Disruptions in Trash-Collecting Genes Fuel Disorder
Genetic mutations that halt a cell's ability to scrap unnecessary proteins may cause a condition marked by ataxia, hypogonadotrophic hypogonadism, and dementia, researchers found.
During whole-exome sequencing of a small group of patients, a loss-of-function mutation in RNF216 appeared to bring on the combination of diseases, either alone or when paired with a mutation in the OTUD4 gene, Nicholas Katsanis, PhD, of Duke University, and colleagues reported online in the New England Journal of Medicine.
Both mutations affect the process of ubiquitination, a system of tagging unneeded proteins within cells that marks them for recycling or destruction. Katsanis said defects in ubiquitination have been reported in other types of disorders, most notably Parkinson's disease.
"We found two 'flavors' of patients," Katsanis told MedPage Today. "The first flavor was complete dysfunction of one gene, RNF216, that was sufficient to lead to both degeneration of the cerebellum and degeneration of neurons that innervate the reproductive system."
"For other patients who had some residual activity of RNF216," he continued, "they got another hit somewhere else in the same pathway. That other hit was the other gene, OTUD4, and there is very little known about it at the moment."
Advances in understanding the genetic causes of ataxia have been made in recent years, but about 40% of cases don't show a clear genetic effect, the researchers wrote, particularly for those who have both ataxia and reproductive endocrine failure -- since genes associated with ataxia have little functional overlap with those associated with hypogonadotropic hypogonadism.
For their study, Katsanis and colleagues looked at 12 patients with ataxia and hypogonadism from eight families who were referred to Massachusetts General Hospital for treatment between 2000 and 2010.
First, they conducted whole-exome sequencing in one patient with ataxia and hypogonadism, followed by targeted sequencing of candidate genes in similarly affected patients.
They found digenic homozygous mutations in RNF216 and OTUD4 in three affected siblings in a consanguineous family; RNF216 encodes a ubiquitin E3 ligase, while OTUD4 encodes a deubiquitinase.
Additional screening revealed compound heterozygous truncating mutations in RNF216 in an unrelated patient and single heterozygous deleterious mutations in four other patients, for a total of eight patients whose disease appeared to be caused by these mutations.
These eight patients had a progressive and debilitating dementia that did not occur in the four other patients who lacked the mutations and only had ataxia and hypogonadism, without dementia, the researchers reported.
To further assess the relationship between these genes and their role in the condition, Katsanis and colleagues conducted additional analyses on zebrafish.
They found that knocking out either gene alone in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum, while taking out both genes simultaneously exacerbated these phenotypes. These problems were corrected, however, by giving human RNF216 or OTUD4 messenger RNA, they reported.
"Taken together, these data highlight a hitherto unknown role of the ubiquitination system in disorders of combined neurodegeneration and reproductive dysfunction," they wrote.
Katsanis said the immediate clinical implications are only knowledge-based, and that the researchers "aren't in a position to offer therapeutic paradigms."
"However, the opportunities and possibilities that are open from this study are quite exciting," Katsanis said. "We now have a firm handle on ubiquitination as a detrimental process to the system, ... and we think this fundamental process may be relevant to patients who have similar pathology."
The study was supported by the National Institutes of Health.
The researchers reported relationships with Becton Dickinson and AstraZeneca.
Primary source: New England Journal of Medicine Source reference: Margolin DH, et al "Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination" N Engl J Med 2013; DOI: 10.1056/NEJMoa1215993.