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Background: Equine recurrent laryngeal neuropathy (RLN) is an economically important upper respiratory tract (URT) disease with a genetic contribution to risk, but genetic variants independent of height have not been identified for Thoroughbreds. The method of clinical assessment for RLN is critical to accurately phenotype groups for genetic studies., Objectives: To identify genetic risk loci for RLN in Thoroughbreds in a genome-wide association study (GWAS) following high-resolution phenotyping., Study Design: Case-control., Methods: Thoroughbred horses were characterised as RLN cases and controls using resting and exercising URT endoscopic examinations and laryngeal ultrasonography, with the case-cohort supplemented using a questionnaire. Genotypes for 43 831 autosomal single-nucleotide polymorphisms (SNPs) from n = 235 horses (n = 110 cases; n = 125 controls) were used to estimate trait heritability and identify significantly associated SNPs in a GWAS. Haplotypes were examined in cases and controls and risk allele frequencies were examined in a population cohort (n = 3126)., Results: Heritability was h 2  = 0.30 including sex and 5PCs as covariates. A SNP on ECA20 located between candidate genes, DAAM2 and LRFN2, was significantly associated with RLN. Six index SNPs with allelic effect sizes OR = 1.5-2.9 were identified on ECA1, ECA14, and ECA20 close to candidate genes ATPA10, KCNN2, and TFAP2A. Eleven ECA20 SNPs defined seven haplotypes with homozygous H2/H2 horses having a 3.1× higher risk of RLN. Risk alleles segregate in the population, and stallions are carriers., Main Limitations: The main study population was young. Horses in the control group had no evidence of RLN as 2- or 3-year olds but may have developed RLN later., Conclusions: Genetic markers for RLN were identified which may be useful for the development of a polygenic risk score. Candidate genes with functions in neuropathies may further the understanding of RLN pathobiology., (© 2025 The Author(s). Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.)

As a neuronal transmembrane protein, leucine‐rich repeat and fibronectin type‐III domain‐containing protein 2 (LRFN2) can recruit and combine with N‐methyl‐d‐aspartate receptors (NMDARs) to promote nerve growth. Genetic studies suggest that mutations in LRFN2 are associated with various cancers. However, the role and mechanism of LRFN2 in the progression of ESCC have not been elucidated. In this study, we demonstrated that LRFN2 was significantly downregulated in ESCC tissues by qRT‐PCR and immunohistochemistry. Low LRFN2 expression was an adverse prognostic factor in patients with ESCC. Overexpression of LRFN2 effectively suppressed the proliferation, migration, invasion, and epithelial‐to‐mesenchymal transition in vitro and tumor growth in vivo. Bioinformatics analysis indicated that Wnt/β‐catenin signaling regulation was one of the most potential mechanisms and studies confirmed that overexpression of LFRN2 obviously downregulated the expression of β‐catenin, c‐Myc, and cyclin D1 in ESCC cells and tumor tissues. Further studies revealed that LRFN2 plays an anti‐ESCC role by binding with NMDAR‐GRIN2B and this effect can be weakened by NR2B‐selective NMDA antagonist‐NMDA‐IN‐1. Moreover, the bioinformatics analysis showed that the interaction of GRIN2B and GSK3β affects the NF‐κB pathway, which was demonstrated by western blot experiments. Collectively, our results indicate that LRFN2 binding to NMDARs inhibits the progression of ESCC by regulating the Wnt/β‐catenin and NF‐κB pathway, which provides a new therapeutic target for improving the prognosis of patients with ESCC. [ABSTRACT FROM AUTHOR]

The endosome-associated cargo adaptor sorting nexin-27 (SNX27) is linked to various neuropathologies through sorting of integral proteins to the synaptic surface, most notably AMPA receptors. To provide a broader view of SNX27-associated pathologies, we performed proteomics in rat primary neurons to identify SNX27-dependent cargoes, and identified proteins linked to excitotoxicity, epilepsy, intellectual disabilities, and working memory deficits. Focusing on the synaptic adhesion molecule LRFN2, we established that SNX27 binds to LRFN2 and regulates its endosomal sorting. Furthermore, LRFN2 associates with AMPA receptors and knockdown of LRFN2 results in decreased surface AMPA receptor expression, reduced synaptic activity, and attenuated hippocampal long-term potentiation. Overall, our study provides an additional mechanism by which SNX27 can control AMPA receptor-mediated synaptic transmission and plasticity indirectly through the sorting of LRFN2 and offers molecular insight into the perturbed function of SNX27 and LRFN2 in a range of neurological conditions.

SALMI (SALM (synaptic adhesion-like molecule), also known as LRFN2 (leucine rich repeat and fibronectin type III domain containing), is a postsynaptic density (PSD)-95-interacting synaptic adhesion molecule implicated in the regulation of NMDA receptor (NMDAR) clustering largely based on in vitro data, although its in vivo functions remain unclear. Here, we found that mice lacking SALM 1/LRFN2 (Lrfn2-/- mice) show a normal density of excitatory synapses but altered excitatory synaptic function, including enhanced NMDAR-dependent synaptic transmission but suppressed NMDAR-dependent synaptic plasticity in the hippocampal CA1 region. Unexpectedly, SALM 1 expression was detected in both glutamatergic and GABAergic neurons and Lrfn2-/- CA1 pyramidal neurons showed decreases in the density of inhibitory synapses and the frequency of spontaneous inhibitory synaptic transmission. Behaviorally, ultrasonic vocalization was suppressed in Lrfn Lrfn2-/- pups separated from their mothers and acoustic startle was enhanced, but locomotion, anxiety-like behavior, social interaction, repetitive behaviors, and learning and memory were largely normal in adult male Lrfn2-/- mice. These results suggest that SALM 1/LRFN2 regulates excitatory synapse function, inhibitory synapse development, and social communication and startle behaviors in mice. [ABSTRACT FROM AUTHOR]