Andrew Donnelly

Mutations in the DLG3 Gene Cause Nonsyndromic X-Linked Mental Retardation

We have identified truncating mutations in the human DLG3 (neuroendocrine dlg) gene in 4 of 329 families with moderate to severe X-linked mental retardation. DLG3 encodes synapse-associated protein 102 (SAP102), a member of the membrane-associated guanylate kinase protein family. Neuronal SAP102 is expressed during early brain development and is localized to the postsynaptic density of excitatory synapses. It is composed of three amino-terminal PDZ domains, an src homology domain, and a carboxyl-terminal guanylate kinase domain. The PDZ domains interact directly with the NR2 subunits of the NMDA glutamate receptor and with other proteins responsible for NMDA receptor localization, immobilization, and signaling. The mutations identified in this study all introduce premature stop codons within or before the third PDZ domain, and it is likely that this impairs the ability of SAP102 to interact with the NMDA receptor and/or other proteins involved in downstream NMDA receptor signaling pathways. NMDA receptors have been implicated in the induction of certain forms of synaptic plasticity, such as long-term potentiation and long-term depression, and these changes in synaptic efficacy have been proposed as neural mechanisms underlying memory and learning. The disruption of NMDA receptor targeting or signaling, as a result of the loss of SAP102, may lead to altered synaptic plasticity and may explain the intellectual impairment observed in individuals with DLG3 mutations.

How Many X-Linked Genes for Non-Specific Mental Retardation (MRX) Are There?

X-linked mental retardation (XLMR) is that proportion of mental retardation (MR) showing the distinctive pattern of inheritance associated with the X chromosome. XLMR is subdivided into syndromal and non-specific (MRX) forms. MRX is clinically homogeneous but genetically heterogeneous. Affected males in families segregating MRX have no consistent phenotypic expression apart from their MR to distinguish them from unaffected males or affected males in other MRX families. Syndromal MRs have additional neurological or phenotypic characteristics that define a syndrome, and most of these syndromes are rare. Within some families an affected male may show {open_quotes}soft{close_quotes} syndromal signs, but where this is not evident in other affected males from the same family, the MR is diagnosed as non-specific. Delineation from fragile X syndrome or FRAXE MR can now be confidently made with the aid of direct molecular tests which detect the (CCG){sub n} expansion at either FRAXA or FRAXE. MRX can be expressed in carrier females but with milder manifestations. The gene in such cases could be partially dominant or result from a skewed X-inactivation pattern in neural tissue. 39 refs., 1 fig., 1 tab.

Fibroblast growth factor homologous factor 2 (FHF2) : gene structure, expression and mapping to the Börjeson-Forssman-Lehmann syndrome region in Xq26 delineated by a duplication breakpoint in a BFLS-like patient

Börjeson-Forssman-Lehmann syndrome (BFLS) is a syndromal X-linked mental retardation, which maps by linkage to the q26 region of the human X chromosome. We have identified a male patient with BFLS-like features and a duplication, 46,Y,dup(X)(q26q28), inherited from his phenotypically normal mother. Fluorescence in situ hybridisation using yeast artificial chromosome clones from Xq26 localised the duplication breakpoint to an ∼400-kb interval in the Xq26.3 region between DXS155 and DXS294/DXS730. Database searches and analysis of available genomic DNA sequence from the region revealed the presence of the fibroblast growth factor homologous factor gene, FHF2, within the duplication breakpoint interval. The gene structure of FHF2 was determined and two new exons were identified, including a new 5′ end exon, 1B. FHF2 is a large gene extending over ∼200 kb in Xq26.3 and is composed of at least seven exons. It shows tissue-specific alternative splicing and alternative transcription starts. Northern blot hybridisation showed highest expression in brain and skeletal muscle. The FHF2 gene localisation and tissue-specific expression pattern suggest it to be a candidate gene for familial cases of the BFLS syndrome and other syndromal and non-specific forms of X-linked mental retardation mapping to the region.

Regional localisation of two non-specific X-linked mental retardation genes (MRX30 and MRX31)

Two genes responsible for X-linked mental retardation have been localised by linkage analysis. MRX30 maps to a 28 cM region flanked by the loci DXS990 (Xq21.3) and DXS424 (Xq24). A significant multipoint lod score of 2.78 was detected between the loci DXS1120 and DXS456. MRX31 maps to a 12 cM region that spans the centromere from DXS1126 (Xp11.23) to DXS1124 (Xq13.3). Significant two-point lod scores, at a recombination fraction of zero, were obtained with the loci DXS991 (Zmax = 2.06), AR (Zmax = 3.44), PGK1P1 (Zmax = 2.06) and DXS453 (Zmax = 3.31). The MRX30 localisation overlaps that of MRX8, 13, 20 and 26 and defines the position of a new MRX gene on the basis of a set of non-overlapping regional localisations. The MRX31 localisation overlaps the localisations of many of the pericentromeric MRX loci (MRX 1, 4, 5, 7, 8, 9, 12, 13, 14, 15, 17, 20, 22 and 26). There are now at least 8 distinct loci associated with non-specific mental retardation on the X chromosome defined, in order from pter to qter, by localisation for MRX24, MRX2, MRX10, MRX1, MRX30, MRX27, FRAXE and MRX3.

Direct molecular diagnosis of myotonic dystrophy.

Hecht BK, Donnelly A, Gedeon AK, Byard RW, Haan EA, Mulley JC. Direct molecular diagnosis of myotonic dystrophy.