ADAMTS9 – Ciliopathy

ADAMTS9 encodes a secreted metalloprotease with thrombospondin type 1 repeats that localizes to basal bodies of primary cilia and interfaces with the extracellular matrix. Ciliopathies encompass a spectrum of multisystem developmental disorders arising from defects in ciliary assembly or function. Biallelic loss-of-function variants in ADAMTS9 have been implicated in both nephronophthisis-related ciliopathies (NPHP-RC) and Joubert syndrome–related disorders (JSRD), highlighting a critical role for ADAMTS9 in ciliogenesis and ciliary signaling.

Homozygosity mapping and whole-exome sequencing in two unrelated families identified biallelic ADAMTS9 variants, including c.194C>G (p.Thr65Arg) and c.4575_4576del (p.Gln1525HisfsTer60), in individuals with NPHP-RC (PMID:30609407). A separate case report described a 4-year-old boy with compound heterozygous ADAMTS9 variants presenting with oculomotor apraxia, global developmental delay, hypotonia, bifid tongue, and mild cerebellar vermis hypoplasia without renal dysfunction, expanding the phenotypic spectrum to JSRD (PMID:34750010).

In vitro, ADAMTS9 deficiency in IMCD3 cells led to shortened primary cilia and impaired sonic hedgehog signaling, with spheroid lumen defects rescued by wild-type but not mutant ADAMTS9 (PMID:30609407). Zebrafish knockdown of adamts9 recapitulated renal cysts and hydrocephalus, reinforcing a conserved ciliary function. Mouse Pofut2 knockout, which blocks O-fucosylation and secretion of ADAMTS9, phenocopied gastrulation defects, further demonstrating that loss of O-fucosylated ADAMTS9 underlies abnormal epithelial organization and mesoderm formation (PMID:27297885).

Collectively, these genetic and experimental data support an autosomal recessive mechanism whereby loss-of-function ADAMTS9 variants disrupt ciliogenesis, extracellular matrix remodeling, and downstream signaling pathways. The allele c.194C>G (p.Thr65Arg) exemplifies a pathogenic missense change affecting a thrombospondin repeat critical for protein secretion. ADAMTS9 should be included in diagnostic gene panels for AR ciliopathies, and functional assays of variant impact on cilia and ECM offer a framework for pathogenicity interpretation.

Key Take-home: Biallelic ADAMTS9 variants cause a spectrum of autosomal recessive ciliopathies, and combined genetic and functional evidence delineates a loss-of-function mechanism critical for clinical diagnosis and genetic counseling.

References

• Developmental Biology | 2016 | Genetic and biochemical evidence that gastrulation defects in Pofut2 mutants result from defects in ADAMTS9 secretion. PMID:27297885
• American Journal of Human Genetics | 2019 | Mutations of ADAMTS9 Cause Nephronophthisis-Related Ciliopathy. PMID:30609407
• Brain & Development | 2022 | Compound heterozygous ADAMTS9 variants in Joubert syndrome-related disorders without renal manifestation. PMID:34750010

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