タナカ　リョウジロウ   Ryojiro Tanaka   田中　亮二郎    所属   川崎医科大学  医学部 臨床医学　小児科学    職種   特任教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Identification of novel OCRL isoforms associated with phenotypic differences between Dent disease-2 and Lowe syndrome.
掲載誌名	正式名：Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 略　 称：Nephrol Dial Transplant ISSNコード：14602385/09310509
掲載区分	国外
巻・号・頁	37(2),pp.262-270
著者・共著者	Nana Sakakibara, Takeshi Ijuin, Tomoko Horinouchi, Tomohiko Yamamura, China Nagano, Eri Okada, Shinya Ishiko, Yuya Aoto, Rini Rossanti, Takeshi Ninchoji, Hiroyuki Awano, Hiroaki Nagase, Shogo Minamikawa, Ryojiro Tanaka, Takeshi Matsuyama, Koji Nagatani, Koichi Kamei, Kumiko Jinnouchi, Yasufumi Ohtsuka, Masafumi Oka, Yoshinori Araki, Toju Tanaka, Mari S Harada, Toru Igarashi, Hikaru Kitahara, Naoya Morisada, Shun-Ichi Nakamura, Taro Okada, Kazumoto Iijima, Kandai Nozu
発行年月	2022/01
概要	BACKGROUND:Although Lowe syndrome and Dent disease-2 are caused by Oculocerebrorenal syndrome of Lowe (OCRL) mutations, their clinical severities differ substantially and their molecular mechanisms remain unclear. Truncating mutations in OCRL exons 1-7 lead to Dent disease-2, whereas those in exons 8-24 lead to Lowe syndrome. Herein we identified the mechanism underlying the action of novel OCRL protein isoforms.METHODS:Messenger RNA samples extracted from cultured urine-derived cells from a healthy control and a Dent disease-2 patient were examined to detect the 5' end of the OCRL isoform. For protein expression and functional analysis, vectors containing the full-length OCRL transcripts, the isoform transcripts and transcripts with truncating mutations detected in Lowe syndrome and Dent disease-2 patients were transfected into HeLa cells.RESULTS:We successfully cloned the novel isoform transcripts from OCRL exons 6-24, including the translation-initiation codons present in exon 8. In vitro protein-expression analysis detected proteins of two different sizes (105 and 80 kDa) translated from full-length OCRL, whereas only one protein (80 kDa) was found from the isoform and Dent disease-2 variants. No protein expression was observed for the Lowe syndrome variants. The isoform enzyme activity was equivalent to that of full-length OCRL; the Dent disease-2 variants retained >50% enzyme activity, whereas the Lowe syndrome variants retained <20% activity.CONCLUSIONS:We elucidated the molecular mechanism underlying the two different phenotypes in OCRL-related diseases; the functional OCRL isoform translated starting at exon 8 was associated with this mechanism.
DOI	10.1093/ndt/gfab274
PMID	34586410