Cystinosin is a melanosomal protein that regulates melanin synthesis
The FASEB Journal, 26(9):3779-89
CHIAVERINI C., SILLARD L., FLORI E., ITO S., BRIGANTI S., WAKAMATSU K., FONTAS E., BERARD E., CAILLIEZ M., COCHAT P., FOULARD M., GUEST G., NIAUDET P., PICARDO M., BERNARD FX., ANTIGNAC C., ORTONNE JP. and BALLOTTI R. (2012)
INSERM, U895, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe 1, Biology and Pathology of Melanocytes, 06204 Cedex 3, Nice, France.
CHU NICE, Department of Dermatology, 06202 Cedex 3, Nice, France.
Université de Nice-Sophia Antipolis, UFR Médecine, 06107, Nice, France.
San Gallicano Dermatological Institute, Via San Gallicano 25/A, 00153 Rome, Italy.
Department of Chemistry, Fujita Health University School of Health Sciences, Toyoake, Aichi 470-1192.
CHU NICE, Department of Clinical Research, 06202 Cedex 3, Nice, France.
CHU NICE, Department of Paediatric Nephrology, 06202 Cedex 3, Nice, France.
APHM, Department of Paediatric Nephrology, 13385 Cedex 5, Marseille, France.
CHU LYON, Centre de Référence des Maladies Rénales Rares, Bron, France.
CHU LILLE, 59037 Lille, France.
APHP, Hôpital Necker-Enfants Malades, Department of Paediatric Nephrology, Paris, France.
Bioalternatives, Gençay, France.
INSERM U983, Hôpital Necker-Enfants Malades, 75015 Paris, France.
Cystinosis is a rare autosomal recessive disease characterized by cystine crystal accumulation leading to multiorgan dysfunctions and caused by mutation in CTNS. CTNS encodes cystinosin, a cystine/H(+) symporter that exports cystine out of the lysosomes. Patients with cystinosis frequently exhibit blond hair and fair complexion, suggesting an alteration in melanogenesis. However, the pigmentation singularities of these patients have not been studied, and the role of cystinosin in melanogenesis has remained unknown.
In our study, a clinical evaluation of 27 patients with cystinosis showed that 44% had a cutaneous pigmentation dilution compared to their relatives. Analysis of the hair melanin content in these patients by HPLC demonstrated a 50% decrease in eumelanin (4360 vs. 9360 ng/mg), and a 2-fold increase in pheomelanin (53 vs. 20 ng/mg), the yellow/red pigments. Cystinosin-deficient mice also showed a 4-fold increase in hair pheomelanin content.
In vitro studies showed that cystinosin was located at melanosomes. CTNS silencing led to a 75% reduction of melanin synthesis that was caused by a degradation of tyrosinase by lysosomal proteases. Our results objectify the pigmentation defect in patients with cystinosis. We also identify the role of CTNS in melanogenesis and add a new gene to the list of the genes involved in the control of skin and hair pigmentation.
KEYWORDS: Pigmentation; Melanocyte; Melanogenesis; Tyrosinase; Cystinosis