Preprint Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis, 2025, Zhang+

Here are the GeneCards links for most of the identified genes I picked out when I first read it through.

• ACE
• ADCY10
• DLG2
• DLGAP1
• DLGAP2
• DLGAP3
• DLGAP4
• DNMT3A
• GRB2
• GRM1
• IL12A
• INS
• LEP
• MAX
• NAMPT
• NLGN1
• NLGN2
• NME1
• NRAS
• PTPN11
• PRKCZ
• PPP2R2A
• PSMB4
• PSMB5
• PSMB7
• PSMD7
• SHARPIN
• SYNGAP1

 

Just focusing on one of those, I've looked through my library for papers on neuroligin (Wikipedia) and spotted this paper that I'd squirrelled away from Jan 2024. It links neuroligin/neurexins (albeit NLGN3), autism, nitric oxide and gastrointestinal dysmotility. I've only read the abstract and it doesn't appear to have been cited thus far, but may be worth a read through the lens of ME.

Faster Gastrointestinal Transit, Reduced Small Intestinal Smooth Muscle Tone and Dysmotility in the Nlgn3R451C Mouse Model of Autism
Hosie, Suzanne; Abo-Shaban, Tanya; Mou, Kevin; Balasuriya, Gayathri K.; Mohsenipour, Mitra; Alamoudi, Mohammed U.; Filippone, Rhiannon T.; Belz, Gabrielle T.; Franks, Ashley E.; Bornstein, Joel C.; Nurgali, Kulmira; Hill-Yardin, Elisa L.

Spoiler: Abstract

Individuals with autism often experience gastrointestinal issues but the cause is unknown. Many gene mutations that modify neuronal synapse function are associated with autism and therefore may impact the enteric nervous system that regulates gastrointestinal function. A missense mutation in the Nlgn3 gene encoding the cell adhesion protein Neuroligin-3 was identified in two brothers with autism who both experienced severe gastrointestinal dysfunction.

Mice expressing this mutation (Nlgn3R451C mice) are a well-studied preclinical model of autism and show autism-relevant characteristics, including impaired social interaction and communication, as well as repetitive behaviour. We previously showed colonic dysmotility in response to GABAergic inhibition and increased myenteric neuronal numbers in the small intestine in Nlgn3R451C mice bred on a mixed genetic background.

Here, we show that gut dysfunction is a persistent phenotype of the Nlgn3 R451C mutation in mice backcrossed onto a C57BL/6 background. We report that Nlgn3R451C mice show a 30.9% faster gastrointestinal transit (p = 0.0004) in vivo and have 6% longer small intestines (p = 0.04) compared to wild-types due to a reduction in smooth muscle tone. In Nlgn3R451C mice, we observed a decrease in resting jejunal diameter (proximal jejunum: 10.6% decrease, p = 0.02; mid: 9.8%, p = 0.04; distal: 11.5%, p = 0.009) and neurally regulated dysmotility as well as shorter durations of contractile complexes (mid: 25.6% reduction in duration, p = 0.009; distal: 30.5%, p = 0.004) in the ileum. In Nlgn3R451C mouse colons, short contractions were inhibited to a greater extent (57.2% by the GABAA antagonist, gabazine, compared to 40.6% in wild-type mice (p = 0.007). The inhibition of nitric oxide synthesis decreased the frequency of contractile complexes in the jejunum (WT p = 0.0006, Nlgn3R451C p = 0.002), but not the ileum, in both wild-type and Nlgn3R451C mice.

These findings demonstrate that changes in enteric nervous system function contribute to gastrointestinal dysmotility in mice expressing the autism-associated R451C missense mutation in the Neuroligin-3 protein.

Link | PDF (International Journal of Molecular Sciences)

 

Further on NLGN1, Genetic risk factors for severe and fatigue dominant long COVID and commonalities with ME/CFS identified by combinatorial analysis (2023, Journal of Translational Medicine) reported the following —