Dysfunction of the ciliary ARMC9/TOGARAM1 protein module causes Joubert syndrome
Joubert syndrome (JBTS) is a recessive neurodevelopmental ciliopathy characterized by a pathognomonic hindbrain malformation. All known JBTS genes encode proteins involved in the structure or function of primary cilia, ubiquitous antenna-like organelles essential for cellular signal transduction. Here, we used the recently identified JBTS-associated protein armadillo repeat motif–containing 9 (ARMC9) in tandem-affinity purification and yeast 2-hybrid screens to identify a ciliary module whose dysfunction underlies JBTS. In addition to the known JBTS-associated proteins CEP104 and CSPP1, we identified coiled-coil domain containing 66 (CCDC66) and TOG array regulator of axonemal microtubules 1 (TOGARAM1) as ARMC9 interaction partners. We found that TOGARAM1 variants cause JBTS and disrupt TOGARAM1 interaction with ARMC9. Using a combination of protein interaction analyses, characterization of patient-derived fibroblasts, and analysis of CRISPR/Cas9-engineered zebrafish and hTERT-RPE1 cells, we demonstrated that dysfunction of ARMC9 or TOGARAM1 resulted in short cilia with decreased axonemal acetylation and polyglutamylation, but relatively intact transition zone function. Aberrant serum-induced ciliary resorption and cold-induced depolymerization in ARMC9 and TOGARAM1 patient cell lines suggest a role for this new JBTS-associated protein module in ciliary stability.
Joubert syndrome (OMIM 213300) is an autosomal recessive disorder with gene heterogeneity. Causal genes and their variants have been identified by sequencing or other technologies for Joubert syndrome subtypes.
Publication date: Available online 22 September 2020Source: Stem Cell ResearchAuthor(s): Eltahir Ali, Rosalba Monica Ferraro, Gaetana Lanzi, Stefania Masneri, Giovanna Piovani, Elena Laura Mazzoldi, Valentina Serpieri, Enza Maria Valente, Lucio Giordano, Silvia Clara Giliani
Abstract The OFD1 gene was initially identified as the gene responsible for the X-linked dominant male lethal OFD type I syndrome, a developmental disorder ascribed to cilia disfunction. The transcript has been subsequently associated to four different X-linked recessive conditions, namely Joubert syndrome, retinitis pigmentosa, primary ciliary dyskinesia and Simpson-Golabi-Behmel type 2 syndrome. The centrosomal/basal body OFD1 protein has indeed been shown to be required for primary cilia formation and left-right asymmetry. The protein is also involved in other tasks, e.g. regulation of cellular protein content,...
AbstractJoubert syndrome is characterized by unique malformation of the cerebellar vermis. More than thirty Joubert syndrome genes have been identified, includingARL13B. However, its role in cerebellar development remains unexplored. We found that knockdown or knockout ofarl13b impaired balance and locomotion in zebrafish larvae. Granule cells were selectively reduced in the corpus cerebelli, a structure homologous to the mammalian vermis. Purkinje cell progenitors were also selectively disturbed dorsomedially. The expression ofatoh1 andptf1, proneural genes of granule and Purkinje cells, respectively, were selectively dow...
ConclusionsOur results suggest that a dysfunction of photoreceptors and bipolar cells occurs in patients with JS with or without retinal dystrophy. The retinal impairment can be detected by ERG recordings and this method should be proposed to evaluate the effectiveness of adequate treatment targeted to improve the retinal impairment in patients with JS.
This report outlines an interesting case of JS, in which two novel mutations in B9D1 were identified. This gene is not commonly associated with JS, and is often implicated in MKS. Functional mRNA study was helpful in delineating the pathogenic role of novel variants in this case. PMID: 32622957 [PubMed - as supplied by publisher]
Conclusion: The prevalence of hereditary ataxia can vary among countries. The consanguineous marriage is an important finding in these diseases. These genetic tests will increase the number of ARCA patients diagnosed.
ConclusionFundus imaging associated with ERG may be significant in IRD diagnosis and visual impairment prognosis, alongside genetic analysis and therapy in selected cases.
Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing f...