HGNC Approved Gene Symbol: TMX2
Cytogenetic location: 11q12.1 Genomic coordinates (GRCh38): 11:57,712,593-57,740,973 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q12.1 | Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity | 618730 | Autosomal recessive | 3 |
TMX2 is a member of the thioredoxin (TXN; 187700) gene family (Meng et al., 2003). TMX2 encodes an endoplasmic reticulum (ER) protein that functions in posttranslational protein modification and folding. It localizes to ER mitochondria-associated membranes (MAMs), where it is involved with calcium flux and cellular redox homeostasis (summary by Vandervore et al., 2019).
Meng et al. (2003) cloned TMX2 from a human fetal cDNA library. The deduced 372-amino acid protein has a calculated molecular mass of 42.5 kD. Sequence analysis indicated that it has an N-terminal signal peptide, a transmembrane domain, an Myb (189990) DNA-binding domain repeat signature, a thioredoxin consensus sequence, an endoplasmic reticulum (ER) membrane retention signal (KKXX-like motif), and a dileucine motif in the C terminus. Northern blot analysis detected a 1.7-kb transcript in all examined tissues, with highest expression in heart, brain, liver, and kidney.
TMX2 is ubiquitously expressed and encodes 2 isoforms; the longest and most biologically relevant isoform encodes a 296-residue protein that resides in the ER. In human brain, TMX2 is expressed steadily from week 8 throughout fetal brain development and increases during postnatal life (summary by Vandervore et al., 2019).
Meng et al. (2003) determined that the TMX2 gene has 7 exons.
Vandervore et al. (2019) stated that the TMX2 gene has 8 exons.
By genomic sequence analysis, Meng et al. (2003) mapped the TMX2 gene to chromosome 11.
Vandervore et al. (2019) noted that the TMX2 gene maps to chromosome 11q12.1.
In HEK293 cells, Vandervore et al. (2019) found that TMX2 localizes to ER mitochondria-associated membranes (MAMs) and physically interacts with calnexin (CANX; 114217), a calcium-binding protein-folding chaperone in the ER. TMX2 also bound to other key calcium regulators and calcium ion channels, including ATP2A2 (SERCA2; 108740), indicating a role in calcium homeostasis necessary for mitochondrial bioenergetics. Proteomics data indicated that TMX2 interacts with mitochondrial inner and outer membrane complex components, as well as proteins involved in the unfolded protein response (UPR) and ER-associated ubiquitin-proteasome system (UPS). Detailed redox studies showed that TMX2 exists in both reduced and oxidized forms, and that H2O2-mediated oxidation causes polymerization of TMX2, which is partially mediated by disulfide bond formation. Vandervore et al. (2019) noted that H2O2 has also been shown to function as a signaling molecule controlling axonal path finding and neurodevelopment in zebrafish. The findings suggested that TMX2 is a key adaptive regulator of neuronal proliferation, migration, and organization in the developing brain.
In 14 patients from 10 unrelated families with neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS; 618730), Vandervore et al. (2019) identified homozygous or compound heterozygous mutations in the TMX2 gene (see, e.g., 616715.0001-616715.0007). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families from whom parental or sib DNA was available. Mutation types included missense, nonsense, frameshift, and splice site, and the mutations were predicted to result in a loss of function. Detailed in vitro functional studies were performed on fibroblasts derived from 2 unrelated patients (P1 and P2; see 616715.0001-616715.0003). Gene ontology analysis using RNA-seq data of these fibroblasts showed differentially expressed genes involved in posttranslational modifications, postsynaptic membrane function, calcium ion channels, and neuronal growth. These patient cells showed impaired mitochondrial respiratory reserve capacity and lower ability to cope with oxidative stress compared to wildtype, which may have resulted from calcium flux. Patient cells also had higher levels of the TMX2 dimer and higher rates of polymerization compared to controls, suggesting that these mutations induce constitutive TMX2 polymerization, mimicking an increased oxidative state. There was no evidence of activation of the ER-stress or unfolded protein response.
In 8 affected patients from 4 unrelated consanguineous families of Middle Eastern or Central Asian descent (Saudi Arabia, Pakistan, Egypt, Kuwait) with NEDMCMS, Ghosh et al. (2020) identified a homozygous mutation in the TMX2 gene (616715.0003); the variant was the same as one identified by Vandervore et al. (2019). Analysis of patient cells showed that TMX2 mRNA levels were reduced to 15 to 50% of controls, suggesting that the mutation affects splicing or mRNA stability, resulting in nonsense-mediated mRNA decay. Abnormal transcripts were not detected, and additional functional studies were not performed. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Haplotype analysis did not indicate a common founder, suggesting that the mutation arose independently in the families. The mutation was not found in a control database of 2,397 Middle Eastern individuals. Patient cells showed no evidence of abnormal repeat expansion of C9ORF72 (614260), with which TMX2 has been associated.
In a male infant (P1) with neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS; 618730) who died at 2 weeks of age, Vandervore et al. (2019) identified compound heterozygous mutations in the TMX2 gene: a c.164A-C (c.164A-C, NM_015959.3) transversion in exon 1, resulting in an asp55-to-ala (D55A) substitution, and a 1-bp duplication in exon 4 (c.391dup; 616715.0002), resulting in a frameshift and premature termination (Leu131ProfsTer6). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were each found in heterozygous state in the unaffected parents, consistent with segregation. The variants were found at low frequencies in the gnomAD database (less than 0.001%). Analysis of patient cells showed decreased mRNA levels, consistent with nonsense-mediated mRNA decay of the frameshift transcript. Another affected patient (P10, family 7), who died at 1 week of age, was compound heterozygous for D55A and a 15-bp deletion (c.609_614+15del; 616715.0006) affecting exon 6/intron 6 of the TMX2 gene, altering a splice site and resulting in a mutant protein lacking 2 residues (Ser203_Thr204del). The latter variant was found in heterozygous state at a low frequency (0.00081%) in gnomAD. Functional studies of the variants and cells from P10 were not performed.
For discussion of the 1-bp duplication in exon 4 of the TMX2 gene (c.391dup, NM_015959.3), resulting in a frameshift and premature termination (Leu131ProfsTer6), that was found in compound heterozygous state in a patient with neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS; 618730) by Vandervore et al. (2019), see 616715.0001.
In a 7-year-old boy (P2) of Portuguese descent (family 2) with neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS; 618730), Vandervore et al. (2019) identified a homozygous c.614G-A transition (c.614G-A, NM_015959.3) in the last nucleotide of exon 6 of the TMX2 gene. The mutation was predicted to result in an arg205-to-gln (R205Q) substitution, but in silico analysis also predicted that it could alter a splice site, causing the production of the wildtype and 3 abnormal transcripts. RT-PCR analysis of patient cells did not show a significant decrease in mRNA levels compared to controls. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present at low frequencies in the gnomAD (0.004%) and Exome Sequencing Project databases (0.01%), as well as in dbSNP.
In 8 affected patients from 4 unrelated consanguineous families of Middle Eastern or Central Asian descent (Saudi Arabia, Pakistan, Egypt, Kuwait) with NEDMCMS, Ghosh et al. (2020) identified a c.500G-A transition in the last nucleotide of exon 6 of the TMX2 gene, predicted to result in an arg167-to-gln (R167Q) substitution. The variant was the same as that identified by Vandervore et al. (2019). Analysis of patient cells showed that TMX2 mRNA levels were reduced to 15 to 50% of controls, suggesting that the mutation affects splicing or mRNA stability, resulting in nonsense-mediated mRNA decay. Abnormal transcripts were not detected, and additional functional studies were not performed. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Haplotype analysis did not indicate a common founder, suggesting that the mutation arose independently in the families. It was not found in a control database of 2,397 Middle Eastern individuals. Patient cells showed no evidence of abnormal repeat expansion of C9ORF72 (614260), with which TMX2 has been associated.
In a 9-year-old girl (P3, family 3) with neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS; 618730), Vandervore et al. (2019) identified compound heterozygous mutations in the TMX2 gene: a c.157C-T transition (c.157C-T, NM_015959.3) in exon 1, resulting in an arg53-to-cys (R53C) substitution, and a c.757C-T transition in the last exon, resulting in an arg253-to-ter (R253X; 616715.0005) substitution. The R53C and R253X mutations, which were found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, were both present at low frequencies in the dbSNP, Exome Sequencing Project, and gnomAD databases (less than 0.00025 and 0.0004% in gnomAD, respectively), but never in homozygosity. RT-PCR of patient cells showed a 23% decrease in mRNA expression compared to controls, suggesting that the nonsense transcript partially escaped nonsense-mediated decay. Additional functional studies were not performed.
For discussion of the c.757C-T transition (c.757C-T, NM_015959.3) in the last exon of the TMX2 gene, predicted to result in an arg253-to-ter (R253X) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS; 618730) by Vandervore et al. (2019), see 616715.0004.
For discussion of the 15-bp deletion (c.609_614+15del, NM_015959.3) affecting exon 6/intron 6 of the TMX2 gene, altering a splice site and resulting in a mutant protein lacking 2 residues (Ser203_Thr204del), that was found in compound heterozygous state in a patient with neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS; 618730) by Vandervore et al. (2019), see 616715.0001.
In 2 adult sibs (P4 and P5), born of Puerto Rican parents (family 4), with neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS; 618730), Vandervore et al. (2019) identified a homozygous c.166G-C transversion (c.166G-C, NM_015959.3) in exon 1 of the TMX2 gene, resulting in a gly56-to-arg (G56R) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was found at a low frequency in heterozygous state in the gnomAD (0.0058%) and dbSNP databases. Functional studies of the variant and studies of patient cells were not performed.
Ghosh, S. G., Wang, L., Breuss, M. W., Green, J. D., Stanley, V., Yang, X., Ross, D., Traynor, B. J., Alhashem, A., Azam, M., Selim, L., Bastaki, L., Elbastawisy, H. I., Temtamy, S., Zaki, M., Gleeson, J. G. Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with microlissencephaly. J. Med. Genet. 57: 274-282, 2020. [PubMed: 31586943] [Full Text: https://doi.org/10.1136/jmedgenet-2019-106409]
Meng, X., Zhang, C., Chen, J., Peng, S., Cao, Y., Ying, K., Xie, Y., Mao, Y. Cloning and identification of a novel cDNA coding thioredoxin-related transmembrane protein 2. Biochem. Genet. 41: 99-106, 2003. [PubMed: 12670024] [Full Text: https://doi.org/10.1023/a:1022073917044]
Vandervore, L. V., Schot, R., Milanese, C., Smits, D. J., Kasteleijn, E., Fry, A. E., Pilz, D. T., Brock, S., Borklu-Yucel, E., Post, M., Bahi-Buisson, N., Sanchez-Soler, M. J., and 37 others. TMX2 is a crucial regulator of cellular redox state, and its dysfunction causes severe brain developmental abnormalities. Am. J. Hum. Genet. 105: 1126-1147, 2019. [PubMed: 31735293] [Full Text: https://doi.org/10.1016/j.ajhg.2019.10.009]