1. COL6A5 variants in familial neuropathic chronic itch
- Author
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Daniele Cazzato, Stephen G. Waxman, Raffaella Lombardi, Paola Grammatico, Nicoletta Zoppi, Margherita Marchi, Sulayman D. Dib-Hajj, Roberto Eleopra, Jenny Sassone, Hassan Fadavi, Marco Ritelli, Claudio Doglioni, Catharina G. Faber, Monique M. Gerrits, Daniela Toniolo, Grazia Devigili, Ingemar S. J. Merkies, Silvia Santoro, Marina Colombi, Chiara Dordoni, Massimiliano Cocca, Marco Castori, Michela Taiana, Giuseppe Lauria, Filippo Martinelli-Boneschi, Andrea Zauli, Rowida Almomani, Rayaz A. Malik, Melissa Sorosina, Martinelli Boneschi, Filippo, Colombi, Marina, Castori, Marco, Devigili, Grazia, Eleopra, Roberto, Malik, Rayaz A, Ritelli, Marco, Zoppi, Nicoletta, Dordoni, Chiara, Sorosina, Melissa, Grammatico, Paola, Fadavi, Hassan, Gerrits, Monique M, Almomani, Rowida, Faber, Catharina G, Merkies, Ingemar S. J, Toniolo, Daniela, Cocca, Massimiliano, Doglioni, Claudio, Waxman, Stephen G, Dib Hajj, Sulayman D, Taiana, Michela M, Sassone, Jenny, Lombardi, Raffaella, Cazzato, Daniele, Zauli, Andrea, Santoro, Silvia, Marchi, Margherita, Lauria, Giuseppe, MUMC+: DA KG Lab Centraal Lab (9), MUMC+: MA Med Staf Spec Neurologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Klinische Neurowetenschappen, Filippo, Martinelli Boneschi, Marina, Colombi, Marco, Castori, Grazia, Devigili, Roberto, Eleopra, Rayaz, Malik, Marco, Ritelli, Nicoletta, Zoppi, Chiara, Dordoni, Melissa, Sorosina, Paola, Grammatico, Hassan, Fadavi, Monique, M. Gerrit, Rowida, Almomani, Catharina, G. Faber, Ingemar, S. J. Merkie, Daniela, Toniolo, Massimiliano, Cocca, Stephen, G. Waxman, Sulayman, D. Dib Hajj, Michela, M. Taiana, SASSONE PAGANO, Jenny, Raffaella, Lombardi, Daniele, Cazzato, Andrea, Zauli, Silvia, Santoro, Margherita, Marchi, and Giuseppe, Lauria
- Subjects
0301 basic medicine ,Male ,Pathology ,Diabetic neuropathy ,SYMPTOMS ,NOCICEPTORS ,DNA Mutational Analysis ,0302 clinical medicine ,Missense mutation ,ATOPIC-DERMATITIS ,CHAINS ,itch ,Exome sequencing ,Skin ,medicine.diagnostic_test ,small fibre neuropathy ,Medicine (all) ,COL6A5 ,neuropathic pain ,PAIN ,Peripheral Nervous System Diseases ,SODIUM-CHANNELS ,Middle Aged ,Itch ,Neuropathic pain ,Small fibre neuropathy ,Arts and Humanities (miscellaneous) ,Neurology (clinical) ,GABAPENTIN ,Female ,Haploinsufficiency ,medicine.drug ,Joint hypermobility ,Adult ,medicine.medical_specialty ,Gabapentin ,Collagen Type VI ,03 medical and health sciences ,CHRONIC PRURITUS ,medicine ,Humans ,Family Health ,business.industry ,Pruritus ,Genetic Variation ,SMALL FIBER NEUROPATHY ,medicine.disease ,030104 developmental biology ,Immunology ,Skin biopsy ,SENSORY NEURONS ,business ,030217 neurology & neurosurgery - Abstract
Itch is thought to represent the peculiar response to stimuli conveyed by somatosensory pathways shared with pain through the activation of specific neurons and receptors. It can occur in association with dermatological, systemic and neurological diseases, or be the side effect of certain drugs. However, some patients suffer from chronic idiopathic itch that is frequently ascribed to psychological distress and for which no biomarker is available to date. We investigated three multigenerational families, one of which diagnosed with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT), characterized by idiopathic chronic itch with predominantly proximal distribution. Skin biopsy was performed in all eight affected members and revealed in six of them reduced intraepidermal nerve fibre density consistent with small fibre neuropathy. Whole exome sequencing identified two COL6A5 rare variants co-segregating with chronic itch in eight affected members and absent in non-affected members, and in one unrelated sporadic patient with type 1 painless diabetic neuropathy and chronic itch. Two families and the diabetic patient carried the nonsense c.6814G>T (p.Glu2272*) variant and another family carried the missense c.6486G>C (p.Arg2162Ser) variant. Both variants were predicted as likely pathogenic by in silico analyses. The two variants were rare (minor allele frequency < 0.1%) in 6271 healthy controls and absent in 77 small fibre neuropathy and 167 JHS/EDS-HT patients without itch. Null-allele test on cDNA from patients' fibroblasts of both families carrying the nonsense variant demonstrated functional haploinsufficiency due to activation of nonsense mediated RNA decay. Immunofluorescence microscopy and western blotting revealed marked disorganization and reduced COL6A5 synthesis, respectively. Indirect immunofluorescence showed reduced COL6A5 expression in the skin of patients carrying the nonsense variant. Treatment with gabapentinoids provided satisfactory itch relief in the patients carrying the mutations. Our findings first revealed an association between COL6A5 gene and familiar chronic itch, suggesting a new contributor to the pathogenesis of neuropathic itch and identifying a new candidate therapeutic target.
- Published
- 2017