Ataxia, Dementia, and Hypogonadotropism

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   SI QUIERES VER ARTICULO COMPLETO VE AL SIGUIENTE LINK   http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215993   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.)