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.
Highlights
Cystinosis (OMIM 219800) is rare autosomal recessive disorder, characterized by lysosomal cystine accumulation causing renal Fanconi syndrome, growth retardation, vomiting, periods of dehydration, constipation, and sometimes rickets
Several cases of cystinosis patients with disturbances in thermoregulation, such as recurrent bouts of fever and heat intolerance, as well as craving for hot and spicy food have been reported, which could potentially be related to altered functional expression of TRPV116–18
To exclude the possibility that the reduced dermal blood flow (DBF) response in the homozygous patients was secondary to impaired neuropeptide release from terminals and/or reduced responsiveness of the vasculature to these neuropeptides, we developed an assay in which we evaluated changes in DBF evoked by topical cinnamaldehyde
Summary
Cystinosis (OMIM 219800) is rare autosomal recessive disorder (incidence of 1 case per 100,000 to 200,000 live births), characterized by lysosomal cystine accumulation causing renal Fanconi syndrome, growth retardation, vomiting, periods of dehydration, constipation, and sometimes rickets. More than the half of the alleles of cystinosis patients in Northern Europe are affected by a 57-kb deletion[3] This deletion inactivates the CTNS gene and removes the entire CARKL (carbohydrate kinase like) gene, which encodes a sedoheptulose kinase, and extends into the non-coding region of the TRPV1 gene. Several cases of cystinosis patients with disturbances in thermoregulation, such as recurrent bouts of fever and heat intolerance, as well as craving for hot and spicy food have been reported, which could potentially be related to altered functional expression of TRPV116–18. To evaluate this possibility, we examined heat and capsaicin sensitivity in cystinosis patients
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