title: COL6A5 variants in familial neuropathic chronic itch.
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.
authors.affiliation: Laboratory of Human Genetics of Neurological Disorders and Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Martinelli-Boneschi
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Colombi
authors.affiliation: Unit of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Castori
authors.affiliation: Neurological Unit, University-Hospital "S. Maria della Misericordia", Udine, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Devigili
authors.affiliation: Neurological Unit, University-Hospital "S. Maria della Misericordia", Udine, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Eleopra
authors.affiliation: Institute of Human Development, Centre for Endocrinology and Diabetes, University of Manchester and Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Rayaz A
authors.initials: RA
authors.lastname: Malik
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ritelli
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Zoppi
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Dordoni
authors.affiliation: Laboratory of Human Genetics of Neurological Disorders and Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Melissa
authors.initials: M
authors.lastname: Sorosina
authors.affiliation: Unit of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Grammatico
authors.affiliation: Institute of Human Development, Centre for Endocrinology and Diabetes, University of Manchester and Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Hassan
authors.initials: H
authors.lastname: Fadavi
authors.affiliation: Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.|Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Monique M
authors.initials: MM
authors.lastname: Gerrits
authors.affiliation: Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.|Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Rowida
authors.initials: R
authors.lastname: Almomani
authors.affiliation: Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.|Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Catharina G
authors.initials: CG
authors.lastname: Faber
authors.affiliation: Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.|Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Ingemar S J
authors.initials: IS
authors.lastname: Merkies
authors.forename: Daniela
authors.initials: D
authors.lastname: Toniolo
authors.affiliation: Department of Medical, Surgical and Health Sciences, University of Trieste, 34100 Trieste, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cocca
authors.affiliation: Department of Pathology, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.affiliation: Department of Neurology and Center for Neuroscience and regeneration Research, Yale University School of Medicine, New Haven, CT 06515, USA.|Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT 06515, USA.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
authors.affiliation: Department of Neurology and Center for Neuroscience and regeneration Research, Yale University School of Medicine, New Haven, CT 06515, USA.|Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT 06515, USA.
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.affiliation: Neuroalgology Unit and Skin Biopsy, Peripheral Neuropathy and Neuropathic Pain Center, IRCCS Foundation "Carlo Besta" Neurological Institute, Milan, Italy.
authors.forename: Michela M
authors.initials: MM
authors.lastname: Taiana
authors.affiliation: Neuroalgology Unit and Skin Biopsy, Peripheral Neuropathy and Neuropathic Pain Center, IRCCS Foundation "Carlo Besta" Neurological Institute, Milan, Italy.
authors.forename: Jenny
authors.initials: J
authors.lastname: Sassone
authors.affiliation: Neuroalgology Unit and Skin Biopsy, Peripheral Neuropathy and Neuropathic Pain Center, IRCCS Foundation "Carlo Besta" Neurological Institute, Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Lombardi
authors.affiliation: Neuroalgology Unit and Skin Biopsy, Peripheral Neuropathy and Neuropathic Pain Center, IRCCS Foundation "Carlo Besta" Neurological Institute, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cazzato
authors.affiliation: Laboratory of Human Genetics of Neurological Disorders and Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Zauli
authors.affiliation: Laboratory of Human Genetics of Neurological Disorders and Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Santoro
authors.affiliation: Neuroalgology Unit and Skin Biopsy, Peripheral Neuropathy and Neuropathic Pain Center, IRCCS Foundation "Carlo Besta" Neurological Institute, Milan, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Marchi
authors.affiliation: Neuroalgology Unit and Skin Biopsy, Peripheral Neuropathy and Neuropathic Pain Center, IRCCS Foundation "Carlo Besta" Neurological Institute, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lauria
mesh_terms: D000328:Adult; D024142:Collagen Type VI / Q000235:genetics*; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000235:genetics*; D011537:Pruritus / Q000150:complications / Q000235:genetics* / Q000473:pathology; D012867:Skin / Q000294:innervation / Q000378:metabolism / Q000473:pathology
chemical_list: C524742:COL6A5 protein, human; D024142:Collagen Type VI
keywords: COL6A5; itch; neuropathic pain; small fibre neuropathy