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.)

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…51 Interestingly, data from the past few years suggest that the actual number of kisspeptin and/or NKB neurons might change during development. 52,53 Mutations in proteins that regulate ubiquitination such as OTU domain-containing protein 4 (encoded by OTUD4) and E3 ubiquitin-protein ligase RNF216 (also known as ring finger protein 216; encoded by RNF216), 54 as well as in proteins involved in lipid metabolism such as neuropathy target esterase (also known as patatin-like phospholipase domain-containing protein 6; encoded by PNPLA6) 55,56 have been identified in patients with Gordon Holmes syndrome (with associated CHH and ataxia). Thus, mutations in these three genes give rise to a broad and progressive neurodegenerative syndrome that includes CHH.…”

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

“…With WES, although several thousand genes are sequenced, bioinformatics analysis generally focuses on validated or candidate genes first, and then on genes coding for proteins involved in biological systems potentially relevant to the pathophysiology of the disease (178). But one of the main advantages of this method, without a priori assumptions, is that it can reveal mutations in unexpected genes, provided there are informative families (with large numbers of affected and unaffected members) available to ensure significant co-segregation between the rare variant(s) and the phenotype (180)(181)(182)(183). In the "targeted exome" approach, only a panel of tens or hundreds of genes previously chosen for their relevance to the disease are sequenced (184).…”

Targeted next generation sequencing approach identifies eighteen new candidate genes in normosmic hypogonadotropic hypogonadism and Kallmann syndrome

“…Quaynor et al 6 The majority of molecular causes of nHH/KS are yet to be characterized. This gap in our understanding may be narrowed with advancements in massively parallel deep resequencing methods, otherwise known as next generation sequencing (NGS), which includes targeted NGS, whole exome sequencing, and whole genome sequencing.…”