Alternative titles; symbols
HGNC Approved Gene Symbol: TANGO2
SNOMEDCT: 1172698005;
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38) : 22:20,017,023-20,067,164 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q11.21 | Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration | 616878 | Autosomal recessive | 3 |
Proteins of the TANGO family, such as TANGO2, are predicted to function in cargo loading of newly synthesized secretory proteins in the endoplasmic reticulum (summary by Lalani et al., 2016).
Lalani et al. (2016) found that the TANGO2 protein localized to the Golgi and cytoplasm. Kremer et al. (2016) reported that the first 30 amino acids of TANGO2 constitute a mitochondrial targeting signal.
Lalani et al. (2016) determined that the TANGO2 gene contains at least 8 coding exons and a 5-prime noncoding exon.
Lalani et al. (2016) and Kremer et al. (2016) reported that the TANGO2 gene maps to chromosome 22q11.2.
Lalani et al. (2016) performed whole-exome sequencing in 12 patients from 9 families with recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN; 616878), who were negative for mutation in rhabdomyolysis-associated genes, and identified homozygosity or compound heterozygosity for mutations in the TANGO2 gene (616830.0001-616830.0004) in all affected individuals. The mutations segregated fully with disease in the families, and none of the variants was present in homozygosity in control databases.
Kremer et al. (2016) performed whole-exome sequencing in 3 unrelated individuals with MECRCN and identified homozygosity or compound heterozygosity for mutations in the TANGO2 gene in all 3 patients (616830.0002; 616830.0005-616830.0006).
In 11 patients from 7 families, including 4 sib pairs, with MECRCN, Jennions et al. (2019) identified biallelic mutations in the TANGO2 gene (see, e.g., 616830.0002; 616830.0004; 616830.0007-616830.0010). The most common mutation, deletion of exons 3-9 (616830.0002), was found in 5 patients from 3 families. All of the mutations were absent or extremely rare (less than 0.002%) in the gnomAD database.
Dines et al. (2019) reported 14 patients from 11 families, including a sib pair and a sib trio, with MECRCN and biallelic mutations in the TANGO2 gene. The most common mutation was the exon 3-9 deletion, which was homozygous in 5 families and compound heterozygous in 4 families. The other mutations included a splice site mutation (616830.0009), a nonsense mutation (R32X), an exon 6 deletion, and 2 missense mutations (R26K; G89C).
In 20 patients from 14 families with MECRCN, Berat et al. (2021) identified homozygous or compound heterozygous mutations in the TANGO2 gene. The mutations included 7 point mutations (5 of which were novel), 2 small deletions, and 1 exon 3-9 deletion. Oxidation of palmitate and glutamate were measured in myoblasts from 2 patients (patients 11 and 18) and did not demonstrate an abnormality in the Krebs cycle or in mitochondrial fatty acid oxidation.
Heiman et al. (2022) evaluated the mitochondrial phenotype in fibroblasts from 3 individuals, including a sib pair, with MECRCN and biallelic mutations in the TANGO2 gene. The sibs (patients 1 and 2) were homozygous for the recurrent deletion of exons 3-9, and patient 3 was compound heterozygous for the exon 3-9 deletion and a splice site mutation (c.605+1G-A). TANGO2 protein expression was absent in fibroblasts from all 3 patients, whereas it was present in whole cell extracts and mitochondrial cellular fractions in control fibroblasts. ATP content was significantly decreased, and reduced oleate flux through fatty acid oxidation was demonstrated in patient fibroblasts. Mitochondrial volume, mtDNA, and oxygen consumption rates were also decreased in patient fibroblasts compared to controls. Heiman et al. (2022) concluded that these results indicate broad mitochondrial dysfunction in MECRCN.
In affected members of 4 Hispanic families (families 1, 3, 4, and 5) with recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN; 616878), Lalani et al. (2016) identified homozygosity for a c.460G-A transition (SCV000245441) in exon 7 of the TANGO2 gene, resulting in a gly154-to-arg (G154R) substitution at a highly conserved residue. The mutation segregated with disease in the 3 families for which parental DNA was available. The authors noted that the G154R variant was enriched in the Hispanic/Latino population, with a minor allele frequency of 0.26% in the ExAC database (overall frequency, 0.02%); however, no G154R homozygotes had been reported in the ExAC, 1000 Genomes Project, dbSNP (build 134), or NHLBI GO Exome Sequencing Project databases. Patient fibroblasts showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density compared to control, suggesting that disruptions in TANGO2 result in an imbalance in the vesicular pathway. Lalani et al. (2016) also studied an affected 6-year-old girl from a family of Hispanic/European origin, who was compound heterozygous for the G154R mutation and an approximately 34-bp deletion (616830.0002) in the TANGO2 gene.
In 4 affected children from 2 unrelated families (families 7 and 8) of European origin with recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN; 616878), Lalani et al. (2016) identified homozygosity for an approximately 34-kb deletion (SCV000245443) encompassing exon 3 to exon 9 of the TANGO2 gene. In a family of Hispanic/European origin, the proband was compound heterozygous for the exon 3-9 deletion and a missense mutation (G154R; 616830.0001). The unaffected parents in all 3 families were heterozygous carriers of the mutations. The authors stated that the 34-kb deletion had a European-specific minor allele frequency of at least 0.062%, but that no homozygous deletions had been reported in public databases.
In a 25-year-old woman with MECRCN (patient 3), Kremer et al. (2016) identified homozygosity for the 34.6-kb deletion involving exons 3-9 (c.[(56+1_57-1)_(*1_?)del], NM_152906.5) of the TANGO2 gene. Her unaffected parents were heterozygous for the deletion, which the authors noted was found in heterozygosity 7 times in an in-house database of 5,300 exomes (minor allele frequency, 0.13%). In addition, an unrelated 3.25-year-old girl with MECRCN (patient 1) was compound heterozygous for the exon 3-9 deletion and a 1-bp deletion in exon 2 (c.4delT; 616830.0005), causing a frameshift predicted to result in a premature termination codon (Cys2AlafsTer35). Her parents were each heterozygous for 1 of the mutations. The authors stated that the 1-bp deletion was not found in in-house control exomes or in the ExAC database.
In a Hispanic boy (family 6) with recurrent metabolic crises associated with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN; 616878), who was born of consanguineous parents, Lalani et al. (2016) identified homozygosity for a c.605+1G-A transition (SCV000245442) in intron 7 of the TANGO2 gene. His unaffected parents were heterozygous carriers of the mutation. The authors noted that this splice site variant had been reported in the ExAC database with a minor allele frequency of 0.25% in the Latino population (overall frequency, 0.03%), but that no homozygotes had been reported in control databases.
In 2 affected sibs from a consanguineous Saudi Arabian family (family 9) with recurrent metabolic crises associated with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN; 616878), Lalani et al. (2016) identified homozygosity for an approximately 9-kb deletion (SCV000245444) encompassing exon 4 to exon 6 of the TANGO2 gene. The unaffected parents were each heterozygous for the deletion, which was not found in public databases.
For discussion of the 1-bp deletion (c.4delT, NM_152906.5) in exon 2 of the TANGO2 gene, causing a frameshift predicted to result in a premature termination codon (Cys2AlafsTer35), that was found in compound heterozygous state in a patient with recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN; 616878), by Kremer et al. (2016), see 616830.0002.
In a 12.5-year-old girl (patient 2) with recurrent metabolic crises associated with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN; 616878), Kremer et al. (2016) identified homozygosity for a c.418C-T transition (c.418C-T, NM_152906.5) in exon 6 of the TANGO2 gene, resulting in an arg140-to-ter (R140X) substitution. The mutation was present in heterozygosity in her unaffected parents, and was found once in heterozygosity in the ExAC database.
In a 34-month-old Arab patient (family 2) with recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN; 616878), Jennions et al. (2019) identified homozygosity for a 1-bp deletion (c.280delC) in exon 5 of the TANGO2 gene, predicted to result in a frameshift and premature termination (His94ThrfsTer3). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents.
In 2 sibs (family 4) with recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN; 616878), Jennions et al. (2019) identified compound heterozygous mutations in the TANGO2 gene: a c.59T-G transversion in exon 3, resulting in a leu20-to-arg (L20R) substitution, and a c.711-3C-G transversion in intron 8 (616830.0009), predicted to result in a splicing abnormality. The mutations were identified by direct sequencing of the TANGO2 gene and segregated with disease in the family.
For discussion of the c.711-3C-G transversion in intron 8 of the TANGO2 gene, predicted to result in a splicing abnormality, that was found in compound heterozygous state in 2 sibs (family 4) with recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN; 616878) by Jennions et al. (2019), see 616830.0008.
In a patient (P1) with MECRCN, Dines et al. (2019) identified compound heterozygosity for the intron 8 splice site mutation (c.711-3C-G, NM_153906.6) and the recurrent 34-kb deletion (616830.0002) in the TANGO2 gene.
In 2 sibs, born of consanguineous North African parents (family 6), with recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN; 616878), Jennions et al. (2019) identified homozygosity for a c.262C-T transition in the TANGO2 gene, resulting in an arg88-to-ter (R88X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents.
Berat, C. M., Montealegre, S., Wiedemann, A., Nuzum, M. L. C., Blondel, A., Debruge, H., Cano, A., Chabrol, B., Hoebeke, C., Polak, M., Stoupa, A., Feillet, F., and 19 others. Clinical and biological characterization of 20 patients with TANGO2 deficiency indicates novel triggers of metabolic crises and no primary energetic defect. J. Inherit. Metab. Dis. 44: 415-425, 2021. [PubMed: 32929747] [Full Text: https://doi.org/10.1002/jimd.12314]
Dines, J. N., Golden-Grant, K., LaCroix, A., Muir, A. M., Cintron, D. L., McWalter, K., Cho, M. T., Sun, A., Merritt, J. L., Thies, J., Niyazov, D., Burton, B., and 20 others. TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants. Genet. Med. 21: 601-607, 2019. Note: Erratum: Genet. Med. 21: 1899, 2019. [PubMed: 30245509] [Full Text: https://doi.org/10.1038/s41436-018-0137-y]
Heiman, P., Mohsen, A. W., Karunanidhi, A., St Croix, C., Watkins, S., Koppes, E., Haas, R., Vockley, J., Ghaloul-Gonzalez, L. Mitochondrial dysfunction associated with TANGO2 deficiency. Sci. Rep. 12: 3045, 2022. [PubMed: 35197517] [Full Text: https://doi.org/10.1038/s41598-022-07076-9]
Jennions, E., Hedberg-Oldfors, C., Berglund, A. K., Kollberg, G., Tornhage, C. J., Eklund, E. A., Oldfors, A., Verloo, P., Vanlander, A. V., De Meirleir, L., Seneca, S., Sterky, F. H., Darin, N. TANGO2 deficiency as a cause of neurodevelopmental delay with indirect effects on mitochondrial energy metabolism. J. Inherit. Metab. Dis. 42: 898-908, 2019. [PubMed: 31276219] [Full Text: https://doi.org/10.1002/jimd.12149]
Kremer, L. S., Distelmaier, F., Alhaddad, B., Hempel, M., Iuso, A., Kupper, C., Muhlhausen, C., Kovacs-Nagy, R., Satanovskij, R., Graf, E., Berutti, R., Eckstein, G., and 9 others. Bi-allelic truncating mutations in TANGO2 cause infancy-onset recurrent metabolic crises with encephalocardiomyopathy. Am. J. Hum. Genet. 98: 358-362, 2016. [PubMed: 26805782] [Full Text: https://doi.org/10.1016/j.ajhg.2015.12.009]
Lalani, S. R., Liu, P., Rosenfeld, J. A., Watkin, L. B., Chiang, T., Leduc, M. S., Zhu, W., Ding, Y., Pan, S., Vetrini, F., Miyake, C. Y., Shinawi, M., and 40 others. Recurrent muscle weakness with rhabdomyolysis, metabolic crises, and cardiac arrhythmia due to bi-allelic TANGO2 mutations. Am. J. Hum. Genet. 98: 347-357, 2016. [PubMed: 26805781] [Full Text: https://doi.org/10.1016/j.ajhg.2015.12.008]