Alternative titles; symbols
HGNC Approved Gene Symbol: TXNL4A
SNOMEDCT: 720640005;
Cytogenetic location: 18q23 Genomic coordinates (GRCh38) : 18:79,970,813-80,033,936 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q23 | Burn-McKeown syndrome | 608572 | Autosomal recessive | 3 |
By SDS-PAGE of human 20S U5 snRNP, followed by EST database analysis, and PCR of a HeLa cell cDNA library, Reuter et al. (1999) cloned TXNL4A, which they called U5-15KD. The deduced protein contained 142 amino acids and contains a thioredoxin-like domain. TXNL4A shares 66% sequence identity with the S. cerevisiae homolog Dib1.
Wood et al. (2022) determined that the TXNL4A promoter region consists of two 22-bp repeated motifs (RR1 and RR2) separated by a 12-bp spacer. They identified potential binding sites for 4 transcription factors, XBP1 (194355), c-JUN (see 165160), AHR/ARNT (see 600253), and ATF3 (603148). Dual luciferase assays demonstrated that RR1 and RR2 contain the critical nucleotides necessary for TXNL4A promoter activity and that RR1 and RR2 act independently and cumulatively to promote TXNL4A expression.
Wood et al. (2022) determined that the TXNL4A gene contains 3 exons.
Gross (2018) mapped the TXNL4A gene to chromosome 18q23 based on an alignment of the TXNL4A sequence (GenBank AF146373) with the genomic sequence (GRCh38).
Crystal Structure
Reuter et al. (1999) analyzed the crystal structure of U5-15KD at 1.4-angstrom resolution and determined that it has a thioredoxin (TXN; 187700)-like fold with a 4-stranded beta-sheet composed of pairs of parallel and antiparallel strands flanked by 3 alpha-helices. Compared to human thioredoxin, U5-15KD contains an additional 37 amino acid residues.
Zhang et al. (1999) used protein-threading search algorithms and multidimensional NMR methods and also determined that the human DIM1 protein adopts a thioredoxin fold.
By genetic depletion of Dib1 in S. cerevisiae, Reuter et al. (1999) showed that Dib1 is strictly required for pre-mRNA splicing in vivo.
In E. coli overexpressing DIM1, Zhang et al. (1999) identified a cleaved form of human DIM1 (residues 1-128) truncated immediately after the predicted thioredoxin homology region. They showed that cleaved DIM1 induced lethality in a dominant-negative manner when expressed in S. pombe. By using conditional mutant S. pombe strains, they showed that cleaved DIM1 induced cell cycle arrest at G2 phase. Zhang et al. (1999) suggested that the short 14-amino acid C-terminal tail of DIM1 is an essential sequence.
Jin et al. (2006) expressed tagged DIM1 in E. coli and performed enzyme cleavage assays on the purified proteins. They found that DIM1 has peptidase activity and undergoes autocleavage. Protease inhibitors EDTA, chymostatin, and 6-aminohexanoic acid inhibited DIM1 cleavage, and the cleaved dominant-negative form of DIM1 retained the autocleavage activity of the full-length protein.
In 9 of 11 families with Burn-McKeown syndrome (BMKS; 608572), Wieczorek et al. (2014) identified biallelic mutations in the TXNL4A gene. Affected members in 8 families were compound heterozygous for a 34-bp deletion in the TXNL4A promoter (designated 'type 1;' 611595.0001) and a truncating point mutation (611595.0002-611595.0004) or another deletion (see, e.g., 611595.0005). In the ninth family, affected individuals were homozygous for an overlapping but different 34-bp TXNL4A promoter deletion (designated 'type 2;' 611595.0006). Functional analysis revealed that both promoter deletions result in reduced expression of TXNL4A; haplotype analysis was consistent with the promoter deletions occurring due to recurrent events rather than a founder effect.
Using whole-genome sequencing, Wood et al. (2022) identified compound heterozygous mutations in the TXNL4A gene in 2 patients with BMKS. Both patients carried the type 1 34-bp deletion in the promoter on one allele; on the other allele, one patient had a 2-bp deletion (c.93_94delCC; 611595.0007) and the other patient had a splice site mutation (c.258-3C-G; 611595.0008). A minigene splicing assay showed that the c.258-3C-G mutation and a previously described mutation in an adjacent nucleotide in a patient with BKMS (c.258-2A-G) caused skipping of the final exon of TXNL4A.
In affected individuals from 8 families with Burn-McKeown syndrome (BMKS; 608572), including patients from 2 families originally reported by Burn et al. (1992) and the 2 German brothers reported by Wieczorek et al. (2003), Wieczorek et al. (2014) identified compound heterozygosity for a 34-bp deletion in the promoter of the TXNL4A gene (chr18:77,748,581-77,748,614del, GRCh37) and a truncating point mutation (611595.0002-611595.0004) or deletion involving TXNL4A (see, e.g., 611595.0005). In each family, the promoter deletion was present in heterozygosity in an unaffected parent. The promoter deletion was not found in the 1000 Genomes Project database; however, analysis of 3,165 population-based samples of German origin and 178 of South Asian origin revealed 45 heterozygous type 1 deletions and 1 homozygous type 1 deletion, for a German allele frequency of 0.76%. Haplotype analysis revealed that the promoter deletions were located on different haplotypes and thus most likely occurred due to recurrent events rather than a founder effect. In the family corresponding to cases 1 and 2 of Burn et al. (1992), the second mutation was a 1.235-Mb terminal deletion (del(18)(q23-qter): 76,841,645-78,077,248, GRCh37); an unrelated affected Vietnamese girl carried an almost identical 1.222-Mb deletion as her second mutation (del(18)(q23-qter): 76,854,774-78,077,248, GRCh37). In the female patient who was case 5 of Burn et al. (1992), the second mutation was a de novo 4.701-Mb terminal deletion on a ring chromosome 18 (46,XX,r(18)(p14q23)arr18q23: 73,376,178-78,077,248, GRCh37). Functional analysis in transfected HEK293 cells demonstrated that the wildtype promoter region enhanced luciferase expression 85-fold compared to control, whereas enhancer activity of the type 1 deletion was reduced by 59% compared to wildtype. Primer extension analysis provided further evidence that the deletion in the promoter region negatively affects transcription, since steady-state transcript levels of the allele carrying wildtype open reading frame (ORF) and the type 1 promoter deletion were reduced compared to transcript levels of the allele with mutant ORF and wildtype promoter.
Wood et al. (2022) identified putative binding sites for 4 transcription factors (XBP1, 194355; c-JUN, see 165160; AHR/ARNT, see 600253; and ATF3, 603148) within a repeat of a 22-bp motif (RR2) in the 34-bp type 1 deletion region. Deletion of RR2 reduced promoter activity to 45% of wildtype, the same as deletion of the full 34-bp type 1 region.
In 2 German brothers with Burn-McKeown syndrome (BMKS; 608572), originally reported by Wieczorek et al. (2003), Wieczorek et al. (2014) identified compound heterozygous mutations in the TXNL4A gene: a 34-bp deletion in the promoter (611595.0001), and a c.349G-T transversion in exon 3, resulting in a glu117-to-ter (E117X) substitution. The nonsense mutation, which was present in heterozygosity in healthy family members, was not found in the 1000 Genomes Project or dbSNP databases or in 3,000 in-house control exomes from individuals with unrelated diseases.
In a 34-year-old Swiss man with Burn-McKeown syndrome (BMKS; 608572), who had bilateral choanal atresia and cleft lip/palate but no reported internal malformations, Wieczorek et al. (2014) identified compound heterozygous mutations in the TXNL4A gene: a 34-bp deletion in the promoter (611595.0001), and a c.37C-T transition in exon 1, resulting in a gln13-to-ter (Q13X) substitution. The nonsense mutation, which was present in heterozygosity in healthy family members, was not found in the 1000 Genomes Project or dbSNP databases or in 3,000 in-house control exomes from individuals with unrelated diseases.
In a Pakistani girl with Burn-McKeown syndrome (BMKS; 608572), who had lower eyelid defects, membranous choanal atresia, cardiac defects, and significant hearing loss with reduced or absent cochlear nerves, Wieczorek et al. (2014) identified compound heterozygous mutations in the TXNL4A gene: a 34-bp deletion in the promoter (611595.0001), and a 1-bp deletion (c.131delT) in exon 1, resulting in a frameshift and a premature termination codon (Val44AlafsTer48). The 1-bp deletion, which was present in heterozygosity in healthy family members, was not found in the 1000 Genomes Project or dbSNP databases or in 3,000 in-house control exomes from individuals with unrelated diseases.
In a 3.75-year-old French boy with Burn-McKeown syndrome (BMKS; 608572), who had lower eyelid defects, bilateral choanal atresia, and unilateral cleft lip but no reported internal malformations, Wieczorek et al. (2014) identified compound heterozygous mutations in the TXNL4A gene: a 34-bp deletion in the promoter (611595.0001) and deletion of exon 3.
In affected members of a large Native Alaskan pedigree with Burn-McKeown syndrome (BMKS; 608572), originally reported by Hing et al. (2006), Wieczorek et al. (2014) identified homozygosity for a 34-bp deletion in the promoter of the TXNL4A gene, comprising the proximal 33 bp of the 56-bp region, plus the preceding nucleotide (chr18:77,748,604-77,748,637del, GRCh37). This 34-bp 'type 2' promoter deletion overlapped but was different from the 34-bp 'type 1' promoter deletion (611595.0001). The mutation segregated with disease in the family; all heterozygous carriers appeared healthy. The type 2 promoter deletion was not found in the 1000 Genomes Project database; however, analysis of 3,165 population-based samples of German origin and 178 of South Asian origin revealed 1 heterozygous type 2 deletion. Functional analysis in transfected HEK293 cells demonstrated that the wildtype promoter region enhanced luciferase expression 85-fold compared to control, whereas enhancer activity of the type 2 deletion was reduced by 72% compared to wildtype.
Wood et al. (2022) identified 1 copy of a repeated 22-bp motif (RR1) in the 34-bp type 2 deletion region of the TXNL4A promoter. Deletion of RR1 reduced promoter activity to 54% of wildtype.
By whole-genome sequencing in a woman (family 1) with Burn-McKeown syndrome (BMKS; 608572), Wood et al. (2022) identified compound heterozygous mutations in the TXNL4A gene: a type 1 34-bp deletion in the promoter (611595.0001) and a 2-bp deletion (c.93_94delCC, NM_006701) resulting in a frameshift and premature termination (His32ArgfsTer21). The frameshift variant was not present in gnomAD. The type 1 deletion was inherited from the mother and the 2-bp deletion from the father. The father, who had some mild features of BMKS, including possible choanal atresia and a flat malar region, had died of esophageal carcinoma, precluding further studies.
By whole-exome sequencing in a boy (family 2) with Burn-McKeown syndrome (BMKS; 608572), Wood et al. (2022) identified compound heterozygous mutations in the TXNL4A gene: a 34-bp deletion in the promoter (611595.0001) and an acceptor splice site mutation (c.258-3C-G, NM_006701). The splice site mutation was not present in gnomAD. A minigene splicing assay showed that the c.258-3C-G variant and a previously described mutation affecting the adjacent nucleotide (c.258-2A-G) in a patient with BMKS caused skipping of the third and final exon of TXNL4A. The splice acceptor variant was maternally inherited and the type 1 34-bp deletion was paternally inherited. Both parents were unaffected.
Burn, J., McKeown, C., Wagget, J., Bray, R., Goodship, J. New dysmorphic syndrome with choanal atresia in siblings. Clin. Dysmorph. 1: 137-144, 1992. [PubMed: 1342861]
Gross, M. B. Personal Communication. Baltimore, Md. 4/6/2018.
Hing, A. V., LeBlond, C., Sze, R. W., Starr, J. R., Monks, S., Parisi, M. A. A novel oculo-oto-facial dysplasia in a native Alaskan community with autosomal recessive inheritance. Am. J. Med. Genet. 140A: 804-812, 2006. [PubMed: 16523509] [Full Text: https://doi.org/10.1002/ajmg.a.31160]
Jin, T., Guo, F., Wang, Y., Zhang, Y.-Z. Identification of human dim1 as a peptidase with autocleavage activity. Chem. Biol. Drug. Des. 68: 266-272, 2006. [PubMed: 17177886] [Full Text: https://doi.org/10.1111/j.1747-0285.2006.00447.x]
Reuter, K., Nottrott, S., Fabrizio, P., Luhrmann, R., Ficner, R. Identification, characterization and crystal structure analysis of the human spliceosomal U5 snRNP-specific 15 kD protein. J. Molec. Biol. 294: 515-525, 1999. [PubMed: 10610776] [Full Text: https://doi.org/10.1006/jmbi.1999.3258]
Wieczorek, D., Newman, W. G., Wieland, T., Berulava, T., Kaffe, M., Falkenstein, D., Beetz, C., Graf, E., Schwarzmayr, T., Douzgou, S., Clayton-Smith, J., Daly, S. B., and 30 others. Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome. Am. J. Hum. Genet. 95: 698-707, 2014. [PubMed: 25434003] [Full Text: https://doi.org/10.1016/j.ajhg.2014.10.014]
Wieczorek, D., Teber, O. A., Lohmann, D., Gillessen-Kaesbach, G. Two brothers with Burn-McKeown syndrome. Clin. Dysmorph. 12: 171-174, 2003. [PubMed: 14564154] [Full Text: https://doi.org/10.1097/01.mcd.0000072163.33788.c4]
Wood, K. A., Ellingford, J. M., Thomas, H. B., Genomics UK Research Consortium, Douzgou, S., Beaman, G. M., Hobson, E., Prescott, K., O'Keefe, R. T., Newman, W. G. Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome. Clin. Genet. 101: 255-259, 2022. [PubMed: 34713892] [Full Text: https://doi.org/10.1111/cge.14082]
Zhang, Y.-Z., Gould, K. L., Dunbrack, R. L., Jr., Cheng, H., Roder, H., Golemis, E. A. The evolutionarily conserved Dim1 protein defines a novel branch of the thioredoxin fold superfamily. Physiol. Genomics 1: 109-118, 1999. [PubMed: 11015569] [Full Text: https://doi.org/10.1152/physiolgenomics.1999.1.3.109]