Heterozygous deletion of the LRFN2 gene is associated with working memory deficits

Abstract

Learning disabilities (LDs) are a clinically and genetically heterogeneous group of diseases. Array-CGH and high-throughput sequencing have dramatically expanded the number of genes implicated in isolated intellectual disabilities and LDs, highlighting the implication of neuron-specific post-mitotic transcription factors and synaptic proteins as candidate genes. We report a unique family diagnosed with autosomal dominant learning disability and a 6p21 microdeletion segregating in three patients. The 870 kb microdeletion encompassed the brain-expressed gene LRFN2, which encodes for a synaptic cell adhesion molecule. Neuropsychological assessment identified selective working memory deficits, with borderline intellectual functioning. Further investigations identified a defect in executive function, and auditory-verbal processes. These data were consistent with brain MRI and FDG-PET functional brain imaging, which, when compared with controls, revealed abnormal brain volume and hypometabolism of gray matter structures implicated in working memory. We performed electron microscopy immunogold labeling demonstrating the localization of LRFN2 at synapses of cerebellar and hippocampal rat neurons, often associated with the NR1 subunit of N-methyl-D-aspartate receptors (NMDARs). Altogether, the combined approaches imply a role for LRFN2 in LD, specifically for working memory processes and executive function. In conclusion, the identification of familial cases of clinically homogeneous endophenotypes of LD might help in both the management of patients and genetic counseling for families.

The expanding spectrum of movement disorders in genetic epilepsies

“…Motor features including spasticity, ataxia, and choreoathetosis are often present. 76,77 Finally, patients with SLC1A2 mutations, affecting the glutamate transporter EAAT2, manifest DEE occasionally in tandem with movement disorders such as upper limb dyskinesia. 78,79 Genes with other cellular functions Biallelic mutations in UBA5, a gene involved in protein posttranslational modification, cause DEE including Ohtahara syndrome, West syndrome, or myoclonic jerks, and axial or peripheral hypotonia.…”

Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice

“…In human, LRFN2 is associated with autism24, learning disabilities25, and antisocial personality disorder26. Lrfn2 overexpression promotes neurite outgrowth27, recruits NMDAR, and enhances the surface expression of transfected GluN2A (NR2A, a glutamate receptor subunit)23.…”

Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2

“…7). In proposing LRFN2 as an accessory protein in the dynamic AMPA receptor trafficking code (55), this reveals a new mechanism for SNX27 controlling AMPA receptor-mediated synaptic transmission and plasticity through the trafficking of a synaptic adhesion molecule, and provides molecular insight into the perturbed function of LRFN2 observed in a range of neurological conditions including antisocial personality disorder (57), autism (58), schizophrenia (58), working memory deficits and learning disabilities (40).…”

“…While the LRFNs have been associated with inhibitory synapses (59) and at the pre-synapse (60), the function of this protein family has principally been linked with organising excitatory synapses (37-39, 41, 61, 62). The PDZ binding motif present in LRFN1, LRFN2 and LRFN4 can associate with PSD-95 (37-39, 63) and, for LRFN2, its extracellular and transmembrane domains associate with the obligatory GluN1 subunit of NMDA receptors and serves to cluster these receptors at the synaptic surface (39,40). We have now shown, for the first time, that LRFN2 can also associate with the AMPA receptor subunits GluA1 and GluA2, interactions that are principally governed by the extracellular LRR and Ig domains of LRFN2.…”

“…Within this cohort, seven proteins were classified as integral membrane proteins (shown in orange in Fig. 1C and Table S1B): the high affinity glutamate transporter, SLC1A3 (30) (PDZ binding motif -E -3 -T-K-M -0 ) and the sodium bicarbonate co-transporter, SLC4A7 (31) (E -3 -T-S-L -0 ); a sodium-dependent transporter, SLC6A11 (32) (E -3 -T-H-F -0 ); an outward rectifying potassium channel, KCNT2 (33) (E -3 -T-Q-L -0 ); a scaffold in neurotrophin signalling, KIDINS220 (34,35) (E -3 -S-I-L -0 ); a receptor for the neuronal secreted protein LGI1 (36), ADAM22 (E -3 -T-S-I -0 ), and LRFN2 (E -3 -S-T-V -0 ), a protein previously implicated in the synaptic clustering of glutamate receptors (37)(38)(39), and genetically associated with patients harbouring working memory deficits (40).…”