Hamdan et al. (2011) hypothesized that de novo mutations in synaptic genes explain an important fraction of sporadic nonsyndromic intellectual disability (NSID) cases. They sequenced 197 genes encoding glutamate receptors and a large subset of their interacting proteins ... Hamdan et al. (2011) hypothesized that de novo mutations in synaptic genes explain an important fraction of sporadic nonsyndromic intellectual disability (NSID) cases. They sequenced 197 genes encoding glutamate receptors and a large subset of their interacting proteins in 95 sporadic cases of NSID. They found 2 patients with mutations in the GRIN1 gene. The first was a 10-year-old girl with moderate mental retardation. There was no evidence of epilepsy, and she had a normal neurologic exam and CT scan. Brain MRI was not performed. The second patient was a 7.5-year-old male with severe mental retardation, partial complex seizures, hypotonia, and normal brain MRI; a CT scan was not performed. Both cases were sporadic.
In a 10-year-old girl with moderate mental retardation, Hamdan et al. (2011) identified a missense mutation in the GRIN1 gene (E662K; 138249.0001). In a 7.5-year-old boy with severe mental retardation and seizures, they detected an in-frame duplication of ... In a 10-year-old girl with moderate mental retardation, Hamdan et al. (2011) identified a missense mutation in the GRIN1 gene (E662K; 138249.0001). In a 7.5-year-old boy with severe mental retardation and seizures, they detected an in-frame duplication of serine at GRIN1 codon 560 (138249.0002). Both mutations occurred de novo. The E662K mutation resulted in increased calcium currents, and there was no effect of receptor affinity on the agonist glycine or its response to magnesium blockade. The ser560dup mutation resulted in loss of activity of the receptor, and structural analysis showed significant change in the 3-dimensional structure at the receptor's channel pore entrance.