title: Clinical, cellular, and neuropathological consequences of AP1S2 mutations: further delineation of a recognizable X-linked mental retardation syndrome.
abstract: Mutations in the AP1S2 gene, encoding the sigma1B 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 sigma subunit is encoded by one single gene, as a model system, we demonstrated that sigma 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 sigma subunits (sigma1A, sigma1B, and sigma1C) and that the phenotype observed in our patients results from a subtle and brain-specific defect of the AP-1-dependent intracellular protein traffic.
authors.affiliation: INSERM U781 and Department of Medical Genetics, Hôpital Necker-Enfants Malades, Université Paris Descartes, Faculté de Médecine, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
authors.forename: Anahi
authors.initials: A
authors.lastname: Mollà-Herman
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Férechté
authors.initials: F
authors.lastname: Encha-Razavi
authors.forename: Anne
authors.initials: A
authors.lastname: Philippe
authors.forename: Laurence
authors.initials: L
authors.lastname: Robel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.forename: Francis
authors.initials: F
authors.lastname: Brunelle
authors.forename: Alexandre
authors.initials: A
authors.lastname: Benmerah
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
mesh_terms: D034002:Adaptor Protein Complex sigma Subunits / Q000235:genetics*; D001923:Brain Chemistry; D002555:Cerebrospinal Fluid / Q000737:chemistry; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D021122:Protein Subunits; D021381:Protein Transport
chemical_list: C516800:AP1S2 protein, human; D034002:Adaptor Protein Complex sigma Subunits; D021122:Protein Subunits