PUBLICATION
Mutations of ADAMTS9 Cause Nephronophthisis-Related Ciliopathy
- Authors
- Choi, Y.J., Halbritter, J., Braun, D.A., Schueler, M., Schapiro, D., Rim, J.H., Nandadasa, S., Choi, W.I., Widmeier, E., Shril, S., Körber, F., Sethi, S.K., Lifton, R.P., Beck, B.B., Apte, S.S., Gee, H.Y., Hildebrandt, F.
- ID
- ZDB-PUB-190105-9
- Date
- 2019
- Source
- American journal of human genetics 104: 45-54 (Journal)
- Registered Authors
- Hildebrandt, Friedhelm
- Keywords
- ADAMTS9, Joubert syndrome, metalloproteinase, nephronophthisis, nephronophthisis-related ciliopathy
- MeSH Terms
-
- ADAMTS9 Protein/deficiency
- ADAMTS9 Protein/genetics*
- Animals
- Cilia/pathology
- Ciliopathies/genetics*
- Ciliopathies/pathology
- Female
- Humans
- Male
- Mutation*
- Phenotype
- Polycystic Kidney Diseases/genetics*
- Polycystic Kidney Diseases/pathology
- Spheroids, Cellular
- Zebrafish/genetics
- Zebrafish Proteins/deficiency
- Zebrafish Proteins/genetics
- PubMed
- 30609407 Full text @ Am. J. Hum. Genet.
Citation
Choi, Y.J., Halbritter, J., Braun, D.A., Schueler, M., Schapiro, D., Rim, J.H., Nandadasa, S., Choi, W.I., Widmeier, E., Shril, S., Körber, F., Sethi, S.K., Lifton, R.P., Beck, B.B., Apte, S.S., Gee, H.Y., Hildebrandt, F. (2019) Mutations of ADAMTS9 Cause Nephronophthisis-Related Ciliopathy. American journal of human genetics. 104:45-54.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping