T, Takeda Y, Nagata M
  • 雑誌名: Nephrol Dial Transplant 巻: 27(2) ページ: 633-9
• [雑誌論文] Histological heterogeneity of glomerular segmental lesions in focal segmental glomerulosclerosis (2012)
  • 著者名/発表者名: Honda K, Taneda S, Yumura W Nitta K, Oda H, Nagata M
  • 雑誌名: Int Urol Nephrol 巻: 44(1) ページ: 183-96
• [雑誌論文] Characteristic tubulointerstitial nephritis in IgG4-related disease (2012)
  • 著者名/発表者名: Yamaguchi Y, Kanetsuna Y, Honda K, Kawano M, Yamanaka N, Nagata M
  • 雑誌名: Human Pathol 巻: 43(4) ページ: 536-549
• [雑誌論文] Clinical and histological changes associated with corticosteroid therapy in IgG4-related tubulointerstitial nephritis (2012)
  • 著者名/発表者名: Mizushima I, Yamada K, Fujii H, Inoue D, Umehara H, Yamagishi M, Yamaguchi Y, Nagata M, Matsumura M, Kawano M
  • 雑誌名: Mod Rheumatol
• [雑誌論文] Molecular analysis of TSC2/PKD1 contiguous gene deletion syndrome (2011)
  • 著者名/発表者名: Oyazato Y, Iijima K, Emi M, Sekine T, Kamei K, Takanashi J, Nakao H, Namai Y, Nozu K, Matsuo M
  • 雑誌名: Kobe J Med Sci. 巻: 57(1) ページ: E1-10
• [雑誌論文] Identification of FOXP3-negative regulatory T-like (CD4(+)CD25(+)CD127(low)) cells in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (2011)
  • 著者名/発表者名: Otsubo K, Kanegane H, Kamachi Y, Kobayashi I, Tsuge I, Imaizumi M, Sasahara Y, Hayakawa A, Nozu K, Iijima K, Ito S, Horikawa R, Nagai Y, Takatsu K, Mori H, Ochs HD, Miyawaki T
  • 雑誌名: Clin Immunol 巻: 141(1) ページ: 111-20
• [雑誌論文] A surviving case of papillorenal syndrome with the phenotype of Potter sequence (2011)
  • 著者名/発表者名: Fujioka K, Morioka I, Nozu K, Nishimoto M, Amano M, Tagami M, Honda S, Yokoyama N, Yamada H, Iijima K, Matsuo M
  • 雑誌名: Pediatr Int. 巻: 53(3) ページ: 406-8
• [雑誌論文] Maintenance therapy with mycophenolate mofetil after rituximab in pediatric patients with steroid-dependent nephrotic syndrome (2011)
  • 著者名/発表者名: Ito S, Kamei K, Ogura M, Sato M, Fujimaru T, Ishikawa T, Udagawa T, Iijima K
  • 雑誌名: Pediatr Nephrol 巻: 26(10) ページ: 1823-8
• [雑誌論文] Recurrent EIARF and PRES with severe renal hypouricemia by compound heterozygous SLC2A9 mutation (2011)
  • 著者名/発表者名: Shima Y, Nozu K, Nozu Y, Togawa H, Kaito H, Matsuo M, Iijima K, Nakanishi K, Yoshikawa N
  • 雑誌名: Pediatrics 巻: 127(6) ページ: e1621-5
• [雑誌論文] Age, gender, and body length effects on reference serum creatinine levels determined by an enzymatic method in Japanese children : a multicenter study (2011)
  • 著者名/発表者名: Uemura O, Honda M, Matsuyama T, Ishikura K, Hataya H, Yata N, Nagai T, Ikezumi Y, Fujita N, Ito S, Iijima K, Kitagawa T
  • 雑誌名: Clin Exp Nephrol 巻: 15(5) ページ: 694-9
• [雑誌論文] Long-term results of a randomized controlled trial in childhood IgA nephropathy (2011)
  • 著者名/発表者名: Kamei K, Nakanishi K, Ito S, Saito M, Sako M, Ishikura K, Hataya H, Honda M, Iijima K, Yoshikawa N; Japanese Pediatric IgA Nephropathy Treatment Study Group
  • 雑誌名: Clin J Am Soc Nephrol 巻: 6(6) ページ: 1301-7
• [雑誌論文] Treatment strategies for Henoch-Schönlein purpura nephritis by histological and clinical severity (2011)
  • 著者名/発表者名: Ninchoji T, Kaito H, Nozu K, Hashimura Y, Kanda K, Kamioka I, Shima Y, Hamahira K, Nakanishi K, Tanaka R, Yoshikawa N, Iijima K, Matsuo M
  • 雑誌名: Pediatr Nephrol 巻: 26(4) ページ: 563-9
• [雑誌論文] Focal segmental glomerulosclerosis as a complication of hepatitis B virus infection (2011)
  • 著者名/発表者名: Sakai K, Morito N, Usui J, Hagiwara M, Hiwatashi A, Fukuda K, Nanmoku T, Toda T, Matsui N, Nagata M, Yamagata K
  • 雑誌名: Nephrol Dial Transplant 巻: 26(1) ページ: 371-3
• [雑誌論文] Morphological and functional analyses of two infants with obstructive renal dysplasia (2011)
  • 著者名/発表者名: Miura K, Sekine T, Nishimura R, Kanamori Y, Yanagisawa A, Sakai K, Nagata M, Igarashi T
  • 雑誌名: Clin Exp Nephrol 巻: 15(4) ページ: 602-6
• [雑誌論文] A case of multicentric Castleman's disease with membranoproliferative glomerulonephritis type 3-like lesion (2011)
  • 著者名/発表者名: Nagai K, Usui J, Noguchi K, Unai K, Hiwatashi A, Arakawa Y, Togashi A, Morito N, Saito C, Yoh K, Tsuruoka S, Kojima H, Aita K, Nagata M, Yamagata K
  • 雑誌名: Pathol Int. 巻: 61(11) ページ: 686-90
• [学会発表] Heterozygous microdeletion of 16q covering SALL1 and RPGRIP1L could be a novel contiguous gene syndrome with renal impairment (2013)
  • 著者名/発表者名: Morisada N, Taniguchi-Ikeda M, Ishimori S, Ninchoji T, Kaito H, Nozu K, Adach Mi, Takeshima Y, SekineT, Iijima K
  • 学会等名: American Society of Human Genetics
  • 発表場所: Boston
  • 年月日: 20130000
• [学会発表] Natural History and Protein Expression Pattern in Autosomal Recessive Alport Syndrome Based on the Comprehensive Strategy for Genetic Analysis (2013)
  • 著者名/発表者名: Kaito H, Nozu K, Oka M, Morisada N, Ninchoji T, Nakanishi K, Yoshikawa N, Iijima K
  • 学会等名: American Society of Nephrology KIDNEY WEEK
  • 発表場所: Atlanta
  • 年月日: 20130000
• [学会発表] 遺伝性腎疾患の最近の知見 (2013)
  • 著者名/発表者名: 飯島一誠
  • 学会等名: 第48回日本小児腎臓病学会学術集会
  • 発表場所: 徳島
  • 年月日: 20130000
• [学会発表] CAKUTの分子遺伝学的アプローチ (2013)
  • 著者名/発表者名: 飯島一誠
  • 学会等名: 第22回日本小児泌尿器科学会総会
  • 発表場所: 東京
  • 年月日: 20130000
• [学会発表] 総排泄腔遺残をともなった1q21.1欠失症候群の1女児例 (2013)
  • 著者名/発表者名: 森貞直哉,野田俊輔,降?めぐみ,池田真理子,竹島泰弘,飯島一誠
  • 学会等名: 日本人類遺伝学会第58回大会
  • 発表場所: 仙台
  • 年月日: 20130000
• [学会発表] Genetical and Clinical Aspects of X-Linked Alport Syndrome in Males with Positive Staining of the alpha5(IV) Chain (2012)
  • 著者名/発表者名: Hashimura Y, Nozu K, Kaito H, Ohtsubo H, Hashimoto F, Ishimori S, Ninchoji T, Morisada N, Nakanishi K, Yoshikawa N, Iijima K
  • 学会等名: 45th Annual Meeting of the American Society of Nephrology
  • 発表場所: San Diego, USA
  • 年月日: 20121101-04
• [図書] 腎低形成・異形成.小児腎臓病学,日本小児腎臓病学会編(編集主幹飯島一誠他) (2012)
  • 著者名/発表者名: 長田道夫
  • 総ページ数: 39-42
  • 出版者: 診断と治療社