Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy.
Milena ŚlęczkowskaRowida AlmomaniMargherita MarchiBianca T A de GreefMaurice SopacuaJanneke G J HoeijmakersPatrick LindseyErika SalviGidon J BönhofDan ZieglerRayaz Ahmed MalikStephen G WaxmanGiuseppe LauriaCatharina G FaberHubert J M SmeetsMonique M GerritsPublished in: International journal of molecular sciences (2022)
Neuropathic pain is common in diabetic peripheral neuropathy (DN), probably caused by pathogenic ion channel gene variants. Therefore, we performed molecular inversion probes-next generation sequencing of 5 transient receptor potential cation channels, 8 potassium channels and 2 calcium-activated chloride channel genes in 222 painful- and 304 painless-DN patients. Twelve painful-DN (5.4%) patients showed potentially pathogenic variants (five nonsense/frameshift, seven missense, one out-of-frame deletion) in ANO3 ( n = 3), HCN1 ( n = 1), KCNK18 ( n = 2), TRPA1 ( n = 3), TRPM8 ( n = 3) and TRPV4 ( n = 1) and fourteen painless-DN patients (4.6%-three nonsense/frameshift, nine missense, one out-of-frame deletion) in ANO1 ( n = 1), KCNK18 ( n = 3), KCNQ3 ( n = 1), TRPA1 ( n = 2), TRPM8 ( n = 1), TRPV1 ( n = 3) and TRPV4 ( n = 3). Missense variants were present in both conditions, presumably with loss- or gain-of-functions. KCNK18 nonsense/frameshift variants were found in painless/painful-DN, making a causal role in pain less likely. Surprisingly, premature stop-codons with likely nonsense-mediated RNA-decay were more frequent in painful-DN. Although limited in number, painful-DN patients with ion channel gene variants reported higher maximal pain during the night and day. Moreover, painful-DN patients with TRP variants had abnormal thermal thresholds and more severe pain during the night and day. Our results suggest a role of ion channel gene variants in neuropathic pain, but functional validation is required.
Keyphrases
- neuropathic pain
- copy number
- end stage renal disease
- spinal cord
- spinal cord injury
- genome wide
- newly diagnosed
- chronic kidney disease
- ejection fraction
- chronic pain
- prognostic factors
- gene expression
- blood pressure
- magnetic resonance imaging
- computed tomography
- patient reported outcomes
- autism spectrum disorder
- brain injury
- high intensity
- fluorescence imaging
- cell free
- clinical evaluation