JOUBERIN AND NEPHROCYSTIN IN JOUBERT SYNDROME

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Joubert syndrome (JS) is a developmental brain disorder characterized by cerebellar vermis hypoplasia, abnormal eye movement, ataxia and mental retardation. JS often involves extra-CNS phenotypes which significantly overlap with several cilia-related disorders, implicating ciliary dysfunction in JS. CEP290 is one of several genes mutated in JS. Nonsense or frame-shift mutations in CEP290 are responsible for a majority of the oculorenal form of JS, whereas an intronic mutation in CEP290 that creates a strong splice-donor site is the single most common identified cause of Leber congenital amaurosis, a severe retinal dystrophy. CEP290 is a large coiled-coil protein with tropomyosin homology domains. CEP290 is known to localize to the centrosome and basal body of ciliated kidney cells and to the connecting cilium of retinal photoreceptors. Moreover, depletion of CEP290 from hTERT-RPE cells was shown to interfere with serum starvation-induced ciliogenesis. However, molecular mechanism of CEP290 function at the basal body remains largely unknown. In this study, we use tandem affinity purification to isolate CEP290 protein complex from hTERT-RPE cells. Identification of proteins in the complex by mass spectrometry will provide vital information for understanding both CEP290 function and the pathological mechanism of JS.