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New Risk Loci for Rare Neurodegenerative Disorder Emerge From Genome Sequencing Study

NEW YORK – An international team led by investigators at the National Institutes of Health and Johns Hopkins University Medical Center has tracked down genes and loci involved in an adult-onset neurological condition, a synucleinopathy called multiple system atrophy (MSA). The rare condition is less well understood than the two other forms of synucleinopathy, Parkinson's disease and Lewy body dementia.

"[T]he molecular causes of MSA are poorly understood due to its rarity in the community (~15,000 patients in the United States), its sporadic nature, the heterogeneous clinical manifestations, and the possibility of mimic syndromes," senior and corresponding author Sonya Scholz, a neurodegenerative disease researcher with the National Institute of Neurological Disorders and Stroke and Johns Hopkins, and her colleagues wrote. "Consequently, MSA remains the least understood member within the synucleinopathy triad."

As they reported in the journal Neuron on Thursday, Scholz and her co-authors from the US, Italy, the UK, and other international centers brought together whole-genome sequence data for 888 individuals with MSA and 7,100 unaffected controls.

Their genome-wide association analysis identified four MSA-associated loci at GAB1, TENM2, RABGEF1, and lnc-LRRC49-3. Using a corresponding transcriptome-wide association analysis, they further highlighted KCTD7, lnc-KCTD7-2, and USP38-DT as potential disease susceptibility genes.

Together, their findings from the GWAS, TWAS, and follow-up analyses revealed the importance of both rare and common genetic variants in MSA, the authors explained, noting that the study's results "provide a valuable resource to stimulate and advance research in this understudied, fatal neurodegenerative disease."

"We created a foundational genomic resource that can be systematically investigated to unravel the architecture of MSA," they wrote. "In this way, our study advances the understanding of MSA's pathogenesis and paves the way for modeling the disease and developing targeted treatments."

For example, the researchers explored the expression of MSA-related genes with the help of single-nucleus RNA sequencing data on cells from more than 400 dorsolateral prefrontal cortex samples from elderly individuals in the Religious Orders Study/Memory and Aging Project, pointing to potential roles for genes expressed in glial cells and neuronal cells in MSA.

Their repeat expansion analyses unearthed pathogenic expansions in a small set of genes such as ATXN1, ATXN3, HTT, and AR in eight of the MSA-affected individuals, though the researchers cautioned that repeat expansions also turned up in almost 0.7 percent of the unaffected control participants.

They also conducted gene-based analyses of genome sequences from study participants with or without MSA, focusing in on loss of function or missense alterations in a handful of candidate genes. These identified rare, missense changes to the potassium channel domain-coding gene KCTD7 that showed nominal, but nonsignificant, ties to MSA.

"Intriguingly, KCTD7 was recently found to regulate calpains, a group of non-lysosomal cysteine proteases, by inducing ubiquitination," the authors explained, adding that "[t]herapeutic strategies targeting malfunctions of calpains are … under development and, based on our work, may be appropriate for therapeutic development in MSA."