Defective ubiquitination underlies oligogenic cerebellar degeneration and reproductive endocrine axis defects. M. Kousi1, D. Margolin2, Y. M. Chan3,4, V. Muto5, S. Servidei6, E. T. Lim3, J. D. Schmahmann2, M. Hadjivassiliou7, J. E. Hall3, I. Adam8, A. Dwyer3, L. Plummer3, S. V. Aldrin3, J. O'Rourke3, A. Kirby9, K. Lage9,10,11,12, A. Milunsky13, J. M. Milunsky13, J. Chan14, E. T. Hedley-Whyte15, M. J. Daly9, M. Tartaglia5, S. B. Seminara3, N. Katsanis1,16 1) Center for Human Disease Modeling, Department of Cell Biology, Duke University Medical Center, Durham, NC; 2) Department of Neurology, Massachusetts General Hospital, Boston, MA; 3) Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA; 4) Division of Endocrinology, Department of Medicine, Boston Childrens Hospital, Boston, MA; 5) Dept. Hematology, Oncology and Molecular Medicine, Section of Physiopathology of Genetic Diseases, Istituto Superiore di SanitÓ, Rome, Italy; 6) Dept. Neurosciences, Institute of Neurology, UniversitÓ Cattolica del Sacro Cuore, Rome Italy; 7) Department of Neurology, The Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, UK; 8) Specialty Hospital, Amman, Jordan; 9) Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA; 10) Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA; 11) Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark; 12) Center for Protein Research, University of Copenhagen, Copenhagen, Denmark; 13) Center for Human Genetics, Inc., Boston, MA; 14) Department of Pathology, Brigham and Womens Hospital, Boston, MA; 15) Department of Neuropathology, Massachusetts General Hospital, Boston, MA; 16) Department of Pediatrics, Duke University Medical Center, Durham, NC.

   We have studied a cohort of ataxia patients who manifest a unique constellation of cerebellar degeneration and defects of the reproductive endocrine axis, hypothesizing that understanding of the genetic drivers in these individuals might inform biological pathways relevant to multiple neuronal populations. Subsequent to whole-exome sequencing in a large consanguineous pedigree and systematic annotation of all rare alleles that segregate with the phenotype, we identified candidate pathogenic mutations in two genes, RNF216 and OTUD4 both of which encode components of the ubiquitin-proteasome pathway. Further analyses in unrelated patients showed that in some families, truncating mutations in RNF216 are likely sufficient to cause the disorder. By contrast, patients with functionally interrogated hypomorphic alleles require additional trans mutations in OTUD4. In vivo testing of not only each allele found in our patients but also of the potential for genetic interaction in zebrafish embryos showed that RNF216 and OTUD4 interact genetically to affect both neurogenesis and cerebellar architecture during development. Encouraged by these findings, we analyzed additional families and identified mutations in additional members of the ubiquitin pathway, highlighting a central role of this fundamental cellular process in cerebellar development and maintenance. Further, these observations have suggested that small molecules known to augment proteasomal function and correct autophagy might be of broad benefit to these phenotypes; preliminary in vivo testing is supportive of this hypothesis. Taken together, our data implicate dysfunction of a core biological process as a driver for neuronal degeneration, highlight the importance of mutational load on biological pathways as a determinant of disease onset and suggest that chemical amelioration of the pathway might be of therapeutic benefit.

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