Alternative titles; symbolsRNA-BINDING MOTIF PROTEIN 35A; RBM35AHGNC Approved Gene Symbol: ESRP1Cytogenetic location: 8q22.1 Genomic coordinates (GRCh38): 8:...
Alternative titles; symbols
HGNC Approved Gene Symbol: ESRP1
Cytogenetic location: 8q22.1 Genomic coordinates (GRCh38): 8:94,640,998-94,707,465 (from NCBI)
ESRP1 is an epithelial cell-type-specific splicing regulator (Warzecha et al., 2009).
▼ Cloning and Expression
Using a cell-based cDNA expression screen with human embryonic kidney 293T cells, Warzecha et al. (2009) identified mouse Esrp1 and Esrp2 (612960) as regulators of FGFR2 (176943) splicing. By database analysis, they identified human ESRP1, which encodes a deduced 681-amino acid protein containing 3 central RNA recognition motifs (RRMs). Comparison of ESRP orthologs in diverse species showed significant sequence conservation within the RRM domains, particularly RRM1. In situ hybridization of neonatal and adult mice revealed distinct epithelial-specific expression of Esrp1 in diverse tissues and organs, with highest expression in skin and gastrointestinal epithelia.
Hartz (2009) mapped the ESRP1 gene to chromosome 8q22.1 based on an alignment of the ESRP1 sequence (GenBank AK00178) with the genomic sequence (GRCh37).
▼ Gene Function
Cell type-specific expression of epithelial and mesenchymal isoforms of FGFR2 is achieved through tight regulation of mutually exclusive exons IIIb and IIIc, respectively. Warzecha et al. (2009) showed that expression of epitope-tagged mouse Esrp1 or Esrp2 in 293T cells induced a substantial switch of endogenous FGFR2 transcripts from the mesenchymal form with exon IIIc to the epithelial form with exon IIIb. Microarray analysis revealed that cell lines classified as epithelial expressed higher levels of ESRP1 and/or ESRP2 than cell lines classified as mesenchymal. Depletion of ESRP1 and ESRP2 in a human prostate epithelial cell line via RNA interference (RNAi) caused a significant switch from exon IIIb to exon IIIc splicing in the endogenous FGFR2 transcript. Rescue experiments with mouse cDNAs showed that FGFR2-IIIb splicing was more dependent on ESRP1 than ESRP2. RNAi experiments revealed that ESRP1 and ESRP2 also regulated splicing of CD44 (107269), CTNND1 (601045), and ENAH (609061), transcripts that undergo changes in splicing during the epithelial-to-mesenchymal transition.
▼ Molecular Genetics
In 2 sibs with profound congenital sensorineural hearing loss (DFNB109; 618013), Rohacek et al. (2017) identified compound heterozygosity for a 19-bp deletion (612959.0001) and a missense mutation (L259V; 612959.0002) in the ESRP1 gene that segregated with disease in their family. Both sibs also showed vestibular abnormalities on CT scan, but neither had a balance or movement disorder. Screening for mutations in ESRP1 and ESRP2 in a cohort of 144 probands with bilateral sensorineural hearing loss revealed rare heterozygous missense substitutions in 3 samples, but no homozygous or compound heterozygous variants were detected.
▼ Animal Model
Rohacek et al. (2017) found that Esrp1 -/- mouse embryos had defects in inner ear morphogenesis, auditory hair cell differentiation, and cell identity along the lateral wall of the cochlear epithelium. RNA sequencing analysis revealed impaired transcription and splicing of genes associated with cochlear development and auditory function in Esrp1 -/- embryos. Aberrant splicing of Fgfr2 from the IIIb (epithelial) to IIIc (mesenchymal) isoforms compromised cell identity along the cochlear lateral wall due to erroneous ligand usage. Furthermore, by observing mouse Esrp1 -/- embryos with heterozygous Fgf9 (600921) knockout, Rohacek et al. (2017) demonstrated that loss of Fgfr2-IIIb due to aberrant splicing was compensated by ectopic Fgf9/Fgfr2-IIIc signaling to promote cochlear duct morphogenesis in Esrp1 mutants.
▼ ALLELIC VARIANTS ( 2 Selected Examples):
.0001 DEAFNESS, AUTOSOMAL RECESSIVE 109 (1 family)
ESRP1, 19-BP DEL, NT665
In an 8-year-old girl and her 14-year-old brother with profound congenital sensorineural hearing loss (DFNB109; 618013), Rohacek et al. (2017) identified compound heterozygosity for mutations in the ESRP1 gene: the first was a paternally inherited 19-bp deletion in exon 7 (c.665_683del), causing a frameshift predicted to result in a premature termination codon prior to the essential RRM domains (Asp222GlyfsTer32), and the second was a maternally inherited c.775C-G transversion in exon 8, resulting in a leu259-to-val (L259V; 612959.0002) substitution. In addition to their unaffected parents, 3 unaffected sibs, including the girl's twin brother, were each heterozygous for 1 of the mutations. Analysis of induced pluripotent stem cell (iPSC) lines derived from lymphoblastoid cells from the affected children and their parents revealed a 50% reduction in ESRP1 transcript and protein in both children and their father compared to their mother. After CRISPR-Cas9 repair of the paternal mutation in proband iPSCs, Sanger sequencing identified the corrected ESRP1 paternal allele in 3 independent clones, in which ESRP1 mRNA and protein levels were significantly increased and were similar to those of the unaffected mother. Analysis of ESRP-dependent splicing events showed significant alterations in the affected children compared to either parent for some genes, and those alterations were restored in the genetically repaired iPSCs from the proband. Analysis of the maternal L259V mutation alone in MDA-MB 231 cells showed significant alterations of splicing events compared to wildtype ESRP1. The authors concluded that the paternal 19-bp deletion results in a nonfunctional allele, whereas the maternal missense mutation is hypomorphic.
.0002 DEAFNESS, AUTOSOMAL RECESSIVE 109 (1 family)
For discussion of the c.775C-G transversion in exon 8 of the ESRP1 gene, resulting in a leu259-to-val (L259V) substitution, that was found in compound heterozygous state in 2 sibs with profound congenital sensorineural hearing loss (DFNB109; 618013) by Rohacek et al. (2017), see 612959.0001.