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

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...

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Veröffentlicht in:eLife Jg. 9
Hauptverfasser: Lekszas, Caroline, Foresti, Ombretta, Raote, Ishier, Liedtke, Daniel, König, Eva-Maria, Nanda, Indrajit, Vona, Barbara, De Coster, Peter, Cauwels, Rita, Malhotra, Vivek, Haaf, Thomas
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England eLife Science Publications, Ltd 26.02.2020
eLife Sciences Publications Ltd
eLife Sciences Publications, Ltd
Schlagworte:
Alleles
Ankylosing spondylitis
Aryl Hydrocarbon Receptor Nuclear Translocator - genetics
Binding sites
Cell Biology
Cell Line, Tumor
collage secretion
Collagen
Collagen (type I)
Collagen - metabolism
Dentinogenesis
Dentinogenesis imperfecta
Diabetes
Diabetes mellitus
Diabetes mellitus (insulin dependent)
Disabilities
Diseases
Displays (Marketing)
Endoplasmic reticulum
Endoplasmic Reticulum - metabolism
Enhancer Elements, Genetic
Exons
Families & family life
Family
Genetic aspects
Golgi apparatus
Golgi Apparatus - metabolism
Hearing loss
Human Biology and Medicine
Humans
Insulin
Intellectual disabilities
Messenger RNA
mRNA
Musculoskeletal abnormalities
Mutation
Parents & parenting
Protein Transport
Proteins
Pruritus
RNA
Scoliosis
Secretion
Short Report
Short stature
TANGO1
Whole Exome Sequencing
California
dentinogenesis imperfecta
human biology
cell biology
TANGO1
diabetes mellitus
medicine
human
collage secretion
ISSN:2050-084X, 2050-084X
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Beschreibung
Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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These authors contributed equally to this work.
These authors also contributed equally to this work.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.51319