--- _id: '14543' abstract: - lang: eng text: The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins, and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Utilizing exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with YnMyr chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), with ages ranging from 1 to 50 years old, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%), and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each), as well as hypertrophy of the clava (24%) were common neuroimaging findings. acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism, and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localisation and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-Myristoylation was similarly affected in acbd6-deficient zebrafish and Xenopus tropicalis models, including Fus, Marcks, and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders. article_processing_charge: No article_type: original author: - first_name: Rauan full_name: Kaiyrzhanov, Rauan last_name: Kaiyrzhanov - first_name: Aboulfazl full_name: Rad, Aboulfazl last_name: Rad - first_name: Sheng-Jia full_name: Lin, Sheng-Jia last_name: Lin - first_name: Aida full_name: Bertoli-Avella, Aida last_name: Bertoli-Avella - first_name: Wouter W full_name: Kallemeijn, Wouter W last_name: Kallemeijn - first_name: Annie full_name: Godwin, Annie last_name: Godwin - first_name: Maha S full_name: Zaki, Maha S last_name: Zaki - first_name: Kevin full_name: Huang, Kevin id: 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3 last_name: Huang orcid: 0000-0002-2512-7812 - first_name: Tracy full_name: Lau, Tracy last_name: Lau - first_name: Cassidy full_name: Petree, Cassidy last_name: Petree - first_name: Stephanie full_name: Efthymiou, Stephanie last_name: Efthymiou - first_name: Ehsan full_name: Ghayoor Karimiani, Ehsan last_name: Ghayoor Karimiani - first_name: Maja full_name: Hempel, Maja last_name: Hempel - first_name: Elizabeth A full_name: Normand, Elizabeth A last_name: Normand - first_name: Sabine full_name: Rudnik-Schöneborn, Sabine last_name: Rudnik-Schöneborn - first_name: Ulrich A full_name: Schatz, Ulrich A last_name: Schatz - first_name: Marc P full_name: Baggelaar, Marc P last_name: Baggelaar - first_name: Muhammad full_name: Ilyas, Muhammad last_name: Ilyas - first_name: Tipu full_name: Sultan, Tipu last_name: Sultan - first_name: Javeria Raza full_name: Alvi, Javeria Raza last_name: Alvi - first_name: Manizha full_name: Ganieva, Manizha last_name: Ganieva - first_name: Ben full_name: Fowler, Ben last_name: Fowler - first_name: Ruxandra full_name: Aanicai, Ruxandra last_name: Aanicai - first_name: Gulsen full_name: Akay Tayfun, Gulsen last_name: Akay Tayfun - first_name: Abdulaziz full_name: Al Saman, Abdulaziz last_name: Al Saman - first_name: Abdulrahman full_name: Alswaid, Abdulrahman last_name: Alswaid - first_name: Nafise full_name: Amiri, Nafise last_name: Amiri - first_name: Nilufar full_name: Asilova, Nilufar last_name: Asilova - first_name: Vorasuk full_name: Shotelersuk, Vorasuk last_name: Shotelersuk - first_name: Patra full_name: Yeetong, Patra last_name: Yeetong - first_name: Matloob full_name: Azam, Matloob last_name: Azam - first_name: Meisam full_name: Babaei, Meisam last_name: Babaei - first_name: Gholamreza full_name: Bahrami Monajemi, Gholamreza last_name: Bahrami Monajemi - first_name: Pouria full_name: Mohammadi, Pouria last_name: Mohammadi - first_name: Saeed full_name: Samie, Saeed last_name: Samie - first_name: Selina Husna full_name: Banu, Selina Husna last_name: Banu - first_name: Jorge Pinto full_name: Basto, Jorge Pinto last_name: Basto - first_name: Fanny full_name: Kortüm, Fanny last_name: Kortüm - first_name: Mislen full_name: Bauer, Mislen last_name: Bauer - first_name: Peter full_name: Bauer, Peter last_name: Bauer - first_name: Christian full_name: Beetz, Christian last_name: Beetz - first_name: Masoud full_name: Garshasbi, Masoud last_name: Garshasbi - first_name: Awatif full_name: Hameed Issa, Awatif last_name: Hameed Issa - first_name: Wafaa full_name: Eyaid, Wafaa last_name: Eyaid - first_name: Hind full_name: Ahmed, Hind last_name: Ahmed - first_name: Narges full_name: Hashemi, Narges last_name: Hashemi - first_name: Kazem full_name: Hassanpour, Kazem last_name: Hassanpour - first_name: Isabella full_name: Herman, Isabella last_name: Herman - first_name: Sherozjon full_name: Ibrohimov, Sherozjon last_name: Ibrohimov - first_name: Ban A full_name: Abdul-Majeed, Ban A last_name: Abdul-Majeed - first_name: Maria full_name: Imdad, Maria last_name: Imdad - first_name: Maksudjon full_name: Isrofilov, Maksudjon last_name: Isrofilov - first_name: Qassem full_name: Kaiyal, Qassem last_name: Kaiyal - first_name: Suliman full_name: Khan, Suliman last_name: Khan - first_name: Brian full_name: Kirmse, Brian last_name: Kirmse - first_name: Janet full_name: Koster, Janet last_name: Koster - first_name: Charles Marques full_name: Lourenço, Charles Marques last_name: Lourenço - first_name: Tadahiro full_name: Mitani, Tadahiro last_name: Mitani - first_name: Oana full_name: Moldovan, Oana last_name: Moldovan - first_name: David full_name: Murphy, David last_name: Murphy - first_name: Maryam full_name: Najafi, Maryam last_name: Najafi - first_name: Davut full_name: Pehlivan, Davut last_name: Pehlivan - first_name: Maria Eugenia full_name: Rocha, Maria Eugenia last_name: Rocha - first_name: Vincenzo full_name: Salpietro, Vincenzo last_name: Salpietro - first_name: Miriam full_name: Schmidts, Miriam last_name: Schmidts - first_name: Adel full_name: Shalata, Adel last_name: Shalata - first_name: Mohammad full_name: Mahroum, Mohammad last_name: Mahroum - first_name: Jawabreh Kassem full_name: Talbeya, Jawabreh Kassem last_name: Talbeya - first_name: Robert W full_name: Taylor, Robert W last_name: Taylor - first_name: Dayana full_name: Vazquez, Dayana last_name: Vazquez - first_name: Annalisa full_name: Vetro, Annalisa last_name: Vetro - first_name: Hans R full_name: Waterham, Hans R last_name: Waterham - first_name: Mashaya full_name: Zaman, Mashaya last_name: Zaman - first_name: Tina A full_name: Schrader, Tina A last_name: Schrader - first_name: Wendy K full_name: Chung, Wendy K last_name: Chung - first_name: Renzo full_name: Guerrini, Renzo last_name: Guerrini - first_name: James R full_name: Lupski, James R last_name: Lupski - first_name: Joseph full_name: Gleeson, Joseph last_name: Gleeson - first_name: Mohnish full_name: Suri, Mohnish last_name: Suri - first_name: Yalda full_name: Jamshidi, Yalda last_name: Jamshidi - first_name: Kailash P full_name: Bhatia, Kailash P last_name: Bhatia - first_name: Barbara full_name: Vona, Barbara last_name: Vona - first_name: Michael full_name: Schrader, Michael last_name: Schrader - first_name: Mariasavina full_name: Severino, Mariasavina last_name: Severino - first_name: Matthew full_name: Guille, Matthew last_name: Guille - first_name: Edward W full_name: Tate, Edward W last_name: Tate - first_name: Gaurav K full_name: Varshney, Gaurav K last_name: Varshney - first_name: Henry full_name: Houlden, Henry last_name: Houlden - first_name: Reza full_name: Maroofian, Reza last_name: Maroofian citation: ama: Kaiyrzhanov R, Rad A, Lin S-J, et al. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain. 2024;147(4):1436-1456. doi:10.1093/brain/awad380 apa: Kaiyrzhanov, R., Rad, A., Lin, S.-J., Bertoli-Avella, A., Kallemeijn, W. W., Godwin, A., … Maroofian, R. (2024). Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain. Oxford University Press. https://doi.org/10.1093/brain/awad380 chicago: Kaiyrzhanov, Rauan, Aboulfazl Rad, Sheng-Jia Lin, Aida Bertoli-Avella, Wouter W Kallemeijn, Annie Godwin, Maha S Zaki, et al. “Bi-Allelic ACBD6 Variants Lead to a Neurodevelopmental Syndrome with Progressive and Complex Movement Disorders.” Brain. Oxford University Press, 2024. https://doi.org/10.1093/brain/awad380. ieee: R. Kaiyrzhanov et al., “Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders,” Brain, vol. 147, no. 4. Oxford University Press, pp. 1436–1456, 2024. ista: Kaiyrzhanov R, Rad A, Lin S-J, Bertoli-Avella A, Kallemeijn WW, Godwin A, Zaki MS, Huang K, Lau T, Petree C, Efthymiou S, Ghayoor Karimiani E, Hempel M, Normand EA, Rudnik-Schöneborn S, Schatz UA, Baggelaar MP, Ilyas M, Sultan T, Alvi JR, Ganieva M, Fowler B, Aanicai R, Akay Tayfun G, Al Saman A, Alswaid A, Amiri N, Asilova N, Shotelersuk V, Yeetong P, Azam M, Babaei M, Bahrami Monajemi G, Mohammadi P, Samie S, Banu SH, Basto JP, Kortüm F, Bauer M, Bauer P, Beetz C, Garshasbi M, Hameed Issa A, Eyaid W, Ahmed H, Hashemi N, Hassanpour K, Herman I, Ibrohimov S, Abdul-Majeed BA, Imdad M, Isrofilov M, Kaiyal Q, Khan S, Kirmse B, Koster J, Lourenço CM, Mitani T, Moldovan O, Murphy D, Najafi M, Pehlivan D, Rocha ME, Salpietro V, Schmidts M, Shalata A, Mahroum M, Talbeya JK, Taylor RW, Vazquez D, Vetro A, Waterham HR, Zaman M, Schrader TA, Chung WK, Guerrini R, Lupski JR, Gleeson J, Suri M, Jamshidi Y, Bhatia KP, Vona B, Schrader M, Severino M, Guille M, Tate EW, Varshney GK, Houlden H, Maroofian R. 2024. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain. 147(4), 1436–1456. mla: Kaiyrzhanov, Rauan, et al. “Bi-Allelic ACBD6 Variants Lead to a Neurodevelopmental Syndrome with Progressive and Complex Movement Disorders.” Brain, vol. 147, no. 4, Oxford University Press, 2024, pp. 1436–56, doi:10.1093/brain/awad380. short: R. Kaiyrzhanov, A. Rad, S.-J. Lin, A. Bertoli-Avella, W.W. Kallemeijn, A. Godwin, M.S. Zaki, K. Huang, T. Lau, C. Petree, S. Efthymiou, E. Ghayoor Karimiani, M. Hempel, E.A. Normand, S. Rudnik-Schöneborn, U.A. Schatz, M.P. Baggelaar, M. Ilyas, T. Sultan, J.R. Alvi, M. Ganieva, B. Fowler, R. Aanicai, G. Akay Tayfun, A. Al Saman, A. Alswaid, N. Amiri, N. Asilova, V. Shotelersuk, P. Yeetong, M. Azam, M. Babaei, G. Bahrami Monajemi, P. Mohammadi, S. Samie, S.H. Banu, J.P. Basto, F. Kortüm, M. Bauer, P. Bauer, C. Beetz, M. Garshasbi, A. Hameed Issa, W. Eyaid, H. Ahmed, N. Hashemi, K. Hassanpour, I. Herman, S. Ibrohimov, B.A. Abdul-Majeed, M. Imdad, M. Isrofilov, Q. Kaiyal, S. Khan, B. Kirmse, J. Koster, C.M. Lourenço, T. Mitani, O. Moldovan, D. Murphy, M. Najafi, D. Pehlivan, M.E. Rocha, V. Salpietro, M. Schmidts, A. Shalata, M. Mahroum, J.K. Talbeya, R.W. Taylor, D. Vazquez, A. Vetro, H.R. Waterham, M. Zaman, T.A. Schrader, W.K. Chung, R. Guerrini, J.R. Lupski, J. Gleeson, M. Suri, Y. Jamshidi, K.P. Bhatia, B. Vona, M. Schrader, M. Severino, M. Guille, E.W. Tate, G.K. Varshney, H. Houlden, R. Maroofian, Brain 147 (2024) 1436–1456. date_created: 2023-11-16T12:36:51Z date_published: 2024-04-01T00:00:00Z date_updated: 2024-07-16T08:23:24Z day: '01' ddc: - '570' department: - _id: GradSch doi: 10.1093/brain/awad380 extern: '1' external_id: pmid: - '37951597' file: - access_level: open_access checksum: 0ee7a8ab9300225d60968f7a3e3cfa0d content_type: application/pdf creator: dernst date_created: 2024-07-16T08:22:13Z date_updated: 2024-07-16T08:22:13Z file_id: '17254' file_name: 2024_Brain_Kaiyrzhanov.pdf file_size: 2641456 relation: main_file success: 1 file_date_updated: 2024-07-16T08:22:13Z has_accepted_license: '1' intvolume: ' 147' issue: '4' keyword: - Neurology (clinical) language: - iso: eng month: '04' oa: 1 oa_version: Submitted Version page: 1436-1456 pmid: 1 publication: Brain publication_identifier: eissn: - 1460-2156 issn: - 0006-8950 publication_status: published publisher: Oxford University Press quality_controlled: '1' scopus_import: '1' status: public title: Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 147 year: '2024' ...