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Mutations of ADAMTS9 Cause Nephronophthisis-Related Ciliopathy

Authors
 Yo Jun Choi  ;  Jan Halbritter  ;  Daniela A. Braun  ;  Markus Schueler  ;  David Schapiro  ;  John Hoon Rim  ;  Sumeda Nandadasa  ;  Won-il Choi  ;  Eugen Widmeier  ;  Shirlee Shril  ;  Friederike Körber  ;  Sidharth K. Sethi  ;  Richard P. Lifton  ;  Bodo B. Beck  ;  Suneel S. Apte  ;  Heon Yung Gee  ;  Friedhelm Hildebrandt 
Citation
 American Journal of Human Genetics, Vol.104(1) : 45-54, 2019 
Journal Title
 American Journal of Human Genetics 
ISSN
 0002-9297 
Issue Date
2019
Keywords
ADAMTS9 ; Joubert syndrome ; metalloproteinase ; nephronophthisis ; nephronophthisis-related ciliopathy
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.
Full Text
https://www.sciencedirect.com/science/article/pii/S0002929718304063
DOI
10.1016/j.ajhg.2018.11.003
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Rim, John Hoon(임정훈) ORCID logo https://orcid.org/0000-0001-6825-8479
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/169365
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