X-linked Mental Retardation (X-link + mental_retardation)

Distribution by Scientific Domains

Selected Abstracts

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

HUMAN MUTATION, Issue 7 2008
Guntram Borck
Abstract Mutations in the AP1S2 gene, encoding the ,1B 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 , subunit is encoded by one single gene, as a model system, we demonstrated that , 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 , subunits (,1A, ,1B, and ,1C) 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. 2008 Wiley-Liss, Inc. [source]

Mutation frequencies of X-linked mental retardation genes in families from the EuroMRX consortium,,

HUMAN MUTATION, Issue 2 2007
Arjan P.M. de Brouwer
Abstract The EuroMRX family cohort consists of about 400 families with non-syndromic and 200 families with syndromic X-linked mental retardation (XLMR). After exclusion of Fragile X (Fra X) syndrome, probands from these families were tested for mutations in the coding sequence of 90 known and candidate XLMR genes. In total, 73 causative mutations were identified in 21 genes. For 42% of the families with obligate female carriers, the mental retardation phenotype could be explained by a mutation. There was no difference between families with (lod score >2) or without (lod score <2) significant linkage to the X chromosome. For families with two to five affected brothers (brother pair=BP families) only 17% of the MR could be explained. This is significantly lower (P=0.0067) than in families with obligate carrier females and indicates that the MR in about 40% (17/42) of the BP families is due to a single genetic defect on the X chromosome. The mutation frequency of XLMR genes in BP families is lower than can be expected on basis of the male to female ratio of patients with MR or observed recurrence risks. This might be explained by genetic risk factors on the X chromosome, resulting in a more complex etiology in a substantial portion of XLMR patients. The EuroMRX effort is the first attempt to unravel the molecular basis of cognitive dysfunction by large-scale approaches in a large patient cohort. Our results show that it is now possible to identify 42% of the genetic defects in non-syndromic and syndromic XLMR families with obligate female carriers. 2007 Wiley-Liss, Inc. [source]

Deletion of the OPHN1 gene detected by aCGH

I. Madrigal
Abstract Background The oligophrenin 1 gene (OPHN1) is an Rho-GTPase-activating protein involved in the regulation of the G-protein cycle required for dendritic spine morphogenesis. Mutations in this gene are implicated in X-linked mental retardation (XLMR). Methods We report a deletion spanning exons 21 and 22 of the OPHN1 gene identified by a tiling path X-chromosome array comparative genomic hybridization (CGH) and multiplex ligation-dependent probe amplification, confirmed by polymerase chain reaction (PCR), in a family with four males with intellectual disabilities. Results Patients harbouring mutations in this gene share the same clinical manifestations reinforcing the idea of a syndromic XLMR. The most important neurological findings are cerebellar hypoplasia and ventriculomegaly. Conclusions We recommend screening of the OPHN1 gene in male patients with XLMR and cerebellar anomalies. This case highlights the value of high-resolution techniques as Multiplex Ligation Probe Amplification (MLPA) and CGH array for a better characterization of copy number changes and suggests that MLPA technology may be very useful for an initial screening of small deletions and duplications in XLMR patients. [source]

Oligophrenin-1, a Rho GTPase-activating protein (RhoGAP) involved in X-linked mental retardation, is expressed in the enteric nervous system

Junhua Xiao
Abstract Oligophrenin-1 is a RhoGTPase-activating protein (RhoGAP) that is involved in the regulation of shape changes in dendritic spines, and outgrowth of axons and dendrites in the brain. These changes in neuronal morphology are central to the mechanisms of plasticity, learning, and memory. Although the enteric nervous system also exhibits long-term changes in neuronal function, the expression and involvement of oligophrenin-1 has not previously been investigated. We show by RT-PCR analysis that oligophrenin-1 mRNA is expressed in the myenteric plexus (MP) of the guinea pig ileum. Sequencing of RT-PCR products showed that guinea pig oligophrenin-1 mRNA is 98% and 87% homologous to human and mouse oligophrenin-1, respectively, except that a 42 bp sequence is absent from the guinea pig mRNA. This 42 bp sequence codes for a sequence of 14 amino acids located near the carboxy-terminal end of the RhoGAP domain in the human sequence. An antibody that recognizes human oligophrenin-1 identified a 91 kDa protein band in rat and mouse brain lysates and in guinea pig sciatic nerve, and a 36 kDa protein band in both purified enteric ganglion cell and brain lysate from guinea pig. Oligophrenin-1 is localized specifically to neurons and varicose axons in the MPs and submucosal plexuses (SMPs) of the guinea pig and rat, but is not detectable in glial cells, smooth muscle, or other cell types. These findings indicate that oligophrenin-1 is expressed in the enteric nervous system, where it may regulate morphological changes in axons and dendrites, and thus modulate neuronal connectivity. Anat Rec Part A 273A:671,676, 2003. 2003 Wiley-Liss, Inc. [source]