AI Article Synopsis

  • Adaptor protein complex 4-associated hereditary spastic paraplegia is caused by mutations in four specific subunits, and diagnosing it typically involves molecular testing, which can be difficult for new variants.
  • The study developed a functional assay using fibroblasts to measure the localization of a protein called ATG9A, providing a reliable metric that meets testing standards for diagnosis.
  • Results indicated that the 'ATG9A ratio' was significantly higher in affected patients compared to controls, suggesting it can serve as a diagnostic marker for this condition.

Article Abstract

Adaptor protein complex 4-associated hereditary spastic paraplegia is caused by biallelic loss-of-function variants in , , or , which constitute the four subunits of this obligate complex. While the diagnosis of adaptor protein complex 4-associated hereditary spastic paraplegia relies on molecular testing, the interpretation of novel missense variants remains challenging. Here, we address this diagnostic gap by using patient-derived fibroblasts to establish a functional assay that measures the subcellular localization of ATG9A, a transmembrane protein that is sorted by adaptor protein complex 4. Using automated high-throughput microscopy, we determine the ratio of the ATG9A fluorescence in the trans-Golgi-network versus cytoplasm and ascertain that this metric meets standards for screening assays (Z'-factor robust >0.3, strictly standardized mean difference >3). The 'ATG9A ratio' is increased in fibroblasts of 18 well-characterized adaptor protein complex 4-associated hereditary spastic paraplegia patients [mean: 1.54 ± 0.13 versus 1.21 ± 0.05 (standard deviation) in controls] and receiver-operating characteristic analysis demonstrates robust diagnostic power (area under the curve: 0.85, 95% confidence interval: 0.849-0.852). Using fibroblasts from two individuals with atypical clinical features and novel biallelic missense variants of unknown significance in , we show that our assay can reliably detect adaptor protein complex 4 function. Our findings establish the 'ATG9A ratio' as a diagnostic marker of adaptor protein complex 4-associated hereditary spastic paraplegia.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557665PMC
http://dx.doi.org/10.1093/braincomms/fcab221DOI Listing

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