{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T01:52:26Z","timestamp":1787795546533,"version":"build-2784847793"},"reference-count":61,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2021,9,25]],"date-time":"2021-09-25T00:00:00Z","timestamp":1632528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Adaptor protein complex 4-associated hereditary spastic paraplegia is caused by biallelic loss-of-function variants in AP4B1, AP4M1, AP4E1 or AP4S1, 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\u2032-factor robust &amp;gt;0.3, strictly standardized mean difference &amp;gt;3). The \u2018ATG9A ratio\u2019 is increased in fibroblasts of 18 well-characterized adaptor protein complex 4-associated hereditary spastic paraplegia patients [mean: 1.54 \u00b1 0.13 versus 1.21 \u00b1 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\u20130.852). Using fibroblasts from two individuals with atypical clinical features and novel biallelic missense variants of unknown significance in AP4B1, we show that our assay can reliably detect adaptor protein complex 4 function. Our findings establish the \u2018ATG9A ratio\u2019 as a diagnostic marker of adaptor protein complex 4-associated hereditary spastic paraplegia.<\/jats:p>","DOI":"10.1093\/braincomms\/fcab221","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T08:10:57Z","timestamp":1632211857000},"source":"Crossref","is-referenced-by-count":22,"title":["High-throughput imaging of ATG9A distribution as a diagnostic functional assay for adaptor protein complex 4-associated hereditary spastic paraplegia"],"prefix":"10.1093","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0026-4714","authenticated-orcid":false,"given":"Darius","family":"Ebrahimi-Fakhari","sequence":"first","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"The Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian E","family":"Alecu","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Brechmann","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Division of Neuropediatrics and Inherited Metabolic Diseases, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Ruprecht-Karls University Heidelberg, Medical School, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Eberhardt","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hellen","family":"Jumo","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica","family":"D\u2019Amore","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2086-0425","authenticated-orcid":false,"given":"Parham","family":"Habibzadeh","sequence":"additional","affiliation":[{"name":"Persian BayanGene Research and Training Center, Shiraz University of Medical Sciences, 71347 Shiraz, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Ali","family":"Faghihi","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan L","family":"De Bleecker","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ghent University Hospital, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Vuillaumier-Barrot","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, AP-HP, Bichat Hospital, 75018 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3874-9749","authenticated-orcid":false,"given":"St\u00e9phane","family":"Auvin","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Department, AP-HP, Robert Debr\u00e9 Hospital, 75019 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo M","family":"Santorelli","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Neuser","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3679-1081","authenticated-orcid":false,"given":"Bernt","family":"Popp","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9912-4163","authenticated-orcid":false,"given":"Edward","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Neuroradiology, Department of Radiology, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee","family":"Barrett","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Rosamund Stone Zander Translational Neuroscience Center, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1594-8780","authenticated-orcid":false,"given":"Alexandra K","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afshin","family":"Saffari","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Division of Neuropediatrics and Inherited Metabolic Diseases, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Hirst","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7044-2953","authenticated-orcid":false,"given":"Mustafa","family":"Sahin","sequence":"additional","affiliation":[{"name":"Department of Neurology, The F.M. 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