Universität zu Köln

Choi, Yo Jun, Halbritter, Jan, Braun, Daniela A., Scheeler, Markus, Schapiro, David, Rim, John Hoon, Nandadasa, Sumeda, Choi, Won-il, Widmeier, Eugen ORCID: 0000-0002-7773-5190, Shril, Shirlee, Korber, Friederike, Sethi, Sidharth K., Lifton, Richard P., Beck, Bodo B., Apte, Suneel S., Gee, Heon Yung ORCID: 0000-0002-8741-6177 and Hildebrandt, Friedhelm (2019). Mutations of ADAMTS9 Cause Nephronophthisis-Related Ciliopathy. Am. J. Hum. Genet., 104 (1). S. 45 - 55. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

Full text not available from this repository.

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_4576de1 [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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Choi, Yo Jun UNSPECIFIED UNSPECIFIED UNSPECIFIED Halbritter, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Braun, Daniela A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Scheeler, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Schapiro, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Rim, John Hoon UNSPECIFIED UNSPECIFIED UNSPECIFIED Nandadasa, Sumeda UNSPECIFIED UNSPECIFIED UNSPECIFIED Choi, Won-il UNSPECIFIED UNSPECIFIED UNSPECIFIED Widmeier, Eugen UNSPECIFIED orcid.org/0000-0002-7773-5190 UNSPECIFIED Shril, Shirlee UNSPECIFIED UNSPECIFIED UNSPECIFIED Korber, Friederike UNSPECIFIED UNSPECIFIED UNSPECIFIED Sethi, Sidharth K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lifton, Richard P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Beck, Bodo B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Apte, Suneel S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gee, Heon Yung UNSPECIFIED orcid.org/0000-0002-8741-6177 UNSPECIFIED Hildebrandt, Friedhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-159528
DOI:	10.1016/j.ajhg.2018.11.003
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	104
Number:	1
Page Range:	S. 45 - 55
Date:	2019
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EXTRACELLULAR-MATRIX; LINKAGE ANALYSIS Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15952