title: TRPV1 dysfunction in cystinosis patients harboring the homozygous 57 kb deletion.
abstract: Cystinosis is a rare autosomal recessive disorder characterized by lysosomal cystine accumulation due to loss of function of the lysosomal cystine transporter (CTNS). The most common mutation in cystinosis patients of Northern Europe consists of a 57-kb deletion. This deletion not only inactivates the CTNS gene but also extends into the non-coding region upstream of the start codon of the TRPV1 gene, encoding the capsaicin- and heat-sensitive ion channel TRPV1. To evaluate the consequences of the 57-kb deletion on functional TRPV1 expression, we compared thermal, mechanical and chemical sensitivity of cystinosis patients with matched healthy controls. Whereas patients heterozygous for the 57-kb deletion showed normal sensory responses, homozygous subjects exhibited a 60% reduction in vasodilation and pain evoked by capsaicin, as well as an increase in heat detection threshold. Responses to cold, mechanical stimuli or cinnamaldehyde, an agonist of the related nociceptor channel TRPA1, were unaltered. We conclude that cystinosis patients homozygous for the 57-kb deletion exhibit a strong reduction of TRPV1 function, leading to sensory deficiencies akin to the phenotype of TRPV1-deficient mice. These deficits may account for the reported sensory alterations and thermoregulatory deficits in these patients, and provide a paradigm for life-long TRPV1 deficiency in humans.
authors.affiliation: Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KULeuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Buntinx
authors.affiliation: Department of Cellular and Molecular Medicine, KULeuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Voets
authors.affiliation: Center for algology and pain management, Department of Cardiovascular Sciences, KULeuven, Weligerveld 1, 3212 Pellenberg, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Morlion
authors.affiliation: Department of Cellular and Molecular Medicine, KULeuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Vangeel
authors.affiliation: Department of internal medicine, Radboud UMC Nijmegen, Geert Grooteplein-Zuid 22, 6525 GA Nijmegen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Janssen
authors.affiliation: Department of Pediatric Nephrology, Radboud UMC Nijmegen, Geert Grooteplein-Zuid 22, 6525 GA Nijmegen, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Cornelissen
authors.affiliation: Department of Development and Regeneration, KULeuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Vriens
authors.affiliation: Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KULeuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: de Hoon
authors.affiliation: Department of Development and Regeneration, KULeuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Levtchenko
mesh_terms: D000171:Acrolein / Q000031:analogs & derivatives / Q000737:chemistry; D000293:Adolescent; D000328:Adult; D000483:Alleles; D002211:Capsaicin / Q000737:chemistry; D003062:Codon; D003554:Cystinosis / Q000235:genetics / Q000378:metabolism*; D005060:Europe; D005260:Female; D017353:Gene Deletion; D006720:Homozygote; D006358:Hot Temperature; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D009154:Mutation; D017384:Sequence Deletion; D000074025:TRPA1 Cation Channel / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D003062:Codon; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D000171:Acrolein; D002211:Capsaicin; C012843:cinnamaldehyde