TRPV1 dysfunction in cystinosis patients harboring the homozygous 57 kb deletion

L Buntinx, T Voets, B Morlion, L Vangeel, M Janssen, E Cornelissen, J Vriens, J de Hoon, E Levtchenko, L Buntinx, T Voets, B Morlion, L Vangeel, M Janssen, E Cornelissen, J Vriens, J de Hoon, E Levtchenko

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.

Trial registration: ClinicalTrials.gov NCT02533076.

Conflict of interest statement

E. Levtchenko, M. Janssen and E. Cornelissen have consulted for and received grant support from Raptor Pharmaceuticals. E. Levtchenko performed consultancy for Orphan Europe.

Figures

Figure 1. Sensitivity of cystinosis patients to…
Figure 1. Sensitivity of cystinosis patients to topical application of capsaicin or cinnamaldehyde.
(a) LDI images showing responses to topical capsaicin application in a healthy volunteer and in a heterozygous and a homozygous cystinosis patient. (b) Mean time course of the DBF expressed as % change from baseline in response to capsaicin or placebo (=vehicle), in healthy volunteers (n = 25), heterozygous patients (n = 14) and homozygous patients (n = 11). (c) Mean area under the curve for the data in (b). (d) Capsaicin induced pain, expressed in NRS-11 over time for the subjects in (b). (e) LDI images showing responses to topical cinnamaldehyde application in a healthy volunteer and in a homozygous cystinosis patient. (f) Mean time course of the DBF expressed as % change from baseline in response to cinnamaldehyde or vehicle, in healthy volunteers (n = 5) and homozygous patients (n = 5). (g) Mean area under the curve for the data in (f). *p < 0.05 between homozygous patients and healthy volunteers. °p < 0.05 between homozygous patients and heterozygous patients (Kruskall-Wallis with post-hoc Dunn’s (capsaicin) or Mann-Whitney-U (cinnamaldehyde)) N.S.: Non-significance. Data are presented as mean ± SEM.
Figure 2. Sensitivity of cystinosis patients to…
Figure 2. Sensitivity of cystinosis patients to thermal and mechanical stimuli.
(a–d): Heat detection thresholds (a), heat pain thresholds (b), cold detection thresholds (c) and cold pain thresholds (d) in healthy volunteers, heterozygous patients and homozygous patients. (e) Detection thresholds and pain thresholds for mechanical stimuli applied via von Frey hairs in healthy volunteers, heterozygous patients and homozygous patients. *p < 0.05 between homozygous patients and healthy volunteers (Kruskall-Wallis with post-hoc Dunn’s or One-way ANOVA with post-hoc Bonferroni). N.S.: Non-significance. Data are presented as mean ± SEM.

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