Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a systematic sequencing screen of the coding exons of the X chromosome in 250 families with X-linked mental retardation (XLMR), we identified two nonsense mutations and one consensus splice-site mutation in the AP1S2 gene on Xp22 in three families. Affected individuals in these families showed mild-to-profound mental retardation. Other features included hypotonia early in life and delay in walking. AP1S2 encodes an adaptin protein that constitutes part of the adaptor protein complex found at the cytoplasmic face of coated vesicles located at the Golgi complex. The complex mediates the recruitment of clathrin to the vesicle membrane. Aberrant endocytic processing through disruption of adaptor protein complexes is likely to result from the AP1S2 mutations identified in the three XLMR-affected families, and such defects may plausibly cause abnormal synaptic development and function. AP1S2 is the first reported XLMR gene that encodes a protein directly involved in the assembly of endocytic vesicles.
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PMID:Mutations in the gene encoding the Sigma 2 subunit of the adaptor protein 1 complex, AP1S2, cause X-linked mental retardation. 1718 71

Fried syndrome, first described in 1972, is a rare X-linked mental retardation that has been mapped by linkage to Xp22. Clinical characteristics include mental retardation, mild facial dysmorphism, calcifications of basal ganglia and hydrocephalus. A large four-generation family in which the affected males have striking clinical features of Fried syndrome were investigated for linkage to X-chromosome markers; the results showed that the gene for this condition lies within the interval DXS7109-DXS7593 in Xp22.2. In total, 60 candidate genes located in this region, including AP1S2, which was recently shown to be involved in mental retardation, were screened for mutations. A mutation in the third intron of AP1S2 was found in all affected male subjects in this large French family. The mutation resulted in skipping of exon 3, predicting a protein with three novel amino-acids and with termination at codon 64. In addition, the first known large Scottish family affected by Fried syndrome was reinvestigated, and a new nonsense mutation, p.Gln66X, was found in exon 3. Using CT, both affected patients from the French family who were analysed had marked calcifications of the basal ganglia, as previously observed in the first Scottish family, suggesting that the presence of distinctive basal ganglia calcification is an essential parameter to recognise this syndromic disorder. It may be possible to use this feature to identify families with X-linked mental retardation that should be screened for mutations in AP1S2.
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PMID:Mutations in the AP1S2 gene encoding the sigma 2 subunit of the adaptor protein 1 complex are associated with syndromic X-linked mental retardation with hydrocephalus and calcifications in basal ganglia. 1761 14

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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PMID:Clinical, cellular, and neuropathological consequences of AP1S2 mutations: further delineation of a recognizable X-linked mental retardation syndrome. 1842 3

Development and implementation of high-density DNA arrays demonstrated the important role of copy number changes on the X chromosome in the etiology of developmental delay and mental retardation (MR). We describe two unrelated patients with developmental delay due to similar interstitial duplications at Xp21-p22. The first patient is a 6-month-old male with multiple affected family members including many females. The second patient is a 5-year-old adopted female. In both patients, chromosome analysis and array comparative genomic hybridization (aCGH) showed duplications of overlapping regions at Xp21-p22. The duplicated segments contain numerous genes associated with MR, including AP1S2, NHS, CDKL5, RPS6KA3, SMS, and ARX. Except for developmental delay, there is little phenotypic overlap between the male and the female patient. Additionally, the female patient and affected female relatives of the male patient have variable severities of cognitive impairment, likely due to different X-inactivation patterns and effects of other, nonduplicated genes important for normal development. These cases illustrate that increased gene dosage of X-linked MR genes lead to cognitive impairment. Precise delineation of chromosome rearrangements by aCGH and identification of genes within duplicated segments helped in establishing genotype-phenotype correlations for each of our patients, in comparing them to each other, as well as with previously reported cases of Xp21-p22 duplications. However, we show that even with detailed molecular characterization, phenotype prediction remains challenging in patients with structural abnormalities of the X chromosome.
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PMID:Clinical and molecular characterization of overlapping interstitial Xp21-p22 duplications in two unrelated individuals. 2035

We identified a 495 Kb interstitial deletion of chromosome Xp22.2, centered on the AP1S2 gene, by means of oligonucleotide array comparative genomic hybridisation (array-CGH) in a child with marked hypotonia in the first months of life, psychomotor retardation, severely delayed walking and speech development, and unspecific dysmorphic facial features. The deletion was inherited from the healthy mother. Point mutations of the AP1S2 gene have been identified in patients with X-linked mental retardation (XLMR). The clinical features of our patient are quite similar to those reported in male patients carrying point mutations, thus suggesting that point mutations and deletions of the AP1S2 gene lead to a recognisable XLMR phenotype in males.
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PMID:Deletion of the AP1S2 gene in a child with psychomotor delay and hypotonia. 2221 Feb 30