DecodeME candidate ME gene
From the Candidate Genes document
Chr17 contained one Tier 1 gene.
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CA10 (Tier 1)
• Protein: Carbonic anhydrase-related protein 10. UniProt. GeneCards.
Note that this gene encodes a protein that lacks catalytic activity. The allele that increases the risk of ME/CFS is associated with increased CA10 expression in prostate.
• Molecular function: CA10 binds both α- and β-neurexins, a major class of presynaptic cell adhesion molecules, and enhances their surface transport (62). CA10 is most highly expressed in the cerebellum, followed by the spinal cord and cerebral cortex, and is localised to synapses (62). CA10 inhibits the addition to neurexins of heparan sulfate (HS) glycosaminoglycan, a post-translation modification that controls the binding of presynaptic neurexins to postsynaptic neuroligins (63,64). This trans-synaptic interaction is crucial for synaptic transmission and plasticity.
In a rat model of nerve injury (spinal nerve ligation [SNL]-associated allodynia in the ipsilateral hind paw), inhibition of such Nrx1b-Neuroligin-1 interactions prevents pain (65). Nrx1β/Nrx1b contributes to neuropathic injury–induced nociceptive hypersensitivity by interacting with neurologin-1 (NL1), which subsequently activates the spinal NL1/PSD-95/pNR2B cascade. Neurexin 2 appears to be involved in pain processing (66,67).
• Cellular function: CA10 is thought to play a role in the central nervous system, especially in brain development.
• Link to disease: Tissue injury-induced synaptic redistribution of NLGN1 appears to be involvedin the development of pain hypersensitivity (68). NLGN1 in the spinal cord dorsal horn (a key site for processing pain signals) is involved in the processing of nociceptive signals. Peripheral inflammation rapidly enhances the synaptic localisation of NLGN1. Peripheral inflammation induces synaptic accumulation of the NMDA receptor. NLGN1 knockdown attenuates this accumulation and alleviates pain hypersensitivity (68).
• Potential relevance to ME/CFS: Altered CA10 expression modulates addition of heparan sulfate to presynaptic neurexins. This changes their affinity for post-synaptic neurologins, cell-cell signalling across the synapse and individuals’ pain sensitivity.
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References
From the Candidate Genes document
CHROMOSOME 17
Chr17 contained one Tier 1 gene.
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CA10 (Tier 1)
• Protein: Carbonic anhydrase-related protein 10. UniProt. GeneCards.
Note that this gene encodes a protein that lacks catalytic activity. The allele that increases the risk of ME/CFS is associated with increased CA10 expression in prostate.
• Molecular function: CA10 binds both α- and β-neurexins, a major class of presynaptic cell adhesion molecules, and enhances their surface transport (62). CA10 is most highly expressed in the cerebellum, followed by the spinal cord and cerebral cortex, and is localised to synapses (62). CA10 inhibits the addition to neurexins of heparan sulfate (HS) glycosaminoglycan, a post-translation modification that controls the binding of presynaptic neurexins to postsynaptic neuroligins (63,64). This trans-synaptic interaction is crucial for synaptic transmission and plasticity.
In a rat model of nerve injury (spinal nerve ligation [SNL]-associated allodynia in the ipsilateral hind paw), inhibition of such Nrx1b-Neuroligin-1 interactions prevents pain (65). Nrx1β/Nrx1b contributes to neuropathic injury–induced nociceptive hypersensitivity by interacting with neurologin-1 (NL1), which subsequently activates the spinal NL1/PSD-95/pNR2B cascade. Neurexin 2 appears to be involved in pain processing (66,67).
• Cellular function: CA10 is thought to play a role in the central nervous system, especially in brain development.
• Link to disease: Tissue injury-induced synaptic redistribution of NLGN1 appears to be involvedin the development of pain hypersensitivity (68). NLGN1 in the spinal cord dorsal horn (a key site for processing pain signals) is involved in the processing of nociceptive signals. Peripheral inflammation rapidly enhances the synaptic localisation of NLGN1. Peripheral inflammation induces synaptic accumulation of the NMDA receptor. NLGN1 knockdown attenuates this accumulation and alleviates pain hypersensitivity (68).
• Potential relevance to ME/CFS: Altered CA10 expression modulates addition of heparan sulfate to presynaptic neurexins. This changes their affinity for post-synaptic neurologins, cell-cell signalling across the synapse and individuals’ pain sensitivity.
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References
