Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus

Idiopathic congenital nystagmus (ICN) is characterised by involuntary, periodic, predominantly horizontal, oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 ICN singleton cases (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina suggesting a specific role in the control of eye movement and gaze stability

Pearson's correlation of real allele frequencies in total sample (calculated from individual genotyping,y-axis) and frequency estimates from pooled DNA (mean RAS-scores of the 15 pools, x-axis) of 32 SNPs (r = 0.8424).

<p>Pearson's correlation of real allele frequencies in total sample (calculated from individual genotyping,y-axis) and frequency estimates from pooled DNA (mean RAS-scores of the 15 pools, x-axis) of 32 SNPs (r  =  0.8424).</p

15 SNPs chosen for individual genotyping with the P-values from the pooling stage.

a<p>Indicates SNPs that did not survive quality control measures to be included in the association validation analysis.</p

Graphical summary of association results from the genome-wide screen of pooled samples.

<p>X-axis represents the chromosome position; y-axis shows -log10 of the P-value obtained for each SNP.</p

Summary of results.

<p>Summary of results.</p

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