Biallelic TANGO1 mutations cause a novel syndromal disease due to hampered cellular collagen secretion

Abstract

The transport and Golgi organization 1 (TANGO1) proteins play pivotal roles in the secretory pathway. Full length TANGO1 is a transmembrane protein localised at endoplasmic reticulum (ER) exit sites, where it binds bulky cargo within the ER lumen and recruits membranes from the ER Golgi intermediate compartment to create an exit route for their export. Here we report the first TANGO1-associated syndrome in humans. A synonymous substitution that results in exon eight skipping in most mRNA molecules, ultimately leading to a truncated TANGO1 protein was identified as disease-causing mutation. The four homozygously affected sons of a consanguineous family display severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the corresponding truncated TANGO1 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1 impairs cellular collagen I secretion.

YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

“…Recently a truncating mutation in the TANGO1 ( MIA3 ) gene, encoding a protein involved in the export of bulky cargos from the ER to the Golgi, has been reported in one consanguineous family with a complex syndrome of dentinogenesis imperfecta, short stature, skeletal abnormalities, sensorineural hearing loss, and mild intellectual disability. All 4 affected individuals also had insulin-dependent diabetes, highlighting the importance of the mechanisms regulating cargo exit from the ER for β cell function ( 48 ). A β cell–specific knockout of cTAGE5, a TANGO1-interacting protein, has been previously shown to impair proinsulin trafficking, induce ER stress, and cause impaired glucose tolerance in mice ( 49 ).…”

COPB2haploinsufficiency causes a coatopathy with osteoporosis and developmental delay

“…Abnormal intracellular trafficking of PC may result in altered post-translational modifications, abnormal folding of the triple helix, and ultimately instability of collagen fibers. Therefore, several defects in vesicular components associated with intracellular collagen trafficking have been reported to cause severe skeletal dysplasias (11)(12)(13)(14)21). The export of fibrillar PC, such as PCI and PCII, is a challenging task for the ER that requires a dedicated set of proteins and, additionally, the retrograde input of membranes from the Golgi/ERGIC (3, 8-10).…”

“…The ER export of fibrillar PC, such as type I and type II procollagen (PCI and PCII), requires the coordinated action of PC receptors such as transport and Golgi organization (TANGO) /cutaneous T cell lymphoma-associated antigen 5 (cTAGE5) proteins, coat protein complex II (COPII) and transport protein particle (TRAPP) complex components, and the retrograde recruitment of coat protein complex I (COPI)-coated ERGIC53-containing vesicles (3,(8)(9)(10). Abnormal export of PCI and PCII from the ER to the Golgi and plasma membrane due to defects in vesicular trafficking components has been associated with skeletal dysplasias (11)(12)(13)(14)(15).…”

A physical mechanism of TANGO1-mediated bulky cargo export

“…Both cytosolic and lumenal activities of TANGO1 are critical for its function. For instance, a recent report identified a disease-causing mutation in TANGO1 in a human family, which results in a substantial fraction of TANGO1 protein being truncated and lacking its cytosolic functions, leading to collagen export defects ( Lekszas et al, 2020 ). Recently, we visualized procollagen export domains with high lateral spatial resolution using stimulated emission depletion (STED) nanoscopy in mammalian tissue cultured cells ( Raote et al, 2017 ; Raote et al, 2018 ).…”