Hamdan et al. (2011) hypothesized that de novo mutations in synaptic genes explain an important fraction of sporadic nonsyndromic intellectual disability (NSID) cases. To investigate the possibility, they sequenced 197 genes encoding glutamate receptors and a large subset ... Hamdan et al. (2011) hypothesized that de novo mutations in synaptic genes explain an important fraction of sporadic nonsyndromic intellectual disability (NSID) cases. To investigate the possibility, they sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. They identified a single patient with a missense mutation in the EPB41L1 gene. The male patient, 6 years old at the time of the report, had severe intellectual disability, no evidence of epilepsy, hypotonia, and normal brain imaging by MRI.
In a patient with nonsyndromic intellectual disability, Hamdan et al. (2011) identified a heterozygous missense mutation in the EPB41L1 gene (P854S; 602879.0001). This mutation affects a highly conserved proline in the C-terminal domain of the 4.1N protein, which ... In a patient with nonsyndromic intellectual disability, Hamdan et al. (2011) identified a heterozygous missense mutation in the EPB41L1 gene (P854S; 602879.0001). This mutation affects a highly conserved proline in the C-terminal domain of the 4.1N protein, which binds AMPA receptor subunits. Coimmunoprecipitation studies showed that the proline-to-serine substitution at codon 854 reduces the binding of 4.1N to GLUR1 (138248) by 50% in HEK293 cells. Moreover, insertion of GLUR1 at the synaptic membrane was significantly decreased in transfected hippocampal neurons producing mutant 4.1N when compared to cells producing wildtype 4.1N.