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Article Dans Une Revue Human Mutation Année : 2008

Clinical, cellular, and neuropathological consequences of AP1S2 mutations: further delineation of a recognizable X-linked mental retardation syndrome

Résumé

Communicated by Andreas Gal Mutations in the AP1S2 gene, encoding the r1B subunit of the clathrin-associated adaptor protein complex (AP)-1, have been recently identified in five X-linked mental retardation (XLMR) families, including the original family with Fried syndrome. Studying four patients in two unrelated families in which AP1S2 nonsense and splice-site mutations segregated, we found that affected individuals presented, in addition to previously described features, with elevated protein levels in cerebrospinal fluid (CSF). Moreover, computed tomography scans demonstrated that the basal ganglia calcifications associated with AP1S2 mutations appeared during childhood and might be progressive. Based on these observations, we propose that AP1S2 mutations are responsible for a clinically recognizable XLMR and autism syndrome associating hypotonia, delayed walking, speech delay, aggressive behavior, brain calcifications, and elevated CSF protein levels. Using the AP-2 complex, in which the r subunit is encoded by one single gene, as a model system, we demonstrated that r subunits are essential for the stability of human AP complexes. By contrast, no major alteration of the stability, subcellular localization, and function of the AP-1 complex was observed in fibroblasts derived from a patient carrying an AP1S2 mutation. Similarly, neither macro-nor microscopic defects were observed in the brain of an affected fetus. Altogether, these data suggest that the absence of an AP-1 defect in peripheral tissues is due to functional redundancy among AP-1 r subunits (r1A, r1B, and r1C) and that the phenotype observed in our patients results from a subtle and brain-specific defect of the AP-1-dependent intracellular protein traffic. Hum Mutat 29(7), 966-974, 2008. r r 2008 Wiley-Liss, Inc.
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Dates et versions

hal-02044435 , version 1 (02-04-2019)

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Guntram Borck, Anahi Mollà-Herman, Nathalie Boddaert, Ferechte Encha-Razavi, Anne Philippe, et al.. Clinical, cellular, and neuropathological consequences of AP1S2 mutations: further delineation of a recognizable X-linked mental retardation syndrome. Human Mutation, 2008, 29 (7), pp.966-974. ⟨10.1002/humu.20531⟩. ⟨hal-02044435⟩
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