Abstract
ABSTRACT TANGO1 (transport and Golgi organization‐1 homolog) encodes a transmembrane protein, which is located at endoplasmic reticulum (ER) exit sites where it binds bulky cargo, such as collagens, in the lumen and recruits membranes from the ER‐Golgi intermediate compartment (ERGIC) to create an export route for cargo secretion. Mice lacking Mia3 (murine TANGO1 orthologue) show defective secretion of numerous procollagens and lead to neonatal lethality due to insufficient bone mineralization. Recently, aberrant expression of truncated TANGO1 in humans has been shown to cause a mild‐to‐moderate severe collagenopathy associated with dentinogenesis imperfecta, short stature, skeletal abnormalities, diabetes mellitus, and mild intellectual disability. We now show for the first time that complete loss of TANGO1 results in human embryonic lethality with near‐total bone loss and phenocopies the situation of Mia3 −/− mice. Whole‐exome sequencing on genomic DNA (gDNA) of an aborted fetus of Indian descent revealed a homozygous 4‐base pair (4‐bp) deletion in TANGO1 that is heterozygously present in both healthy parents. Parental fibroblast studies showed decreased TANGO1 mRNA expression and protein levels. Type I collagen secretion and extracellular matrix organization were normal, supporting a threshold model for clinical phenotype development. As such, our report broadens the phenotypic and mutational spectrum of TANGO1‐related collagenopathies, and underscores the crucial role of TANGO1 for normal bone development, of which deficiency results in a severe‐to‐lethal form of osteochondrodysplasia. © 2021 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
Highlights
The identification of the transport and Golgi organization-1 homolog (TANGO1) protein as a key player between cytoplasmic coat protein complex (COP) II coats and cargoes, kindled the interest in the pathway by which cells export bulky secretory cargoes such as collagens.[1,2,3] Its encoding gene TANGO1, located at chromosome 1q41, comprises 8142 base pairs which code for two distinct alternative spliced isoforms, full-length TANGO1 and TANGO1-short
We report an Indian family with third degree consanguinity (Fig. 1B), with a history of three induced termination-ofpregnancy because of clinical suspicion of lethal osteogenesis imperfecta (OI) and one full-term pregnancy
In 2011, Wilson and colleagues[11] demonstrated that mice deficient for Mia3 present with a chondrodysplasia characterized by severe dwarfism and neonatal lethality, which was caused by impaired chondrocyte maturation and lack of bone mineralization
Summary
The identification of the transport and Golgi organization-1 homolog (TANGO1) protein as a key player between cytoplasmic coat protein complex (COP) II coats and cargoes, kindled the interest in the pathway by which cells export bulky secretory cargoes such as collagens.[1,2,3] Its encoding gene TANGO1, located at chromosome 1q41, comprises 8142 base pairs (bp) which code for two distinct alternative spliced isoforms, full-length TANGO1 and TANGO1-short.
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