Inherited disorders of lysosomal membrane transporters

Abstract

Disorders caused by defects in lysosomal membrane transporters form a distinct subgroup of lysosomal storage disorders (LSDs). To date, defects in only 10 lysosomal membrane transporters have been associated with inherited disorders. The clinical presentations of these diseases resemble the phenotypes of other LSDs; they are heterogeneous and often present in children with neurodegenerative manifestations. However, for pathomechanistic and therapeutic studies, lysosomal membrane transport defects should be distinguished from LSDs caused by defective hydrolytic enzymes. The involved proteins differ in function, localization, and lysosomal targeting, and the diseases themselves differ in their stored material and therapeutic approaches. We provide an overview of the small group of disorders of lysosomal membrane transporters, emphasizing discovery, pathomechanism, clinical features, diagnostic methods and therapeutic aspects. We discuss common aspects of lysosomal membrane transporter defects that can provide the basis for preclinical research into these disorders.

Keywords: Lysosomal ion transport; Lysosomal metabolite export; Lysosomal metabolite import; Lysosomal storage disease (LSD); Lysosomal targeting motif; Organelle acidification; Solute carrier transporter (SLC).

Figure 1:. Simplified overview of lysosomal transmembrane transport proteins involved in human inherited disorders.

Features of the 10 transmembrane proteins discussed in this review are indicated per category: A, Lysosomal catabolite export proteins. B, Lysosomal membrane ion transport proteins. C, Lysosomal export of endocytosed component proteins. D, Defective transmembrane importer/enzyme protein. E, Lysosomal transport proteins with other or unknown function. Topology cartoons are not to scale, position and amino acid sequence of lysosomal sorting signals are indicated with arrows, location of frequent mutations are marked with * (deletions and splice site mutations are not indicated). See text for details and references.

Figure 1:. Simplified overview of lysosomal transmembrane transport proteins involved in human inherited disorders.

Features of the 10 transmembrane proteins discussed in this review are indicated per category: A, Lysosomal catabolite export proteins. B, Lysosomal membrane ion transport proteins. C, Lysosomal export of endocytosed component proteins. D, Defective transmembrane importer/enzyme protein. E, Lysosomal transport proteins with other or unknown function. Topology cartoons are not to scale, position and amino acid sequence of lysosomal sorting signals are indicated with arrows, location of frequent mutations are marked with * (deletions and splice site mutations are not indicated). See text for details and references.