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:
CreatorsEmailORCIDORCID Put Code
Choi, Yo JunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Halbritter, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braun, Daniela A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheeler, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schapiro, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rim, John HoonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nandadasa, SumedaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Choi, Won-ilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Widmeier, EugenUNSPECIFIEDorcid.org/0000-0002-7773-5190UNSPECIFIED
Shril, ShirleeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Korber, FriederikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sethi, Sidharth K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lifton, Richard P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beck, Bodo B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Apte, Suneel S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gee, Heon YungUNSPECIFIEDorcid.org/0000-0002-8741-6177UNSPECIFIED
Hildebrandt, FriedhelmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
EXTRACELLULAR-MATRIX; LINKAGE ANALYSISMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15952

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item