Abstract
Pruritus is a common irritating sensation that provokes the desire to scratch. Environmental and genetic factors contribute to the onset of pruritus. Moreover, itch can become a major burden when it becomes chronic. Interestingly, the rare Collagen VI alpha 5 (COL6A5) gene variant p.Glu2272* has been identified in two families and an independent patient with chronic neuropathic itch. These patients showed reduced COL6A5 expression in skin and normal skin morphology. However, little progress has been made until now toward understanding the relationships between this mutation and chronic itch. Therefore, we developed the first mouse model that recapitulates COL6A5-p.Glu2272* mutation using the CRISPR-Cas technology and characterized this new mouse model. The mutant mRNA, measured by RT-ddPCR, was expressed at normal levels in dorsal root ganglia and was decreased in skin. The functional exploration showed effects of the mutation with some sex dysmorphology. Mutant mice had increased skin permeability. Elevated spontaneous scratching and grooming was detected in male and female mutants, with increased anxiety-like behavior in female mutants. These results suggest that the COL6A5-p.Glu2272* mutation found in patients contributes to chronic itch and induces in mice additional behavioral changes. The COL6A5-p.Glu2272* mouse model could elucidate the pathophysiological mechanisms underlying COL6A5 role in itch and help identify potential new therapeutic targets.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
No datasets were generated or analysed during the current study.
References
Arai KY, Hara T, Nagatsuka T et al (2017) Postnatal changes and sexual dimorphism in collagen expression in mouse skin. PLoS ONE 12:1–21. https://doi.org/10.1371/journal.pone.0177534
Arbogast T, Ouagazzal A-M, Chevalier C et al (2016) Reciprocal effects on neurocognitive and metabolic phenotypes in mouse models of 16p11.2 deletion and duplication syndromes. PLoS Genet 12:e1005709. https://doi.org/10.1371/journal.pgen.1005709
Azzi L, El-Alfy M, Martel C, Labrie F (2005) Gender differences in mouse skin morphology and specific effects of sex steroids and dehydroepiandrosterone. J Investig Dermatol 124:22–27. https://doi.org/10.1111/j.0022-202X.2004.23545.x
Calabro K, Curtis A, Galarneau J-R et al (2011) Gender variations in the optical properties of skin in murine animal models. J Biomed Opt 16:011008. https://doi.org/10.1117/1.3525565
Dubos A, Meziane H, Iacono G et al (2018) A new mouse model of ARX dup24 recapitulates the patients’ behavioral and fine motor alterations. Hum Mol Genet 27:2138–2153. https://doi.org/10.1093/hmg/ddy122
Duchon A, Pothion S, Brault V et al (2011) The telomeric part of the human chromosome 21 from Cstb to Prmt2 is not necessary for the locomotor and short-term memory deficits observed in the Tc1 mouse model of Down syndrome. Behav Brain Res 217:271–281. https://doi.org/10.1016/j.bbr.2010.10.023
Ebbinghaus M, Tuchscherr L, von Banchet GS et al (2020) Gain-of-function mutation in SCN11A causes itch and affects neurogenic inflammation and muscle function in Scn11a+/L799P mice. PLoS ONE 15:1–17. https://doi.org/10.1371/journal.pone.0237101
Fitzgerald J, Rich C, Zhou FH, Hansen U (2008) Three novel collagen VI chains, α4(VI), α5(VI), and α6(VI). J Biol Chem 283:20170–20180. https://doi.org/10.1074/jbc.M710139200
Fu Y, Rusznák Z, Herculano-Houzel S et al (2013) Cellular composition characterizing postnatal development and maturation of the mouse brain and spinal cord. Brain Struct Funct 218:1337–1354. https://doi.org/10.1007/s00429-012-0462-x
Li Z, Cao T, Li Q et al (2023) Cross-disease characterization of fibroblast heterogeneities and their pathogenic roles in skin inflammation. Clin Immunol 255:109742. https://doi.org/10.1016/j.clim.2023.109742
Liu T, Han Q, Chen G et al (2016) Alloknesis, and spinal astrocyte activation in male mice. Pain 157:806–817
Long Q, Jin H, You X et al (2022) Eczema is a shared risk factor for anxiety and depression: a meta-analysis and systematic review. PLoS ONE. https://doi.org/10.1371/journal.pone.0263334
Martinelli-Boneschi F, Colombi M, Castori M et al (2017) COL6A5 variants in familial neuropathic chronic itch. Brain 140:555–567. https://doi.org/10.1093/brain/aww343
Meixiong J, Dong X, Weng HJ (2020) Neuropathic itch. Cells 9:5–7. https://doi.org/10.3390/cells9102263
Misery L, Brenaut E, Le Garrec R et al (2014) Neuropathic pruritus. Nat Rev Neurol 10:408–416. https://doi.org/10.1038/nrneurol.2014.99
Oaklander AL (2011) Neuropathic itch. Semin Cutan Med Surg 30:87–92. https://doi.org/10.1016/j.sder.2011.04.006
Pereira MP, Wiegmann H, Agelopoulos K, Ständer S (2021) Neuropathic itch: routes to clinical diagnosis. Front Med. https://doi.org/10.3389/fmed.2021.641746
Philippeos C, Telerman SB, Oulès B et al (2018) Spatial and single-cell transcriptional profiling identifies functionally distinct human dermal fibroblast subpopulations. J Investig Dermatol 138:811–825. https://doi.org/10.1016/j.jid.2018.01.016
Sabatelli P, Gara SK, Grumati P et al (2011) Expression of the collagen VI α5 and α6 Chains in normal human skin and in skin of patients with collagen VI-related myopathies. J Investig Dermatol 131:99–107. https://doi.org/10.1038/jid.2010.284
Salvatierra J, Dong X, Bosmans F (2018) A disease mutation reveals a role for Na V 1.9 in acute itch. J Clin Invest 128:5434–5447
Sanders KM, Sakai K, Henry TD et al (2019) A subpopulation of amygdala neurons mediates the affective component of itch. J Neurosci 39:3345–3356. https://doi.org/10.1523/JNEUROSCI.2759-18.2019
Shimada SG, LaMotte RH (2008) Behavioral differentiation between itch and pain in mouse. Pain 139:681–687. https://doi.org/10.1016/j.pain.2008.08.002
Shuster S, Black MM, McVitie E (1975) The influence of age and sex on skin thickness, skin collagen and density. Br J Dermatol 93:639–643. https://doi.org/10.1111/j.1365-2133.1975.tb05113.x
Söderhäll C, Marenholz I, Kerscher T et al (2007) Variants in a novel epidermal collagen gene (COL29A1) are associated with atopic dermatitis. PLoS Biol 5:1952–1961. https://doi.org/10.1371/journal.pbio.0050242
Stumpf A, Ständer S (2013) Neuropathic itch: diagnosis and management. Dermatol Ther 26(2):104–9
Sun YG, Chen ZF (2007) A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 448:700–703. https://doi.org/10.1038/nature06029
Szalus K, Zysk W, Gleń J et al (2023) The associations of single nucleotide polymorphisms of the COL3A1, COL6A5, and COL8A1 genes with atopic dermatitis. J Pers Med 13:1. https://doi.org/10.3390/jpm13040661
Thomas S, Enders J, Kaiser A, Rovenstine L et al (2023) Abnormal intraepidermal nerve fiber density in disease: a scoping review. Front Neurol 14:11161077. https://doi.org/10.3389/fneur.2023.1161077
Ueda Y, Inoue T, Rahman MA et al (2006) A new chronic itch model accompanied by skin lesions in hairless mice. Int Immunopharmacol 6:1609–1615. https://doi.org/10.1016/j.intimp.2006.06.002
Wang XD, Yang G, Bai Y et al (2018) The behavioral study on the interactive aggravation between pruritus and depression. Brain Behav 8:1–9. https://doi.org/10.1002/brb3.964
Weisshaar E, Szepietowski JC, Dalgard FJ et al (2019) European S2k Guideline on Chronic Pruritus. Acta dermato-venereologica 99:469–506. https://doi.org/10.2340/00015555-3164
Yosipovitch G, Rosen JD, Hashimoto T (2018) Itch: from mechanism to (novel) therapeutic approaches. J Allergy Clin Immunol 142:1375–1390. https://doi.org/10.1016/j.jaci.2018.09.005
Yu YQ, Barry DM, Hao Y et al (2017) Molecular and neural basis of contagious itch behavior in mice. Science 355:1072–1076. https://doi.org/10.1126/science.aak9748
Zhang Y, Hwang BJ, Liu Z et al (2018) BP180 dysfunction triggers spontaneous skin inflammation in mice. Proc Natl Acad Sci USA 115:6434–6439. https://doi.org/10.1073/pnas.1721805115
Zhao ZQ, Huo FQ, Jeffry J et al (2013) Chronic itch development in sensory neurons requires BRAF signaling pathways. J Clin Investig 123:4769–4780. https://doi.org/10.1172/JCI70528
Zhao X, Yu C, Ye F et al (2018) Chronic itch impairs mood and HPA axis function in mice: modulation by CRFR1 antagonist. Pain 159:2201–2213. https://doi.org/10.1097/j.pain.0000000000001319
Acknowledgments
We thank Romain Lorentz and Valérie Erbs in the ICS genetic engineering team, Sylvie Jacquot and all members of the ICS genotyping team, and all ICS teams for their help in creating the mutant mouse model. We also thank Loïc Lindner and Pauline Cayrou for their help in ddPCR design and training. We thank the animal caretakers Sophie Brignon, Charley Pinault, and Dalila Ali-Hadji at PHENOMIN-ICS and IGBMC animal facility for their services. We thank the team of Marie-Christine Birling's laboratory at ICS for generating this mouse model. Elodie EY at ICS for her kind help for mice live tracking.
Funding
The Molecule-to-Man Pain Network has funded this work, a European Commission Multi-Center Collaborative Project, through the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 721841-Pain-Net. This work has been supported by the National Centre for Scientific Research (CNRS), the French National Institute of health and medical research (INSERM), and the University of Strasbourg (Unistra). The French state funds through the “Agence Nationale de la Recherche” under the frame of Programme Investissements d’Avenir labelled ANR-10-IDEX-0002-02, ANR-10-LABX-0030-INRT, ANR-10-INBS-07 PHENOMIN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Author information
Authors and Affiliations
Contributions
The conceptualization of the study was done by GL, CGR and YH; The data curation and formal analysis by AR, CGR, YH; the funding Acquisition by GL, YH; the investigation by AR based on methodology developed by AR, CG, MCB, and YH: the project was administrated by YH with resources from MCB; The supervision and validation was done by CGR, YH; The original draft was prepared by AR, CGR, YH; The Review & Editing of the final manuscript was done by all authors.
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Rasheed, A.A.B., Birling, MC., Lauria, G. et al. The COL6A5-p.Glu2272* mutation induces chronic itch in mice. Mamm Genome (2024). https://doi.org/10.1007/s00335-024-10032-9
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00335-024-10032-9