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Research Emphasis Area on Joubert Syndrome

Coordinator: Ian Glass, M.D.

Joubert syndrome is an autosomal recessive developmental disorder of the cerebellum with a characteristic radiologic appearance on magnetic resonance imaging known as the "molar tooth sign" and the cardinal features of hypotonia, developmental delays, and an abnormal breathing pattern and/or eye movements. It has been estimated to occur in approximately 1 in 100,000 individuals.

Several Joubert-related conditions share the molar tooth sign on MRI but also have clinical manifestations of retinal, renal, and/or hepatic disease, thereby increasing the prevalence of this distinctive hindbrain malformation. These conditions are collectively termed “Joubert syndrome and related disorders (JSRD)” or cerebello-oculo-renal syndromes. Over the past several years, investigators in this REA have identified two of the five known genes responsible for JSRD.  Despite this progress, these five genes account for only ~40% of all JSRD cases. All but one of these causative genes have been shown to play a role in the primary cilium/basal body/centrosome apparatus, thereby placing Joubert syndrome in the expanding list of “ciliopathy” disorders linked to the diverse functions of this organelle.

Other developmental disorders of the cerebellum of interest to this REA that are distinct from the molar tooth group of disorders include the Dandy-Walker malformation and Dandy-Walker variants, a relatively common group of hindbrain disorders consisting of partial agenesis of the cerebellar vermis, cystic dilatation of the 4th ventricle of the brain, and hydrocephalus. Pontocerebellar hypoplasia and cerebellar hypoplasia are poorly understood and genetically heterogeneous disorders characterized by developmental defects or early-onset atrophy of the pons and/or cerebellum and often accompanied by a variety of other congenital anomalies. In contrast to the prevailing assumption that the cerebellum has a limited role in cognitive development, learning delays and/or intellectual disability are almost universal in individuals with Joubert syndrome and many other cerebellar malformation conditions.

The Joubert syndrome REA represents an interdisciplinary collaboration by investigators with the shared purpose to understand cerebellar malformation conditions and their impact on learning.

• The first goal is to elucidate the genetic and molecular basis of Joubert syndrome, related molar tooth malformation syndromes, and other conditions characterized by cerebellar dysgenesis. To facilitate identification of specific genes and genotype-phenotype correlations, a more careful clinical delineation of these disorders is necessary. It has become clear that genetic heterogeneity is typical for many of these conditions. Certain subtypes of cerebello-oculo-renal conditions are likely to share specific genetic etiologies and risk factors for the development of other medical complications. Scientific approaches include traditional genetic linkage analysis, identity-by-descent genetic mapping using high-density SNP genotyping in consanguineous probands, screening of candidate genes within identified genetic intervals, and novel approaches to gene identification based on phylogenetic comparisons, ciliary/basal body databases, and expression studies. These studies will also utilize the high-throughput DNA sequencing facilities and the microarray core for genotyping and analysis of microarray data.
• A second focus is to promote the application of neuroimaging and ophthalmologic testing technologies to the understanding cerebellar disorders. Tools such as functional MRI and diffusion-tensor imaging will help elucidate the role of the cerebellum in coordinating motor tasks and possibly higher cognitive processes. Likewise, imaging and electrophysiological modalities to evaluate retinal and oculomotor function may enhance an understanding of the distinctive visual deficits and aberrant CNS pathways in individuals with these conditions.
• A third goal is to better understand the molecular mechanisms underlying the development of the cerebellum and the basis of cerebellar malformation disorders. A variety of experiments is planned, including biochemical analysis in cultured cells, genetic manipulation of model organisms such as mice and rats, and RNA knockdown using morpholinos in zebrafish.  Gene expression studies in human fetal tissue utilizing microarray and subtractive hybridization to identify genetic pathways may also be pursued.
• A fourth goal is to develop tools for the assessment and treatment for children with cerebellar developmental disorders. Previous studies have suggested that children with Joubert syndrome have a unique neuropsychological profile, and some have autism. Coordinated approaches to the evaluation of this unique patient population will lead to strategies for appropriate educational/developmental interventions and potential behavioral treatments. In addition, promising therapeutic interventions for those at risk to develop renal failure and hepatic fibrosis is a distinct possibility; treatments are being developed in murine and rat models with genetic lesions in orthologous JSRD-related genes.

Faculty Investigators

• Ian Glass, M.D., Professor, Pediatrics, Coordinator
• Nigel Bamford, M.D., Assistant Professor, Pediatrics
• Theo K. Bammler, Ph.D., Acting Instructor, Environmental Health
• Craig Bennett, Ph.D., Research Assistant Professor, Pediatrics
• Richard P. Beyer, Ph.D., Research Scientist, Environmental Health
• David Breiger, Ph.D., Clinical Assistant Professor, Psychiatry and Behavioral Sciences
• Phillip Chance, M.D., Professor, Neurology and Pediatrics
• Daniel Doherty, M.D., Ph.D., Assistant Professor of Pediatrics
• Michael O. Dorschner, Ph.D., Acting Instructor, Medicine and Genome Sciences
• Alan Fantel, Ph.D., Research Professor, Pediatrics
• Federico M. Farin, M.D., Principal Research Scientist, Environmental Health
• Sidney Gospe, Jr., M.D., Ph.D., Professor, Pediatrics and Neurology
• Raj Kapur, M.D., Ph.D., Associate Professor, Pathology
• Albert La Spada, M.D., Ph.D., Associate Professor, Laboratory Medicine
• Cecilia Moens Ph.D., Professor, Fred Hutchinson Cancer Research Center
• Kelly Owens  Ph.D., Postdoctoral fellow, Biological Structure
• Melissa Parisi, M.D., Ph.D., Assistant Professor, Pediatrics
• James Phillips, Ph.D., Research Assistant Professor, Otolaryngology/Head and Neck Surgery
• David W. Raible, Ph.D., Associate Professor, Biological Structure
• Wendy Raskind, M.D., Ph.D., Professor, Medicine
• Edwin Rubel, Ph.D., Professor, Otolaryngology/Head and Neck Surgery and Physiology & Biophysics
• Dennis Shaw, M.D., Professor, Radiology
• Avery Weiss, M.D., Professor, Ophthalmology

University of Washington Joubert Center