Genetic disorders of cellular trafficking

• Published in: Trends in genetics Vol. 38; no. 7; pp. 724 - 751
• Main Authors: García-Cazorla, Angeles, Oyarzábal, Alfonso, Saudubray, Jean-Marie, Martinelli, Diego, Dionisi-Vici, Carlo
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2022
• Subjects: autophagy; Autophagy - genetics; cellular trafficking; Cytoskeleton - genetics; inherited metabolic diseases; membrane contact sites; Organelles; vesicular trafficking; cellular trafficking; autophagy; vesicular trafficking; membrane contact sites; inherited metabolic diseases
• ISSN: 0168-9525
• DOI: 10.1016/j.tig.2022.02.012

Cellular trafficking is essential to maintain critical biological functions. Mutations in 346 genes, most of them described in the last 5 years, are associated with disorders of cellular trafficking. Whereas initially restricted to membrane trafficking, the recent detection of many diseases has contributed to the discovery of new biological pathways. Accordingly, we propose to redesign this rapidly growing group of diseases combining biological mechanisms and clinical presentation into the following categories: (i) membrane trafficking (including organelle-related); (ii) membrane contact sites; (iii) autophagy; (iv) cytoskeleton-related. We present the most recently described pathophysiological findings, disorders and phenotypes. Although all tissues and organs are affected, the nervous system is especially vulnerable. The machinery of proteins and the mechanisms that regulate cell trafficking is of great complexity. In the last few years, the discovery of new genetic diseases linked to cell trafficking has enormously grown.In addition to membrane trafficking, other mechanisms such as membrane contact sites and cytoskeleton transport arise the question of establishing a more inclusive concept of cellular trafficking and related disorders.The nervous system is particularly affected and includes both early onset encephalopathies and late onset presentations, mostly motor and neurodegenerative disorders.The prodigious expansion of genetic disorders that impact cellular trafficking raise the question of reclassifying inherited metabolic disorders according to a holistic cell physiological approach rather than to the classic separation between intermediary metabolism, organelles and structural proteins.