Abstract
Bone complications of cystinosis have been recently described. The main objectives of this paper were to determine in vitro the impact of CTNS mutations and cysteamine therapy on human osteoclasts and to carry out a genotype-phenotype analysis related to osteoclastic differentiation. Human osteoclasts were differentiated from peripheral blood mononuclear cells (PBMCs) and were treated with increasing doses of cysteamine (0, 50, 200 µM) and then assessed for osteoclastic differentiation. Results are presented as median (min-max). A total of 17 patients (mainly pediatric) were included, at a median age of 14 (2–61) years, and a eGFR of 64 (23–149) mL/min/1.73 m2. Most patients (71%) were under conservative kidney management (CKM). The others were kidney transplant recipients. Three functional groups were distinguished for CTNS mutations: cystinosin variant with residual cystin efflux activity (RA, residual activity), inactive cystinosin variant (IP, inactive protein), and absent protein (AP). PBMCs from patients with residual cystinosin activity generate significantly less osteoclasts than those obtained from patients of the other groups. In all groups, cysteamine exerts an inhibitory effect on osteoclastic differentiation at high doses. This study highlights a link between genotype and osteoclastic differentiation, as well as a significant impact of cysteamine therapy on this process in humans.
Highlights
Nephropathic cystinosis (NC; 1/200,000 live births) is a monogenic autosomal recessive lysosomal storage disease caused by a bi-allelic mutation of the CTNS gene (17p13.2), consisting of 12 exons [1]
A total of 13 patients were included in the analysis, as results of cell cultures were not satisfacremaining four patients
Transplant patients were sigpoint of view, we here confirm that bone involvement is a late complication of cystinosis nificantly older than patients under conservative management, and they presented a occurring in teenagers and young adults
Summary
Nephropathic cystinosis (NC; 1/200,000 live births) is a monogenic autosomal recessive lysosomal storage disease caused by a bi-allelic mutation of the CTNS gene (17p13.2), consisting of 12 exons [1] This gene encodes cystinosin, a lysosomal seven-transmembrane domain cystine transporter of 367 amino acids. The natural history of this disorder is marked by chronic interstitial nephritis, leading to end stage renal disease during the second decade of life. In this regard, the beneficial role of cysteamine therapy in NC has been well known for nearly four decades: it does not prevent nor improve tubulopathy, it considerably slows the progression of renal lesions [4,5], delays the need for transplantation [6], and prevents late complications [7]
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