UC San Diego

Key PointsCystinosis is a multi-systemic lysosomal storage disease caused by inactivating mutations in, or the absence of, the lysosomal membrane exporter for cystine, cystinosin; cystinosis is the main cause of hereditary renal Fanconi syndromeTreatment with cysteamine efficiently depletes lysosomal cystine and delays progression to renal insufficiency; however, cysteamine does not reverse established renal Fanconi syndrome, indicating functions of cystinosin beyond cystine transportInsights from mechanistic studies suggest that the pathological mechanisms of Fanconi syndrome in cystinosis are multifactorial, involving oxidative stress and impaired vesicular trafficking, autophagy, and mTORC1 and TFEB signallingHaematopoietic stem cell (HSC) transplantation ameliorates renal Fanconi syndrome in cystinotic mice; HSCs differentiate into macrophages that transfer cystinosin-bearing lysosomes into proximal tubule cells via tunnelling nanotubes that cross the tubular basement membraneSince tunnelling nanotubes contain donor-derived cytosol and carry all types of organelles, this mechanism should be generic and could be used to correct other genetic diseases that affect proximal tubule cells