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    Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications
    (2024) Chelban, Viorica; Aksnes, Henriette; Maroofian, Reza; LaMonica, LaurenC.; Seabra, Luis; Siggervåg, Anette; Devic, Perrine; İpek, Rojan
    Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning. © 2024. The Author(s).
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    Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants
    (Oxford University Press, 2020) Neuray, Caroline; Maroofian, Reza; Scala, Marcello; Sultan, Tipu; Pai, Gurpur Shashidhar; Mojarrad, Majid; Khashab, Heba Youssef E.L.; deHoll, Leigh; Yue, Wyatt Wai Yin; Alsaif, Hessa S.; Zanetti, María Natalia; Bello, Oscar; Person, Richard Erwin; Eslahi, Atieh; Khazaei, Zaynab; Feizabadi, Masoumeh Heidari; Efthymiou, Stephanie; El-Bassyouni, Hala Tabie; Soliman, Doaa Refaey; Tekeş, Selahattin; Özer, Leyla; Baltacı, Volkan; Khan, Suliman; Beetz, Christian; Amr, Khalda; Salpietro, Vincenzo; Jamshidi, Yalda; Alkuraya., Fowzan S.; Houlden, Henry H.; Groppa, Stanislav A.; Karashova, Blagovesta Marinova; Nachbauer, Wolfgang; Boesch, Sylvia M.; Arning, Larissa; Timmann, Dagmar; Cormand, Bru; Pérez-Dueñas, Belén; Di Rosa, Gabriella; Goraya, Jatinder Singh; Mine, June; Avdjieva-Tzavella, Daniela Mircheva; Kathom, Hadil Mohamed; Tincheva, Radka Stefanova; Banu, Selina H.; Pineda-Marfà, Mercedes; Veggiotti, Pierangelo; Ferrari, Michel D.; Verrottï, Alberto; Marseglia, Gian Luigi; Savasta, Salvatore; García-Silva, Mayte; Ruiz, Alfons Macaya; Garavaglia, Barbara; Borgione, Eugenia; Portaro, Simona; Sanchez, Benigno Monteagudo; Boles, Richard G.; Papacostas, Savvas S.; Vikelis, Michail; Papanicolaou, Eleni Zamba; Dardiotis, Efthymios; Maqbool, Shazia; Ibrahim, Shahnaz Hamid; Kirmani, Salman; Rana, Nuzhat Noureen; Atawneh, Osama M.; Koutsis, Georgios; Breza, Marianthi; Mangano, Salvatore; Scuderi, Carmela; Morello, Giovanna; Stojkovic, Tanya; Zollo, M.; Heimer, Gali; Dauvilliers, Yves A.; Striano, Pasquale; Al-Khawaja, Issam; Al-Mutairi, Fuad; Sherifa, Hamed
    Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1-/- mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy. © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.