A novel mutation in the DLG3 gene encoding the synapse-associated protein 102 (SAP102) causes non-syndromic mental retardation.

We have identified a novel splice site mutation (IVS6-1G > A) in the disc-large homolog 3 (DLG3) gene, encoding the synapse-associated protein 102 (SAP102) in one out of 300 families with moderate to severe non-syndromic mental retardation. SAP102 is a member of the neuronal membrane-associated guanylate kinase protein subfamily comprising SAP97, postsynaptic density (PSD)95, and PSD93, which interacts with methyl-D-aspartate receptor and associated protein complexes at the postsynaptic density of excitatory synapses. DLG3 is the first mental retardation gene directly linked to glutamate receptor signalling and trafficking, increasingly recognised as a central mechanism in the regulation of synaptic formation and plasticity in brain and cognitive development.

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

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.