title: Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination.
abstract: BACKGROUND
  The combination of ataxia and hypogonadism was first described more than a century ago, but its genetic basis has remained elusive.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Digenic 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.
  
  
  CONCLUSIONS
  The 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.).
authors: Department of Neurology, Massachusetts General Hospital, Boston 02115, USA.
authors: David H
authors: DH
authors: Margolin
authors: Maria
authors: M
authors: Kousi
authors: Yee-Ming
authors: YM
authors: Chan
authors: Elaine T
authors: ET
authors: Lim
authors: Jeremy D
authors: JD
authors: Schmahmann
authors: Marios
authors: M
authors: Hadjivassiliou
authors: Janet E
authors: JE
authors: Hall
authors: Ibrahim
authors: I
authors: Adam
authors: Andrew
authors: A
authors: Dwyer
authors: Lacey
authors: L
authors: Plummer
authors: Stephanie V
authors: SV
authors: Aldrin
authors: Julia
authors: J
authors: O'Rourke
authors: Andrew
authors: A
authors: Kirby
authors: Kasper
authors: K
authors: Lage
authors: Aubrey
authors: A
authors: Milunsky
authors: Jeff M
authors: JM
authors: Milunsky
authors: Jennifer
authors: J
authors: Chan
authors: E Tessa
authors: ET
authors: Hedley-Whyte
authors: Mark J
authors: MJ
authors: Daly
authors: Nicholas
authors: N
authors: Katsanis
authors: Stephanie B
authors: SB
authors: Seminara
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics*; D003241:Consanguinity; D003704:Dementia / Q000235:genetics*; D059472:Exome; D005260:Female; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D008297:Male; D010375:Pedigree; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination; D015027:Zebrafish
chemical_list: C458527:RNF216 protein, human; D044767:Ubiquitin-Protein Ligases
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