Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders
Authors: Kaiyrzhanov Rauan , Rad Aboulfazl , Lin Sheng-Jia , Bertoli-Avella Aida , Kallemeijn Wouter W , Godwin Annie , Zaki Maha S , Huang Kevin , Lau Tracy , Petree Cassidy , Efthymiou Stephanie , Karimiani Ehsan Ghayoor , Hempel Maja , Normand Elizabeth A , Rudnik-Schöneborn Sabine , Schatz Ulrich A , Baggelaar Marc P , Ilyas Muhammad , Sultan Tipu , Alvi Javeria Raza , Ganieva Manizha , Fowler Ben , Aanicai Ruxandra , Tayfun Gulsen Akay , Al Saman Abdulaziz , Alswaid Abdulrahman , Amiri Nafise , Asilova Nilufar , Shotelersuk Vorasuk , Yeetong Patra , Azam Matloob , Babaei Meisam , Monajemi Gholamreza Bahrami , Mohammadi Pouria , Samie Saeed , Banu Selina Husna , Pinto Basto Jorge , Kortüm Fanny , Bauer Mislen , Bauer Peter , Beetz Christian , Garshasbi Masoud , Issa Awatif Hameed , Eyaid Wafaa , Ahmed Hind , Hashemi Narges , Hassanpour Kazem , Herman Isabella , Ibrohimov Sherozjon , Abdul-Majeed Ban A , Imdad Maria , Isrofilov Maksudjon , Kaiyal Qassem , Khan Suliman , Kirmse Brian , Koster Janet , Lourenço Charles Marques , Mitani Tadahiro , Moldovan Oana , Murphy David , Najafi Maryam , Pehlivan Davut , Rocha Maria Eugenia , Salpietro Vincenzo , Schmidts Miriam , Shalata Adel , Mahroum Mohammad , Talbeya Jawabreh Kassem , Taylor Robert W , Vazquez Dayana , Vetro Annalisa , Waterham Hans R , Zaman Mashaya , Schrader Tina A , Chung Wendy K , Guerrini Renzo , Lupski James R , Gleeson Joseph , Suri Mohnish , Jamshidi Yalda , Bhatia Kailash P , Vona Barbara , Schrader Michael , Severino Mariasavina , Guille Matthew , Tate Edward W , Varshney Gaurav K , Houlden Henry , Maroofian Reza 
Published: November 2023

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.