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  High-Throughput Imaging of ATG9A Distribution as a Diagnostic Functional Assay for Adaptor Protein Complex 4 - Associated Hereditary Spastic Paraplegia

Ebrahimi-Fakhari, D., Brechmann, B., Ziegler, M., Alecu, J. E., Eberhardt, K., Jumo, H., et al. (2021). High-Throughput Imaging of ATG9A Distribution as a Diagnostic Functional Assay for Adaptor Protein Complex 4 - Associated Hereditary Spastic Paraplegia. Annals of Neurology, 90(S27): K-211, S195-S195.

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 Creators:
Ebrahimi-Fakhari, Darius1, Author
Brechmann, Barbara1, Author
Ziegler, Marvin1, Author
Alecu, Julian E.1, Author
Eberhardt, Kathrin1, Author
Jumo, Hellen1, Author
D'Amore, Angelica1, Author
Davies, Alexandra K.2, Author              
Neuser, Sonja1, Author
Popp, Bernt1, Author
Yang, Edward1, Author
Barrett, Lee1, Author
Hirst, Jennifer1, Author
Sahin, Mustafa1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: Neurosciences & Neurology;
 Abstract: Adaptor protein complex 4 (AP-4)-associated hereditary spastic paraplegia (AP-4-HSP) 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 AP-4-HSP 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 AP-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’-robust > 0.3, SSMD > 3). The ‘ATG9A ratio’ is increased in fibroblasts of 17 well-characterized AP-4-HSP patients (mean: 1.54 ± 0.13 vs. 1.21 ± 0.05 (SD) in controls) and receiver-operating-characteristic analysis demonstrates robust diagnostic power (AUC: 0.85, 95%CI: 0.849-0.852). 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 AP-4 function. Our findings establish the ‘ATG9A ratio’ as a diagnostic marker of AP-4-HSP.

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Language(s): eng - English
 Dates: 2021
 Publication Status: Published in print
 Pages: 1
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000704705300401
DOI: 10.1002/ana.26180
 Degree: -

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Title: 146th Annual Meeting American Neurological Association
Place of Event: ELECTR NETWORK
Start-/End Date: 2021-10-17 - 2021-10-19

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Title: Annals of Neurology
Source Genre: Journal
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Publ. Info: Boston : American Neurological Association
Pages: - Volume / Issue: 90 (S27) Sequence Number: K-211 Start / End Page: S195 - S195 Identifier: ISSN: 0364-5134
CoNE: https://pure.mpg.de/cone/journals/resource/954925523748