Cystinosin is a melanosomal protein that regulates melanin synthesis

Abstract

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.

Photoprotection versus photodamage: updating an old but still unsolved controversy about melanin

“…Eumelanosomes and pheomelanosomes seem to be independent machineries inside cells with differential expression of proteins and different roles. For instance, the Pmel/silver protein seems to be specific to eumelanosome and the cystinosin protein need for cystine availability seems to be specific for pheomelanosomes . Thus, formation of both types of organelles is genetically regulated and melanin formation is confined to these organelles.…”

Melanocytes and Their Diseases

“…Of note, metal ions including zinc and copper serve as catalysts and/or chelators when melanin is synthesized (Simon et al 2009) and metal remnants in fossils enable us to predict the colors of dinosaurs (Wogelius et al 2011), in addition to determining the configurations of melanosomes ). Cystinosin, a cysteine/H þ symporter that exports cysteine out of lysosomes, is the gene associated with cystinosis, a rare autosomal recessive disorder with multiple organ dysfunctions including hypopigmentation (Chiaverini et al 2012). Additionally, NAD(P)H:quinone oxidoreductase-1 enhances melanogenesis by increasing the levels of TYR protein (Choi et al 2010).…”

Cistinosis en pacientes adolescentes y adultos: Recomendaciones para la atención integral de la cistinosis

“…Consiste en la detección de niveles elevados de cistina intraleucocitaria en leucocitos totales 76 . En la actualidad se aplican las técnicas de cromatografía líquida de alta presión-espectrometría de masas en tándem (HPLC-MS/MS) en muestra de granulocitos que es una técnica más sensible 78,79 .…”