PXD024957

PXD024957 is an original dataset announced via ProteomeXchange.

Title	Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive complex movement disorders
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 describe 43 affected individuals from 27 unrelated families 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 (21 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 (97%), facial dysmorphism (94%), movement disorders (94%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (74%), oculomotor (68%) and behavioural abnormalities (63%), weight gain (59%), microcephaly (38%) and epilepsy (37%). The most conspicuous and common movement disorder was dystonia (90%), frequently leading to early-onset progressive postural deformities (93%), limb dystonia (40%), and cervical dystonia (25%). A jerky tremor in the upper limbs (61%), a mild head tremor (56%), parkinsonism/hypokinesia developing with advancing age (31%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (66.6%), hypoplasia/agenesis of the anterior commissure (62.9%), short midbrain and small inferior cerebellar vermis (40.7% each), hypertrophy of the clava (18.5%) 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 with 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 models, including of 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.
HostingRepository	PRIDE
AnnounceDate	2024-05-22
AnnouncementXML	Submission_2024-05-22_02:05:13.495.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Marc Baggelaar
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-23 07:47:13	ID requested
⏵ 1	2024-05-22 02:05:14	announced

10.1093/brain/awad380;

Kaiyrzhanov R, Rad A, Lin SJ, Bertoli-Avella A, Kallemeijn WW, Godwin A, Zaki MS, Huang K, Lau T, Petree C, Efthymiou S, Karimiani EG, Hempel M, Normand EA, Rudnik-Sch, ö, neborn S, Schatz UA, Baggelaar MP, Ilyas M, Sultan T, Alvi JR, Ganieva M, Fowler B, Aanicai R, Tayfun GA, Al Saman A, Alswaid A, Amiri N, Asilova N, Shotelersuk V, Yeetong P, Azam M, Babaei M, Monajemi GB, Mohammadi P, Samie S, Banu SH, Pinto Basto J, Kort, ü, m F, Bauer M, Bauer P, Beetz C, Garshasbi M, Issa AH, 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, Louren, ç, o 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, Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain, 147(4):1436-1456(2024) [pubmed]

submitter keyword: N-myristoylation, metabolic tagging, myristic acid alkyne YnMyr, chemical proteomics, IMP-1088, ACBD6

Edward W. Tate
contact affiliation	Department of Chemistry, Imperial College London, Molecular Research Science Hub, 80 Wood Lane, London W12 0BZ, United Kingdom. The Francis Crick Institute, 1 Midland Road, London NW1 1AT, United Kingdom.
contact email	e.tate@imperial.ac.uk
lab head
Marc Baggelaar
contact affiliation	Utrecht University
contact email	m.p.baggelaar@uu.nl
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/05/PXD024957

PRIDE project URI

• PRIDE
  1. PXD024957
     1. Label: PRIDE project
     2. Name: Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive complex movement disorders