Alt. symbols:

Approved name: debranching RNA lariats 1
Alt. names: debranching enzyme (S. Cerevisiae) homolog 1, debranching enzyme homolog 1 (S. cerevisiae)

Location: 3q22.3: 138160988 - 138174949 (-)
Gene type: protein_coding, 10 transcripts.

Scores: LoFtool: 0.633000 | pLI: 0.00008705 | LOEUF: 1.016

HGNC: 15594

NCBI: 51163, RefSeq: .0

Ensembl: ENSG00000138231.14

LRG_ | Status: none

OMIM: 607024

Expression | ProteinAtlas

DBR1 encodes an RNA lariat debranching enzyme with a role in pre-mRNA processing. It hydrolyzes 2'-5' prime branched phosphodiester bonds at the branchpoint of excised lariat intron RNA, converting them to linear molecules that are then degraded, thus facilitating ribonucleotide turnover.

Zhang et al. (2018) first identified bi-allelic hypomorphic DBR1 mutations in unrelated patients from different ethnicities, each of whom had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus (PMID: 29474921). The authors showed that all of the mutations led to significantly impaired DBR1 expression and function. DBR1 patient fibroblasts were highly susceptible to HSV-1 and accumulated RNA lariats, further enhanced by HSV-1 infection. Shamseldin et al. ( 2023) identified the same homozygous mutation in 4 patients with prematurity, IUGR, a congenital ichthyosis-like presentation (collodion membrane, skin peeling, xerosis), and death before age 1. Patient fibroblasts also showed DBR1 LOF and RNA lariat accumulation (PMID: 37656279). Chan et al. (2024) identified a homozygous, previously reported mutation (I120T) in a 14yo boy with isolated SARS-CoV-2 brainstem encephalitis (PMID: 39023559). They found similarly low levels of DBR1 protein and high levels of RNA lariats in fibroblasts from this and an unrelated patient, whilst iPSC-derived hindbrain neurons were highly susceptible to SARS-CoV-2 infection. Of note, expression of exogenous RNA lariats also increased the susceptibility of WT hindbrain neurons to SARS-CoV-2 infection, while exogenous WT DBR1 expression in patient fibroblasts and hindbrain neurons rescued the RNA lariat accumulation phenotype. Daxing Gao presented data showing that RNA lariat accumulation in human DBR1-deficient cells interfered with stress granule (SG) assembly by promoting proteasomal degradation of key SG components (G3BP1 and G3BP2), leading to impaired PKR recruitment, activation and activity against viruses. PKR ablation also abolished DBR1-dependent antiviral effects in vitro. Finally, Dbr1Y17H/Y17H mice were susceptible to similar viral infections in vivo and showed decreased G3BP1/2 expression and PKR phosphorylation in their cells. [Publication pending, presented at ESID 2024] [Load More]