Cystinosin is a melanosomal protein that regulates melanin synthesis.
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.
Institut National de Santé et de Recherche Médical (INSERM), U1065, Centre Méditerranéen de Médecine Moléculaire, Equipe 1, Biology and Pathology of Melanocytes, Nice, France.
Christine
C
Chiaverini
Laura
L
Sillard
Enrica
E
Flori
Shosuke
S
Ito
Stefania
S
Briganti
Kazumasa
K
Wakamatsu
Eric
E
Fontas
Etienne
E
Berard
Mathilde
M
Cailliez
Pierre
P
Cochat
Michel
M
Foulard
Geneviève
G
Guest
Patrick
P
Niaudet
Mauro
M
Picardo
François-Xavier
FX
Bernard
Corinne
C
Antignac
Jean Paul
JP
Ortonne
Robert
R
Ballotti
D000293:Adolescent; D000328:Adult; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D003554:Cystinosis / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008543:Melanins / Q000096:biosynthesis*; D020460:Melanosomes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012880:Skin Pigmentation / Q000235:genetics; D055815:Young Adult
D026921:Amino Acid Transport Systems, Neutral; C111445:CTNS protein, human; D008543:Melanins