Dysfunction of the ciliary ARMC9/TOGARAM1 protein module causes Joubert syndrome

Latour, Brooke; Weghe, Julie C. Van De; Rusterholz, Tamara D. S.; Letteboer, Stef J.F.; Gómez, Arianna; Shaheen, Ranad; Gesemann, Matthias; Karamzade, Arezou; Asadollahi, Mostafa; Barroso‐Gil, Miguel; Chitre, Manali; Grout, Megan E.; Reeuwijk, Jeroen van; Beersum, Sylvia E. C. van; Miller, Caitlin V.; Dempsey, Jennifer C.; Morsy, Heba; Bamshad, Michael J.; Nickerson, Deborah A.; Neuhauss, Stephan C. F.; Boldt, Karsten; Ueffing, Marius; Keramatipour, Mohammad; Sayer, John A.; Alkuraya, Fowzan S.; Bachmann‐Gagescu, Ruxandra; Roepman, Ronald; Doherty, Dan

doi:10.1172/jci131656

Cited by 54 publications

(117 citation statements)

References 82 publications

Supporting

Mentioning

110

Contrasting

Order By: Relevance

“…The core components of the axonemal MAP module are CEP104, CSPP1, TOGARAM‐1/Crescerin‐1 (hereafter TOGARAM‐1), ARMC9, and CCDC66. Their interactions were mapped by a combination of proximity labeling, tandem affinity purification, yeast two‐hybrid and immunoprecipitation experiments [49–53]. While these MAPs all localize to cilia in ciliated cells, we highlight that they also localize to other cellular compartments including centrosomes, centriolar satellites, and/or cytoplasmic and spindle microtubules [50,51,54–57].…”

Section: Maps During Ciliary Axoneme Assembly Maintenance and Disasmentioning

confidence: 99%

“…These studies defined reduced ciliogenesis efficiency and shorter cilia as shared phenotypes. Additionally, cells from TOGARAM‐1 and ARMC9 ciliopathy patients displayed decreased acetylation and glutamylation of the ciliary axoneme [52]. In light of their direct microtubule association, ciliary functions, and disease links, we propose and discuss the following possible mechanisms by which these MAPs could impart their functions on the ciliary axoneme: (1) increasing structural complexities of the cilia, (2) regulating microtubule dynamics at the + TIPs of axonemal microtubules, and (3) regulating axonemal PTMs and stability.…”

Section: Maps During Ciliary Axoneme Assembly Maintenance and Disasmentioning

confidence: 99%

“…Another possible mechanism for these axonemal MAPs is the maintenance of the mechanical stability of the ciliary axoneme. Multiple components of this module including CCDC66, ARMC9, CSPP1, and TOGARAM‐1 localize along the primary cilium axoneme, in addition to their specific enrichment at the ciliary tip [51,52,54,68,75]. Of note, CCDC66 and TOGARAM‐1 decorate the axoneme in a punctate pattern with irregular spacing and the axonemal pool of CCDC66 in steady‐state cilium is immobile [55,75].…”

Section: Maps During Ciliary Axoneme Assembly Maintenance and Disasmentioning

confidence: 99%

“…Of note, centriolar satellites are membrane-less dynamic granules that regulate centrosomal and ciliary targeting of various proteins including CCDC66 [50,58,59]. Mutations affecting CEP104, CSPP1, TOGARAM-1, ARMC9, and CCDC66 have been linked to the neurodevelopmental ciliopathy Joubert syndrome or retinal degeneration [52,57,[60][61][62][63][64][65]. Specifically, CEP104, CSPP1, TOGARAM-1, and ARMC9 zebrafish mutants showed a variety of ciliopathy phenotypes including retinal dystrophy, kidney cysts, and/or cranial nerve development defects and TOGARAM-1 C. elegans mutants were defective in chemotaxis [51,52,55,57].…”

Section: Maps During Ciliary Axoneme Assembly Maintenance and Disasmentioning

confidence: 99%

“…Mutations affecting CEP104, CSPP1, TOGARAM-1, ARMC9, and CCDC66 have been linked to the neurodevelopmental ciliopathy Joubert syndrome or retinal degeneration [52,57,[60][61][62][63][64][65]. Specifically, CEP104, CSPP1, TOGARAM-1, and ARMC9 zebrafish mutants showed a variety of ciliopathy phenotypes including retinal dystrophy, kidney cysts, and/or cranial nerve development defects and TOGARAM-1 C. elegans mutants were defective in chemotaxis [51,52,55,57]. These lines of data support the significance of this module in sensory functions and define it as a ciliary ciliopathy module as well.…”

Section: Maps During Ciliary Axoneme Assembly Maintenance and Disasmentioning

confidence: 99%

See 4 more Smart Citations

Microtubule‐associated proteins and emerging links to primary cilium structure, assembly, maintenance, and disassembly

Conkar

Fırat-Karalar

2020

The FEBS Journal

View full text Add to dashboard Cite

The primary cilium is a microtubule‐based structure that protrudes from the cell surface in diverse eukaryotic organisms. It functions as a key signaling center that decodes a variety of mechanical and chemical stimuli and plays fundamental roles in development and homeostasis. Accordingly, structural and functional defects of the primary cilium have profound effects on the physiology of multiple organ systems including kidney, retina, and central nervous system. At the core of the primary cilium is the microtubule‐based axoneme, which supports the cilium shape and acts as the scaffold for bidirectional transport of cargoes into and out of cilium. Advances in imaging, proteomics, and structural biology have revealed new insights into the ultrastructural organization and composition of the primary cilium, the mechanisms that underlie its biogenesis and functions, and the pathologies that result from their deregulation termed ciliopathies. In this viewpoint, we first discuss the recent studies that identified the three‐dimensional native architecture of the ciliary axoneme and revealed that it is considerably different from the well‐known '9 + 0' paradigm. Moving forward, we explore emerging themes in the assembly and maintenance of the axoneme, with a focus on how microtubule‐associated proteins regulate its structure, length, and stability. This far more complex picture of the primary cilium structure and composition, as well as the recent technological advances, open up new avenues for future research.

show abstract

Section: Maps During Ciliary Axoneme Assembly Maintenance and Disasmentioning

confidence: 99%

Section: Maps During Ciliary Axoneme Assembly Maintenance and Disasmentioning

confidence: 99%

Section: Maps During Ciliary Axoneme Assembly Maintenance and Disasmentioning

confidence: 99%

Section: Maps During Ciliary Axoneme Assembly Maintenance and Disasmentioning

confidence: 99%

Section: Maps During Ciliary Axoneme Assembly Maintenance and Disasmentioning

confidence: 99%

See 3 more Smart Citations

Microtubule‐associated proteins and emerging links to primary cilium structure, assembly, maintenance, and disassembly

Conkar

Fırat-Karalar

2020

The FEBS Journal

View full text Add to dashboard Cite

show abstract

Survey of disorders of sex development in a large cohort of patients with diverse Mendelian phenotypes

Abualsaud

Hashem

Alhashem

et al. 2020

American J of Med Genetics Pt A

Self Cite

View full text Add to dashboard Cite

Disorders of sex development (DSD) are congenital conditions with atypical development of chromosomal, gonadal, or anatomical sex. The estimated incidence ranges from 1 in 4,500-5,500 for strictly defined "ambiguous genitalia" to 1 in 300 or higher when a broader definition is implemented. In this study, we aim to define DSD phenotypes encountered in a large heterogeneous cohort of molecularly characterized Mendelian disorders in a single center. Data were retrieved for patients with documented abnormal genitalia based on the 2006 consensus criteria. Out of 149 patients (129 families) with compatible human phenotype ontology, 76 patients (68 families) had an identified genetic cause and were included in our analysis. Potentially causal variants were identified in 42 genes, and two patients had a dual molecular diagnosis. Six genes have no associated phenotype in OMIM (PIANP, CELSR2, USP2, FAM179B, TXNDC15, and CCDC96). Thirteen genes have non-DSD OMIM phenotypes, thus we are expanding their phenotype to include DSD. We also highlight how certain disorders are under-recognized despite their established DSD phenotype in OMIM, especially CTU2-related DREAM-PL syndrome and TSPYL1-related sudden infant death with dysgenesis of the testes syndrome. In conclusion, this study of a large heterogeneous Mendelian cohort expands the list of genes and disorders beyond those classically DSD-linked. K E Y W O R D S ambiguous genitalia, differences in sex development, sex reversal 1 | INTRODUCTION Disorders of sex development (DSD) are defined as congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical (Lee et al., 2016). The clinical phenotypes of these disorders are heterogenous and include micropenis, cryptorchidism, clitoromegaly and, in more severe cases, ambiguous genitalia. The exact incidence can be challenging to determine accurately due to discrepancy in the definition used by the different epidemiological studies and the changes in classification over time. However, it is estimated to be 1 in 4,500-5,500 for strictly defined "ambiguous genitalia" and increases to 1 in 300 or higher if a broader definition is used (

show abstract

Genotype–phenotype correlates in Joubert syndrome: A review

Gana

Serpieri

Valente

2022

American J of Med Genetics Pt C

View full text Add to dashboard Cite

Joubert syndrome (JS) is a genetically heterogeneous primary ciliopathy characterized by a pathognomonic cerebellar and brainstem malformation, the “molar tooth sign,” and variable organ involvement. Over 40 causative genes have been identified to date, explaining up to 94% of cases. To date, gene‐phenotype correlates have been delineated only for a handful of genes, directly translating into improved counseling and clinical care. For instance, JS individuals harboring pathogenic variants in TMEM67 have a significantly higher risk of liver fibrosis, while pathogenic variants in NPHP1, RPGRIP1L, and TMEM237 are frequently associated to JS with renal involvement, requiring a closer monitoring of liver parameters, or renal functioning. On the other hand, individuals with causal variants in the CEP290 or AHI1 need a closer surveillance for retinal dystrophy and, in case of CEP290, also for chronic kidney disease. These examples highlight how an accurate description of the range of clinical symptoms associated with defects in each causative gene, including the rare ones, would better address prognosis and help guiding a personalized management. This review proposes to address this issue by assessing the available literature, to confirm known, as well as to propose rare gene‐phenotype correlates in JS.

show abstract

Dysfunction of the ciliary ARMC9/TOGARAM1 protein module causes Joubert syndrome

Cited by 54 publications

References 82 publications

Microtubule‐associated proteins and emerging links to primary cilium structure, assembly, maintenance, and disassembly

Microtubule‐associated proteins and emerging links to primary cilium structure, assembly, maintenance, and disassembly

Survey of disorders of sex development in a large cohort of patients with diverse Mendelian phenotypes

Genotype–phenotype correlates in Joubert syndrome: A review

Contact Info

Product

Resources

About