Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders.

TitleBi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders.
Publication TypeJournal Article
Year of Publication2024
AuthorsKaiyrzhanov, R, Rad, A, Lin, S-J, Bertoli-Avella, A, Kallemeijn, WW, Godwin, A, Zaki, MS, Huang, K, Lau, T, Petree, C, Efthymiou, S, Karimiani, EGhayoor, Hempel, M, Normand, EA, Rudnik-Schöneborn, S, Schatz, UA, Baggelaar, MP, Ilyas, M, Sultan, T, Alvi, JRaza, Ganieva, M, Fowler, B, Aanicai, R, Tayfun, GAkay, Saman, AAl, Alswaid, A, Amiri, N, Asilova, N, Shotelersuk, V, Yeetong, P, Azam, M, Babaei, M, Monajemi, GBahrami, Mohammadi, P, Samie, S, Banu, SHusna, Basto, JPinto, Kortüm, F, Bauer, M, Bauer, P, Beetz, C, Garshasbi, M, Issa, AHameed, 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, CMarques, Mitani, T, Moldovan, O, Murphy, D, Najafi, M, Pehlivan, D, Rocha, MEugenia, Salpietro, V, Schmidts, M, Shalata, A, Mahroum, M, Talbeya, JKassem, 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
JournalBrain
Volume147
Issue4
Pagination1436-1456
Date Published2024 Apr 04
ISSN1460-2156
KeywordsAdolescent, Adult, Animals, ATP-Binding Cassette Transporters, Child, Child, Preschool, Female, Humans, Infant, Intellectual Disability, Male, Microcephaly, Middle Aged, Movement Disorders, Nervous System Malformations, Neurodevelopmental Disorders, Tremor, Young Adult, Zebrafish
Abstract

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. Using 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 myristic acid alkyne (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), aged 1-50 years, 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 localization 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 X. 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.

DOI10.1093/brain/awad380
Alternate JournalBrain
PubMed ID37951597
PubMed Central IDPMC10994533
Grant ListC29637/A21451 / CRUK_ / Cancer Research UK / United Kingdom
FC001057 / ARC_ / Arthritis Research UK / United Kingdom
FC001057 / WT_ / Wellcome Trust / United Kingdom
/ WT_ / Wellcome Trust / United Kingdom
U62 PS001042 / PS / NCHHSTP CDC HHS / United States
BB/N01541X/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom
MR/V012177/1 / MRC_ / Medical Research Council / United Kingdom
U01 HG011758 / HG / NHGRI NIH HHS / United States

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