Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders.
Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders.
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双等位基因 ACBD6 变异会导致神经发育综合征，并伴有进行性和复杂的运动障碍。
DOI：
10.1093/brain/awad380
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Rud
中科院分区：
文献类型：
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作者：
Kaiyrzhanov,Rauan;Rad,Aboulfazl;Lin,Sheng-Jia;Bertoli-Avella,Aida;Kallemeijn,WouterW;Godwin,Annie;Zaki,MahaS;Huang,Kevin;Lau,Tracy;Petree,Cassidy;Efthymiou,Stephanie;Karimiani,EhsanGhayoor;Hempel,Maja;Normand,ElizabethA;Rud
酰基辅酶A结合结构域蛋白6(ACBD6)广泛表达，参与脂类和蛋白质的酰化反应，调节蛋白的肉豆蔻酰化。然而，它在细胞中的确切功能仍不清楚，ACBD6缺陷对人类病理生理学的影响也是如此。利用外显子组测序和广泛的国际数据共享努力，我们从28个无关家系(血缘关系93%)鉴定出45名患者患有ACBD6的双等位致病，主要是功能丧失(18/20)变异。我们通过CRISPR/Cas9获得了斑马鱼和热带非洲爪哇的6个敲除基因，并在模式生物和人类细胞中研究了ACBD6在蛋白质N-肉豆蔻酸化肉豆蔻化(YnMyr)化学蛋白质组学中的作用，后者也受到了ACBD6过氧化体定位的进一步研究。受影响的患者(23名男性和22名女性)，年龄1-50 ，典型的复杂和进展性疾病，包括中到重度全球发育迟缓/智力残疾(100%)，严重的语言表达障碍(98%)，运动障碍(97%)，面部变形(95%)和轻度小脑性共济失调(85%)，伴随步态障碍(94%)，肢体痉挛/高张力(76%)，眼球运动(71%)和行为异常(65%)，超重(59%)，小头畸形(39%)和癫痫(33%)。最明显和最常见的运动障碍是肌张力障碍(94%)，经常导致早发性进行性姿势畸形(97%)，肢体肌张力障碍(55%)和颈部肌张力障碍(31%)。其他常见的运动障碍包括上肢剧烈震颤(63%)、轻度头部震颤(59%)、帕金森症/运动减退(32%)以及单纯的运动和发声痉挛。中线脑畸形是常见的神经影像表现，包括胼胝体异常(70%)、前连合发育不良/发育不全(66%)、中脑和小脑下部较短(各38%)以及锁骨肥大(24%)。Acbd6缺陷斑马鱼和Xenopus模型有效地概括了患者的许多临床表型，包括运动障碍、进行性神经运动障碍、癫痫、小头畸形、颅面畸形和中脑缺陷，并伴有发育延迟，随着时间的推移，死亡率增加。与ACBD5不同，ACBD6没有表现出过氧化体定位，ACBD6缺乏与患者成纤维细胞中过氧化体参数的改变无关。在患者来源的成纤维细胞中，68个共和18个翻译后N-肉豆蔻化蛋白的YnMyr标记有显著差异。在acbd6基因缺失的斑马鱼和x中，N-肉豆蔻化也受到类似的影响。热带病模型，包括FUS、Marcks和Chchd相关蛋白，与神经系统疾病有关。本研究提供的证据表明，ACBD6的双等位基因致病变异会导致一种独特的神经发育综合征，并伴有复杂和进行性的认知和运动障碍。
The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates theN-myristoylation of proteins viaN-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence ofACBD6defects 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 inACBD6. We generated zebrafish andXenopus tropicalis acbd6knockouts by CRISPR/Cas9 and characterized the role ofACBD6on proteinN-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 andXenopusmodels 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-translationallyN-myristoylated proteins in patient-derived fibroblasts.N-myristoylation was similarly affected inacbd6-deficient zebrafish andX. tropicalismodels, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants inACBD6lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders.