Rare variants linked with Parkinson’s disease

By Eleanor McDermid, Senior medwireNews Reporter

Researchers using exome sequencing in families with Parkinson’s disease (PD) have identified two genes that could be associated with the condition.

The two genes are TNK2, which encodes a nonreceptor tyrosine kinase with an important role in cell growth, survival and migration; and TNR (tenascin R), which encodes an extracellular matrix glycoprotein that is specific to the central nervous system.

In an editorial accompanying the report in JAMA Neurology, Mathias Toft (Oslo University Hospital, Norway) and Owen Ross (Mayo Clinic, Jacksonville, Florida, USA) note that the study is one of the first efforts to explore exome sequencing in familial PD.

“Given that most patients with familial PD do not carry mutations in the known mendelian PD genes, this is likely the next step forward in gene discovery”, they write.

But they say that “as with most explorations into the unknown, results must be treated with cautious enthusiasm”, and stress that replication studies are now needed.

Researcher Tatiana Foroud (Indiana University School of Medicine, Indianapolis, USA) and team found a total of nine mutations that potentially altered the function of the proteins encoded by the two genes. These mutations affected 12 families across discovery and replication cohorts comprising 93 patients from 32 families and 49 patients from 49 families, respectively.

A third gene, TOPORS, was identified in the discovery cohort, but not the replication cohort.

TNK2 and TNR had an average genic intolerance percentile of 17.2%, giving them an intolerance of functional mutations that was potentially greater than that of genes already known to cause autosomal dominant PD. And they had Combined Annotation Dependent Depletion (CADD) scores that placed seven of the mutations in the top 1% most deleterious variants in the genome and the other two in the top 10%, all supporting the likelihood of a role in PD.

In their editorial, Toft and Ross stress the importance of sharing genetic data between research groups to establish the significance of such rare variants in PD susceptibility. And they commend Foroud et al for publishing an expanded candidate variant list for all the families they studied.

“These data open the door for collaborative efforts on rare variants of unknown significance”, they conclude.

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