A New Gene for Familial Parkinson’s? ( found loss-of-function mutations in TMEM230 in affected family members of several families.)

10 Jun 2016

In the June 6 Nature Genetics, scientists identify a new gene responsible for some cases of familial Parkinson’s disease (PD). Researchers led by Teepu Siddique and first author Han-Xiang Deng, Northwestern University Feinberg School of Medicine, Chicago, found loss-of-function mutations in TMEM230 in affected family members of several families. 

They report that the transmembrane protein coded by the gene sits on vesicles that recycle synaptic components in neurons. The finding adds weight to theory that the endosomal recycling system goes awry in Parkinson’s disease (PD).

“This is a pretty comprehensive analysis,” said Mark Cookson, National Institute on Aging, Bethesda, Maryland. While he thought the data were strong, Cookson stressed the need for replication by independent groups. “The cell biology is very consistent with other genes linked to PD, particularly synuclein and LRRK2. It fits with what we might expect to see,” he said.

The discovery started with a large North American family in Saskatchewan, Canada. Fifteen members from three generations developed PD between the ages of 48 and 85 in an autosomal-dominant fashion, but none carried mutations in known PD genes, such as the α-synuclein gene SNCA, LRRK2, or VPS35. Scientists had been studying this family for 20 years, but were not been able to pinpoint which genetic variant caused their disease. In an independent study, researchers led by Matthew Farrer, University of British Columbia, Vancouver, had found a variant in the gene for DNAJC13 that partially segregated with disease, but three affected members did not carry the variant, while one member without symptoms did (Vilariño-Güell et al., 2014). DNAJC13 codes for a protein that regulates clathrin coats on early endosomes.

Now, Deng and colleagues report a different mutation runs in this same kindred. Through genetic analysis, they found that all affected family members shared the same genetic sequence on the tip of the short arm of chromosome 20. Guessing that the disease-causing variant was hiding somewhere in this neighborhood of 141 genes, the researchers used whole-exome sequencing to look for codon changes. They found all affected family members had a guanine-to-thymine switch that replaced an arginine with a leucine at amino acid 141 of TMEM230. Two other mutations in this gene turned up in a search of more than 800 additional PD patients from North America. Both associated with early onset disease. One added six amino acids to the TMEM230 C-terminal tail and was found in a man who had been diagnosed at age 33. The second replaced a tyrosine with a cysteine at amino acid 92 and was found in a man who developed PD at age 34. These two variants, and the original R141L, were absent from more than 1,000 controls from North America.

Looking farther afield, Deng searched for mutations in a Chinese Parkinson’s cohort comprising 225 familial and 349 sporadic cases. He found another TMEM230 mutation in nine patients from seven unrelated families. Five of the patients were homozygous for the mutation, indicating their parents all carried at least one copy of the variant. Since one of the parents remained free of any symptoms at 96 years old, the authors suggested this particular mutation may not be fully penetrant.

This mutation, which did not turn up in Chinese controls, adds seven amino acids on to the C-terminal tail of TMEM230. Curiously, this addition, and the six-amino-acid addition found in the North American cohort, have the same last five amino acids.

The scientists wondered what TMEM230 does in the cell. Computer models predicted it to be a transmembrane protein, but it had not been biochemically characterized. Interestingly, all four mutations appeared in areas expected to lie outside or inside the plasma membrane 

http://www.alzforum.org/news/research-news/new-gene-familial-parkinsons