Biallelic TANGO1 mutations cause a novel syndromal disease due to hampered cellular collagen secretion
- Institute of Human Genetics, Julius Maximilians University Würzburg, Germany
- Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Spain
- Department of Otorhinolaryngology, Head and Neck Surgery, Tübingen Hearing Research Centre (THRC), Eberhard Karls University Tübingen, Germany
- Department of Pediatric Dentistry and Special Care, PaeCoMeDis Research Group, Ghent University Hospital, Belgium
Figures
Figure 1
A novel syndrome caused by biallelic TANGO1 mutations in a consanguineous family.
(A) Structure of TANGO1 protein. The lumenal portion contains an N-terminal signal sequence followed by an SH3-like domain required for cargo binding, as well as a coiled-coil domain. A trans- and …
Figure 2 with 3 supplements
Effects of the TANGO1 (c.3621A > G) mutation on pre-mRNA splicing.
(A) The synonymous variant, which was identified by WES and validated by Sanger sequencing in all family members, resides in exon 8 of TANGO1 at genomic position 222,822,182 (GRCh37/hg19). It is …
Figure 2—figure supplement 1
Sequence analysis.
(A) Splicing of TANGO1 exon 8, as predicted by Alamut Visual. The window shows the binding sites of various SR proteins (color code at the bottom) required for correct splicing. The height of the …
Figure 2—figure supplement 2
Minigene assay.
(A) Map of the pSPL3b-cam vector. (B) Sequence of the 521 bp amplicon (TANGO1 exon eight and ~250 bp flanking intronic sequences) inserted into pSPL3b-cam. (C) Vector constructs for the minigene …
Figure 2—figure supplement 3
Possible mechanisms underlying TANGO1 exon eight skipping.
(A) Exon skipping during pre-mRNA splicing could be due to disruption of an ESE motif, which prevents the human SR protein SC35 from binding (hypothesis I). On the other hand, the mutation creates a …
Figure 3
Quantification of TANGO1 splice products in homozygous and heterozygous mutation carriers, compared to a control individual (without mutation).
The right bar diagram shows the relative amounts of the normally spliced TANGO1 cDNA and the left diagram of splice products lacking exon 8. The standard deviation of each bar represents the results …
Figure 4
Ex8 mutant does not localise to ER exit sites.
Immunofluorescence images of U2OS cells, transiently transfected with WT TANGO1-HA or Ex8-HA. Representative images of three independent experiments. (A) Cells were probed with anti-HA (green), …
Figure 5 with 3 supplements
Ex8 mutant expression reduces collagen I secretion in U2OS cells.
(A) Media of U2OS control cells (CTRL) or stably expressing Ex8-HA mutant (Ex8) were replaced with OptiMEM media containing 0.25 mM ascorbic acid and 50 μM cycloheximide to block protein synthesis …
Figure 5—figure supplement 1
TANGO1 exon eight mutant (Ex8) expression reduces collagen I expression in U2OS cells without inducing UPR.
(A) Immunofluorescence Z-stack projections of control or Ex8-HA expressing U2OS cells, probed with anti-HA antibody (red) and anti-Collagen I antibody (green). Nuclear borders were traced from DIC …
Figure 5—figure supplement 2
Ex8 mutant expression reduces collagen XII and collagen IV secretion in U2OS cells.
Media of U2OS control cells (CTRL) or stably expressing Ex8-HA mutant (Ex8) were replaced with OptiMEM media containing 0.25 mM ascorbic acid and 50 μM cycloheximide to block protein synthesis and …
Figure 5—figure supplement 3
TANGO1 full-length overexpression has no effect on collagen I secretion in U2OS cells.
(A) Media of U2OS control cells (CTRL) or stably expressing TANGO1-HA were replaced with OptiMEM media containing 0.25 mM ascorbic acid and 50 μM cycloheximide to block protein synthesis and follow …
Tables
Table 1
Clinical symptoms in four affected brothers
| II.1 | II.2 | II.4 | II.5 | |
|---|---|---|---|---|
| Dentinogenesis imperfecta | x | x | x | x |
| Delayed eruption of permanent teeth | x | x | x | x |
| Juvenile periodontitis with early tooth loss | x | x | ||
| Growth retardation | x | x | x | x |
| Proportionate short stature | x | x | x | x |
| High nasal bridge | x | x | x | x |
| Retrognathia | x | |||
| Phalangeal brachydactyly of fingers | x | x | x | x |
| Clinodactyly of 5th finger | x | x | x | x |
| Cone-shaped epiphyses in the hands | x | x | x | |
| Brachydactyly of toes | x | x | ||
| Platyspondyly (flattened vertebral corpora) | x | x | x | x |
| Scoliosis | x | x | ||
| Prominent knees | x | x | x | x |
| Mild intellectual disability | x | x | x | x |
| Sensorineural hearing loss | x | x | x | x |
| Mild retinopathy | x | x | ||
| Insulin-dependent diabetes mellitus | x | x | x | x |
| Primary obesity | x | x | x | x |
| Early onset puberty | x | |||
| Pruritus | x | x | x | x |
| Asthma | x | x | x | x |
| Osteopenia | x | x | ||
| Hydronephrosis (junctional stenosis) | x | |||
| Nephropathy (microalbuminuria) | x |
Additional files
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Supplementary file 1
Whole Exon Sequencing (WES) was performed in the four affected bothers and their parents.
Shown are the 10 variants found to be homozygous in all affected children and heterozygous in both parents.
- https://cdn.elifesciences.org/articles/51319/elife-51319-supp1-v2.xlsx
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Transparent reporting form
- https://cdn.elifesciences.org/articles/51319/elife-51319-transrepform-v2.docx
