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최요준
최요준 (Yo Jun Choi) 저자 이메일 보기
연세대학교 의과대학
 
조회 531  인쇄하기 주소복사 트위터 공유 페이스북 공유 
Mutations of ADAMTS9 Cause Nephronophthisis-Related Ciliopathy
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Abstract

Nephronophthisis-related ciliopathies (NPHP-RCs) are a group of inherited diseases that are associated with defects in primary cilium structure and function. To identify genes mutated in NPHP-RC, we performed homozygosity mapping and whole-exome sequencing for >100 individuals, some of whom were single affected individuals born to consanguineous parents and some of whom were siblings of indexes who were also affected by NPHP-RC. We then performed high-throughput exon sequencing in a worldwide cohort of 800 additional families affected by NPHP-RC. We identified two ADAMTS9 mutations (c.4575_4576del [p.Gln1525Hisfs ?60] and c.194C>G [p.Thr65Arg]) that appear to cause NPHP-RC. Although ADAMTS9 is known to be a secreted extracellular metalloproteinase, we found that ADAMTS9 localized near the basal bodies of primary cilia in the cytoplasm. Heterologously expressed wild-type ADAMTS9, in contrast to mutant proteins detected in individuals with NPHP-RC, localized to the vicinity of the basal body. Loss of ADAMTS9 resulted in shortened cilia and defective sonic hedgehog signaling. Knockout of Adamts9 in IMCD3 cells, followed by spheroid induction, resulted in defective lumen formation, which was rescued by an overexpression of wild-type, but not of mutant, ADAMTS9. Knockdown of adamts9 in zebrafish recapitulated NPHP-RC phenotypes, including renal cysts and hydrocephalus. These findings suggest that the identified mutations in ADAMTS9 cause NPHP-RC and that ADAMTS9 is required for the formation and function of primary cilia.

Keywords : nephronophthisis-related ciliopathy, nephronophthisis, Joubert syndrome, ADAMTS9, metalloproteinase

논문정보
- 형식: Research article
- 게재일: 2019년 01월 (BRIC 등록일 2019-01-04)
- 연구진: 국내(교신)+국외 연구진태극기
- 분야: Genetics
  댓글 1
회원작성글 sardius  (2019-01-15 21:40)
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지헌영 (연세대학교 의과대학)
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Genetics

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Google (by Yo Jun Choi)
Pubmed (by Yo Jun Choi)
프리미엄 Bio일정 Bio일정 프리미엄 안내
제2회 오가노이드 심포지엄 및 핸즈온워크샵 [2019 CHA Organoid Center Symposium]
제2회 오가노이드 심포지엄 및 핸즈온워크샵 [2019 CHA Organoid Center Symposium]
날짜: 2019.05.09
장소: 판교 차바이오컴플렉스 국제회의실
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