• David H Margolin, Maria Kousi, Yee-Ming Chan, Elaine T Lim, Jeremy D Schmahmann, Marios Hadjivassiliou, Janet E Hall, Ibrahim Adam, Andrew Dwyer, Lacey Plummer, Stephanie V Aldrin, Julia O'Rourke, Andrew Kirby, Kasper Lage, Aubrey Milunsky, Jeff M Milunsky, Jennifer Chan, E Tessa Hedley-Whyte, Mark J Daly, Nicholas Katsanis, and Stephanie B Seminara.
• Department of Neurology, Massachusetts General Hospital, Boston 02115, USA.
• N. Engl. J. Med. 2013 May 23; 368 (21): 1992-2003.

BackgroundThe combination of ataxia and hypogonadism was first described more than a century ago, but its genetic basis has remained elusive.MethodsWe performed whole-exome sequencing in a patient with ataxia and hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes in similarly affected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. The effects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model.ResultsDigenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase and a deubiquitinase, respectively, were found in three affected siblings in a consanguineous family. Additional screening identified compound heterozygous truncating mutations in RNF216 in an unrelated patient and single heterozygous deleterious mutations in four other patients. Knockdown of rnf216 or otud4 in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, human RNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss was observed in cerebellar pathways and the hippocampus; surviving hippocampal neurons contained ubiquitin-immunoreactive intranuclear inclusions. Defects were detected at the hypothalamic and pituitary levels of the reproductive endocrine axis.ConclusionsThe syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4. These findings link disordered ubiquitination to neurodegeneration and reproductive dysfunction and highlight the power of whole-exome sequencing in combination with functional studies to unveil genetic interactions that cause disease. (Funded by the National Institutes of Health and others.).

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