@article{14543,
  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. 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.},
  author       = {Kaiyrzhanov, Rauan and Rad, Aboulfazl and Lin, Sheng-Jia and Bertoli-Avella, Aida and Kallemeijn, Wouter W and Godwin, Annie and Zaki, Maha S and Huang, Kevin and Lau, Tracy and Petree, Cassidy and Efthymiou, Stephanie and Ghayoor Karimiani, Ehsan and Hempel, Maja and Normand, Elizabeth A and Rudnik-Schöneborn, Sabine and Schatz, Ulrich A and Baggelaar, Marc P and Ilyas, Muhammad and Sultan, Tipu and Alvi, Javeria Raza and Ganieva, Manizha and Fowler, Ben and Aanicai, Ruxandra and Akay Tayfun, Gulsen and Al Saman, Abdulaziz and Alswaid, Abdulrahman and Amiri, Nafise and Asilova, Nilufar and Shotelersuk, Vorasuk and Yeetong, Patra and Azam, Matloob and Babaei, Meisam and Bahrami Monajemi, Gholamreza and Mohammadi, Pouria and Samie, Saeed and Banu, Selina Husna and Basto, Jorge Pinto and Kortüm, Fanny and Bauer, Mislen and Bauer, Peter and Beetz, Christian and Garshasbi, Masoud and Hameed Issa, Awatif and Eyaid, Wafaa and Ahmed, Hind and Hashemi, Narges and Hassanpour, Kazem and Herman, Isabella and Ibrohimov, Sherozjon and Abdul-Majeed, Ban A and Imdad, Maria and Isrofilov, Maksudjon and Kaiyal, Qassem and Khan, Suliman and Kirmse, Brian and Koster, Janet and Lourenço, Charles Marques and Mitani, Tadahiro and Moldovan, Oana and Murphy, David and Najafi, Maryam and Pehlivan, Davut and Rocha, Maria Eugenia and Salpietro, Vincenzo and Schmidts, Miriam and Shalata, Adel and Mahroum, Mohammad and Talbeya, Jawabreh Kassem and Taylor, Robert W and Vazquez, Dayana and Vetro, Annalisa and Waterham, Hans R and Zaman, Mashaya and Schrader, Tina A and Chung, Wendy K and Guerrini, Renzo and Lupski, James R and Gleeson, Joseph and Suri, Mohnish and Jamshidi, Yalda and Bhatia, Kailash P and Vona, Barbara and Schrader, Michael and Severino, Mariasavina and Guille, Matthew and Tate, Edward W and Varshney, Gaurav K and Houlden, Henry and Maroofian, Reza},
  issn         = {1460-2156},
  journal      = {Brain},
  keywords     = {Neurology (clinical)},
  publisher    = {Oxford University Press},
  title        = {{Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders}},
  doi          = {10.1093/brain/awad380},
  year         = {2023},
}

@article{12174,
  abstract     = {Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease.
Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures included early lethal encephalopathies with rapidly progressive massive brain atrophy, severe developmental epileptic encephalopathies and static intellectual disability with epilepsy. The first clinical manifestation was early hypotonia, in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic encephalopathies failed to achieve any developmental, communicative or motor skills. Less severe outcomes were observed in 23% of patients who, at a mean age of 10 years and 6 months, exhibited moderate intellectual disability, with independent walking and variable epilepsy. None of the patients developed communicative language. Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs.</jats:p>
               <jats:p>Fibroblasts of two patients with developmental epileptic encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased organelle pH, consistent with lysosomal impairment and loss of V-ATPase function. Fibroblasts of two patients with milder disease, exhibited a different phenotype with increased Lysotracker staining, decreased organelle pH and no significant modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes in cellular extracts from four patients revealed discrete accumulation. Transmission electron microscopy of fibroblasts of four patients with variable severity and of induced pluripotent stem cell-derived neurons from two patients with developmental epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic material and lamellated membrane structures resembling phospholipids. Quantitative assessment in induced pluripotent stem cell-derived neurons identified significantly smaller lysosomes.
ATP6V1A-related encephalopathy represents a new paradigm among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane protein causing altered pH homeostasis. Its pathophysiology implies intracellular accumulation of substrates whose composition remains unclear, and a combination of developmental brain abnormalities and neurodegenerative changes established during prenatal and early postanal development, whose severity is variably determined by specific pathogenic variants.},
  author       = {Guerrini, Renzo and Mei, Davide and Szigeti, Margit Katalin and Pepe, Sara and Koenig, Mary Kay and Von Allmen, Gretchen and Cho, Megan T and McDonald, Kimberly and Baker, Janice and Bhambhani, Vikas and Powis, Zöe and Rodan, Lance and Nabbout, Rima and Barcia, Giulia and Rosenfeld, Jill A and Bacino, Carlos A and Mignot, Cyril and Power, Lillian H and Harris, Catharine J and Marjanovic, Dragan and Møller, Rikke S and Hammer, Trine B and Keski Filppula, Riikka and Vieira, Päivi and Hildebrandt, Clara and Sacharow, Stephanie and Maragliano, Luca and Benfenati, Fabio and Lachlan, Katherine and Benneche, Andreas and Petit, Florence and de Sainte Agathe, Jean Madeleine and Hallinan, Barbara and Si, Yue and Wentzensen, Ingrid M and Zou, Fanggeng and Narayanan, Vinodh and Matsumoto, Naomichi and Boncristiano, Alessandra and la Marca, Giancarlo and Kato, Mitsuhiro and Anderson, Kristin and Barba, Carmen and Sturiale, Luisa and Garozzo, Domenico and Bei, Roberto and Masuelli, Laura and Conti, Valerio and Novarino, Gaia and Fassio, Anna},
  issn         = {1460-2156},
  journal      = {Brain},
  keywords     = {Neurology (clinical)},
  number       = {8},
  pages        = {2687--2703},
  publisher    = {Oxford University Press},
  title        = {{Phenotypic and genetic spectrum of ATP6V1A encephalopathy: A disorder of lysosomal homeostasis}},
  doi          = {10.1093/brain/awac145},
  volume       = {145},
  year         = {2022},
}