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THIOREDOXIN-LIKE 4A; TXNL4A

THIOREDOXIN-LIKE 4A; TXNL4A

Alternative titles; symbolsDIM1, S. POMBE, HOMOLOG OF; DIM1U5 snRNP-SPECIFIC PROTEIN, 15-KDU5-15KDHGNC Approved Gene Symbol: TXNL4ACytogenetic location: 18q23 ...

Alternative titles; symbols

  • DIM1, S. POMBE, HOMOLOG OF; DIM1
  • U5 snRNP-SPECIFIC PROTEIN, 15-KD
  • U5-15KD

HGNC Approved Gene Symbol: TXNL4A

Cytogenetic location: 18q23 Genomic coordinates (GRCh38): 18:79,970,812-80,033,935 (from NCBI)

▼ Cloning and Expression

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.

▼ Mapping

Gross (2018) mapped the TXNL4A gene to chromosome 18q23 based on an alignment of the TXNL4A sequence (GenBank AF146373) with the genomic sequence (GRCh38).

▼ Biochemical Features

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.

▼ Gene Function

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.

▼ Molecular Genetics

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.

▼ ALLELIC VARIANTS ( 6 Selected Examples):

.0001 BURN-MCKEOWN SYNDROME
TXNL4A, 34-BP DEL, PROMOTER DELETION 1

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.

.0002 BURN-MCKEOWN SYNDROME
TXNL4A, GLU117TER

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.

.0003 BURN-MCKEOWN SYNDROME
TXNL4A, GLN13TER

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.

.0004 BURN-MCKEOWN SYNDROME
TXNL4A, 1-BP DEL, 131T

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.

.0005 BURN-MCKEOWN SYNDROME
TXNL4A, EX3DEL

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.

.0006 BURN-MCKEOWN SYNDROME
TXNL4A, 34-BP DEL, PROMOTER DELETION 2

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.

Tags: 18q23