Overlapping Machinery in Lysosome-Related Organelle Trafficking: A Lesson from Rare Multisystem Disorders

Abstract

Lysosome-related organelles (LROs) are a group of functionally diverse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic granules, lamellar bodies and other compartments with distinct morphologies and functions allowing specialised and unique functions of their host cells. The formation, maturation and secretion of specific LROs are compromised in a number of hereditary rare multisystem disorders, including Hermansky-Pudlak syndromes, Griscelli syndrome and the Arthrogryposis, Renal dysfunction and Cholestasis syndrome. Each of these disorders impacts the function of several LROs, resulting in a variety of clinical features affecting systems such as immunity, neurophysiology and pigmentation. This has demonstrated the close relationship between LROs and led to the identification of conserved components required for LRO biogenesis and function. Here, we discuss aspects of this conserved machinery among LROs in relation to the heritable multisystem disorders they associate with, and present our current understanding of how dysfunctions in the proteins affected in the disease impact the formation, motility and ultimate secretion of LROs. Moreover, we have analysed the expression of the members of the CHEVI complex affected in Arthrogryposis, Renal dysfunction and Cholestasis syndrome, in different cell types, by collecting single cell RNA expression data from the human protein atlas. We propose a hypothesis describing how transcriptional regulation could constitute a mechanism that regulates the pleiotropic functions of proteins and their interacting partners in different LROs.

Gain-of-function variants in CLCN7 cause hypopigmentation and lysosomal storage disease

“…ClC-7-related osteopetrosis is owed to the impaired formation and/or function of the acid-secreting ruffled border of osteoclasts that is created by lysosome exocytosis ( 12 ). Pigmentation defects may be explained by dysfunction of melanosomes as in other lysosomal diseases ( 62 , 63 , 64 ).…”

Novel Variants of <i>HPS6</i> Cause Suspected Ocular Albinism: A Report of 2 Cases and the Profile of <i>HPS6</i> Variants

“…HPS is genetically heterogeneous, and at present, eleven causative genes have been identified in 11 subtypes, which marked as HPS-1 to HPS-11 in humans [1,9]. Except for HPS2 (AP3B1) and HPS10 (AP3D1) which impair the subunits of the adapter protein 3 complex, other HPS subtypes cause deficiencies involving the biogenesis of lysosome-related organelle complexes (BLOCs) and lead to the abnormalities of intracellular vesicle formation (e.g., melanosomes, platelet dense bodies, and lytic granules) and intracellular protein trafficking, resulting in the dysfunction of lysosomerelated organelles [10][11][12]. The early diagnosis of HPS is based on ocular symptoms combined with the diagnostic hallmark of absent or greatly decreased platelet dense granules under electron microscopy [3,13], while the precise genotyping is determined by the burgeoning gene sequencing technologies in recent years.…”