Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders.
Creators: name: Kaiyrzhanov, Rauan
name: Rad, Aboulfazl
name: Lin, Sheng-Jia
name: Bertoli-Avella, Aida
name: Kallemeijn, Wouter W
name: Godwin, Annie
name: Zaki, Maha S
name: Huang, Kevin
name: Lau, Tracy
name: Petree, Cassidy
name: Efthymiou, Stephanie
name: Karimiani, Ehsan Ghayoor
name: Hempel, Maja
name: Normand, Elizabeth A
name: Rudnik-Schöneborn, Sabine
name: Schatz, Ulrich A
name: Baggelaar, Marc P
name: Ilyas, Muhammad
name: Sultan, Tipu
name: Alvi, Javeria Raza
name: Ganieva, Manizha
name: Fowler, Ben
name: Aanicai, Ruxandra
name: Tayfun, Gulsen Akay
name: Al Saman, Abdulaziz
name: Alswaid, Abdulrahman
name: Amiri, Nafise
name: Asilova, Nilufar
name: Shotelersuk, Vorasuk
name: Yeetong, Patra
name: Azam, Matloob
name: Babaei, Meisam
name: Monajemi, Gholamreza Bahrami
name: Mohammadi, Pouria
name: Samie, Saeed
name: Banu, Selina Husna
name: Basto, Jorge Pinto
name: Kortüm, Fanny
name: Bauer, Mislen
name: Bauer, Peter
name: Beetz, Christian
name: Garshasbi, Masoud
name: Issa, Awatif Hameed
name: Eyaid, Wafaa
name: Ahmed, Hind
name: Hashemi, Narges
name: Hassanpour, Kazem
name: Herman, Isabella
name: Ibrohimov, Sherozjon
name: Abdul-Majeed, Ban A
name: Imdad, Maria
name: Isrofilov, Maksudjon
name: Kaiyal, Qassem
name: Khan, Suliman
name: Kirmse, Brian
name: Koster, Janet
name: Lourenço, Charles Marques
name: Mitani, Tadahiro
name: Moldovan, Oana
name: Murphy, David
name: Najafi, Maryam
name: Pehlivan, Davut
name: Rocha, Maria Eugenia
name: Salpietro, Vincenzo
name: Schmidts, Miriam
name: Shalata, Adel
name: Mahroum, Mohammad
name: Talbeya, Jawabreh Kassem
name: Taylor, Robert W
name: Vazquez, Dayana
name: Vetro, Annalisa
name: Waterham, Hans R
name: Zaman, Mashaya
name: Schrader, Tina A
name: Chung, Wendy K
name: Guerrini, Renzo
name: Lupski, James R
name: Gleeson, Joseph
name: Suri, Mohnish
name: Jamshidi, Yalda
name: Bhatia, Kailash P
name: Vona, Barbara
name: Schrader, Michael
name: Severino, Mariasavina
name: Guille, Matthew
name: Tate, Edward W
name: Varshney, Gaurav K
name: Houlden, Henry
name: Maroofian, Reza
Publisher: name: The Francis Crick Institute
Year: 2024
Subjects: classificationCode: Biochemistry & Proteomics
subject: Biochemistry &amp; Proteomics
classificationCode: Cell Biology
subject: Cell Biology
classificationCode: Model organisms
subject: Model organisms
classificationCode: Infectious Disease
subject: Infectious Disease

description: 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.