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Cited by 44Genetics and Neurodevelopmental DisordersCellular transport and secretionGenomics and Rare Diseases

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

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Borck, Guntram, Mollà-Herman, Anahi, Boddaert, Nathalie, Encha-Razavi, Férechté, Philippe, Anne, Robel, Laurence, Desguerre, Isabelle, Brunelle, Francis +3 more·2008·Human Mutation
DOI 10.1002/humu.20531
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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.

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  • Mutations in AP1S2 have been previously implicated in phenotypic features associated with autism spectrum disorder and X-linked mental retardation.

    “Interestingly, mutations in AP1S2 have been previously implicated in phenotypic features associated with ASD and X-linked mental retardation (Borck et al., 2008; Tarpey et al., 2006).”

    From A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains (2014) · cites this paper as Borck et al., 2008

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Authors
Borck, G., Mollà-Herman, A., Boddaert, N., Encha-Razavi, F., Philippe, A., Robel, L., Desguerre, I., Brunelle, F., Benmerah, A., Munnich, A., & Colleaux, L.
Affiliations
  • Hôpital Necker-Enfants Malades (FR)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
Colleaux, Laurence
ORCID
Venue
Human Mutation
Publisher
Hindawi Limited
Published
2008-07
Volume
29
Issue
7
Pages
966-974
ISSN
  • 1059-7794 (ISSN-L)
  • 1098-1004
DOI
10.1002/humu.20531
OpenAlex
W2158256295
Cited by
44
References
38
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2021: 2 · 2019: 5 · 2018: 1 · 2016: 1 · 2015: 4 · 2014: 5 · 2013: 4 · 2012: 2
FWCI
2.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Human Mutation (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
X-linked intellectual disability, autism spectrum disorder, basal ganglia calcification, cerebrospinal fluid protein elevation, AP-2, intracellular protein trafficking, fibroblasts, hypotonia, speech delay
MeSH terms
Brain Chemistry, Cerebrospinal Fluid, Family, Female, Humans, Male, Mutation, Pedigree, Phenotype, Protein Subunits, Protein Transport, Adaptor Protein Complex sigma Subunits, X-Linked Intellectual Disability

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