TMEM230is not a gene for Parkinson’s disease

• DOI: 10.1101/097030
• Publication Date: 2017-01-02T06:10:11Z
• Authors: Matthew J. Farrer; Austen J Milnerwood; Jordan Follett; Ilaria Guella
• Keywords: 0303 health sciences; 03 medical and health sciences; 3. Good health

TMEM230 mutations have been reported as a pathogenic cause of familial parkinsonism. However, we demonstrate TMEM230 p.Arg141Leu is an erroneous assignment due to incorrect genotyping. Pathogenicity is dubious given the frequency of substitutions at this non-conserved codon, and the inconsistency in genotype-phenotype correlations among families. While TMEM230 mutations are claimed to impair synaptic vesicle trafficking, the experiments are inappropriately described and inadequately controlled. In the largest family, with autosomal dominant, clinically typical and Lewy body-confirmed Parkinson disease, we previously reported a disease-segregating DNAJC13 p.Asn855Ser mutation for which genetic support remains ostensibly greater. Here we demonstrate profound deficits in endosomal tubulation and/or endosomal proliferation in mature neuronal cultures from heterozygous and homozygous DNAJC13 p.Asn855Ser knock in mice.