Reply to: MIDN locus structural variants and Parkinson’s disease risk

Abstract

Dear Editor,We thank Billingsley et al. for their interest in our study that showed a genetic association of MIDN deletions with Parkinson's disease (PD) in a British population. 1 In their letter to the editor, they noted that they could not identify any PD-associated deletions within 100 kb of MIDN in 3868 individuals analyzed by wholegenome sequencing (WGS) and raised issues regarding using SNP genotyping to identify structural variants. 2 We respect their analyzed data. However, as we obtained consistent results in British and Japanese cohort studies, our results may be reproduced in other cohorts if analyzed by array-based technology. In fact, a variety of deletions or multiplications within the MIDN locus have been identified in a general population and shown in public databases analyzed mainly by microarrays (Database of Genomic Variants; http://dgv.tcag.ca/dgv/app/ home or UCSC Genome Browser; https://genome.ucsc.ed u) 3,4 ( Fig. S1). Additionally, we examined the physiological functions of MIDN in neuronal cells using genome editing and RNA interference methodologies and demonstrated that MIDN is responsible for neurite outgrowth and expression of Parkin E3 ubiquitin ligase, which is associated with PD phenotypes. 5 High-resolution array-based analysis is widely used in basic research and clinical practice. For example, deletions at 22q11.2 in idiopathic PD have been identified using an analytical method very similar to ours (the same datasets from UK Wellcome Trust Case Control Consortium 2 and the same analysis algorithms). 6 Recently, duplications in 19p13.3, including MIDN and other adjacent genes, were demonstrated to be associated with male infertility according to array-based analysis. 7 However, because genome-wide copy number variation (CNV) detection power varies depending on platforms and analysis software, 8,9 we recognize the necessity of multiple analysis algorithms and independent experimental validation for array-based CNV detection studies. As in the case of array-based analysis, each different sequencing-based method (algorithms, experimental methods) has different strengths and weaknesses for detection, depending on the variant type or properties, and unique and common CNVs are often discovered using various approaches. 9 Furthermore, more than 90% of the lengths of discovered variants were less than 1 Kbp in sequence-based analysis, and the median length of deletions detected by sequencing was 742 bp, whereas that by SNP microarray was 50,265 bp. 9 In our analysis of the PD case group, the so-called CNV length was 42.6 Kbp (mean)/12.1 Kbp (median) in a British population and 169 Kbp (mean)/103 Kbp (median) in a Japanese population. Such large CNVs spanning the MIDN locus have been identified, suggesting that these 604 deletion or multiplication sizes are relatively insensitive range to identify efficiently by WGS-based analysis. 9 Long-read sequencing is assumed to be more preferable for detection of segmental duplications, gene loss, and fusion events in this case rather than short-r...

Structural Variants of <i>Midnolin</i>, a Genetic Risk Factor for Parkinson’s Disease, in a Yamagata Cohort

“…11) We assume that discrepancies between our conclusions and those of Billingsley et al reflect the different methodologies used in the studies. 12) We identified no MIDN loss in healthy controls in the Yamagata cohort study, possibly because of Japanese genetic characteristics or because our previous Yamagata cohort study was not large enough to identify MIDN structural variants unlike in the large British population. Therefore, we reanalyzed MIDN variants in 3021 subjects of the Yamagata Prefecture general population in more detail.…”

Insulin Enhances Gene Expression of Midnolin, a Novel Genetic Risk Factor for Parkinson’s Disease, via Extracellular Signal-Regulated Kinase, Phosphoinositide 3-Kinase and Multiple Transcription Factors in SH-SY5Y Cells

“…Although typical DNA-binding or transcription-activating domains have not been identified in the MIDN protein, MIDN affects the transcription levels of a number of genes, including PD-related genes (Obara and Ishii, 2018), indicating that MIDN functions as a transcription modulator. Thus, we believe that MIDN loss is associated with PD although this is controversial (Billingsley et al, 2020;Obara et al, 2020).…”

Viable mutations of mouse midnolin suppress B cell malignancies

“…However, no further work on MIDN in the pancreas has been reported. Rather, several reports have focused on a putative association between MIDN gene copy number reductions and sporadic Parkinson’s disease ( Billingsley et al, 2020 ; Obara et al, 2017 , 2019 , 2020 ; Obara and Ishii, 2018 ; Sagehashi et al, 2022 ; Sato et al, 2023 ), which has been disputed ( Billingsley et al, 2020 ). Knockdown of MIDN in rat PC12 cells, a cell line derived from the adrenal gland, resulted in downregulated expression of the E3 ubiquitin ligase Parkin and the transcription factor ATF4, but the neurological significance of this is not known ( Obara et al, 2017 ).…”