HGNC Approved Gene Symbol: RBM20
Cytogenetic location: 10q25.2 Genomic coordinates (GRCh38): 10:110,643,245-110,839,468 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q25.2 | Cardiomyopathy, dilated, 1DD | 613172 | Autosomal dominant | 3 |
By searching for genes in a region of chromosome 10 associated with dilated cardiomyopathy, followed by exon-specific PCR of human genomic DNA, Brauch et al. (2009) obtained full-length RBM20. The deduced protein contains an RNA recognition motif-1 (RRM1), an arginine/serine (RS)-rich domain, and a U1-type zinc finger domain. The combination of RRM1 and RS domain is characteristic of spliceosomal proteins. Expression profiling of human and mouse tissues showed highest RBM20 expression in heart, followed by skeletal muscle. RT-PCR analysis confirmed RBM20 expression in human heart.
Brauch et al. (2009) determined that the RBM20 gene contains 14 coding exons.
Brauch et al. (2009) reported that the RBM20 gene maps to chromosome 10q25.2.
In 2 large multigenerational families with dilated cardiomyopathy (CMD1DD; 613172) mapping to chromosome 10q25-q26, Brauch et al. (2009) analyzed candidate genes and identified 2 different missense mutations in exon 9 of the RBM20 gene (613171.0001 and 613171.0002, respectively). DHPLC analysis of the RBM20 gene in a cohort of 278 CMD patients revealed 6 additional families with mutations in the RBM20 gene (613171.0003-613171.0005). The mutations all clustered in the RS domain in exon 9 of RBM20, cosegregated with disease, and were absent in controls. RBM20 mutations are associated with young age at diagnosis of CMD, end-stage heart failure, and high mortality.
Using DNA from 312 CMD probands, Li et al. (2010) analyzed exons 6 through 9 of the RBM20 gene and identified heterozygous missense mutations in 6 unrelated probands (see, e.g., 613171.0002, 613171.0004, and 613171.0006).
In affected members from 2 large multigenerational families with dilated cardiomyopathy (CMD1DD; 613172), 1 of Norwegian ancestry ('DC-12') and 1 of German ancestry ('DC-50'), Brauch et al. (2009) identified heterozygosity for a 1913C-T transition in exon 9 of the RBM20 gene, resulting in a pro638-to-leu (P638L) substitution at a conserved residue in the RS domain.
In affected members of a large multigenerational family of Scottish ancestry ('DC-35') with dilated cardiomyopathy (CMD1DD; 613172), Brauch et al. (2009) identified heterozygosity for a 1901G-A transition in exon 9 of the RBM20 gene, resulting in an arg634-to-gln (R634Q) substitution at a conserved residue in the RS domain.
In a woman (Pedigree B) who was diagnosed with CMD at age 46 years and was negative for mutation in 14 known CMD-associated genes, Li et al. (2010) identified heterozygosity for a c.1959G-A transition (c.1959G-A, NM_001134363) in exon 9 of the RBM20 gene, resulting in the R634Q substitution. The mutation was not found in the dbSNP database or in DNA from 450 Caucasian controls. The patient died from decompensated heart failure 7 years after diagnosis. Li et al. (2010) noted that the CMD phenotype in the large Scottish family reported by Brauch et al. (2009) was aggressive, with onset at 18 years of age and 7 premature deaths, suggesting that the R634Q mutation is malignant whether present in sporadic or familial CMD.
In affected members of 3 large multigenerational families with dilated cardiomyopathy (CMD1DD; 613172), 2 of Norwegian ancestry ('DC-9' and 'DC-27') and 1 of German ancestry ('DC-46'), Brauch et al. (2009) identified heterozygosity for a 1906C-A transversion in exon 9 of the RBM20 gene, resulting in an arg636-to-ser (R636S) substitution at a conserved residue in the RS domain.
In a brother and sister with dilated cardiomyopathy (CMD1DD; 613172) from a family of German ancestry (kindred 'DC-49'), Brauch et al. (2009) identified heterozygosity for a 1907G-A transition in exon 9 of the RBM20 gene, resulting in an arg636-to-his (R636H) substitution at a conserved residue in the RS domain.
In a mother and 2 children (Pedigree E) with CMD, who were of Caucasian and Native American ancestry and were negative for mutation in 14 known CMD-associated genes, Li et al. (2010) identified heterozygosity for a c.1965G-A transition (c.1965G-A, NM_001134363) in exon 9 of the RBM20 gene, resulting in the R636H substitution. The mutation was not found in the dbSNP database or in DNA from 450 Caucasian controls.
In affected members of a family with dilated cardiomyopathy (CMD1DD; 613172) of English ancestry ('DC-22'), Brauch et al. (2009) identified heterozygosity for a 1909A-G transition in exon 9 of the RBM20 gene, resulting in an ser637-to-gly (S637G) substitution at a conserved residue in the RS domain.
In a mother and son (Pedigree D) with dilated cardiomyopathy (CMD1DD; 613172), who were negative for mutation in 14 known CMD-associated genes, Li et al. (2010) identified heterozygosity for a c.1964C-T transition (c.1964C-T, NM_001134363) in exon 9 of the RBM20 gene, resulting in an arg636-to-cys (R636C) substitution at a highly conserved residue in the RS domain. The mutation was not found in the dbSNP database or in DNA from 450 Caucasian controls. The proband died at 64 years of age while awaiting heart transplantation; her son was diagnosed with CMD at age 23 years and showed interventricular conduction delay and nonspecific ST-T wave changes on electrocardiography. Family history included early death in the proband's sister (age 25) and 2 nieces (ages 14 and 16 years) from arrhythmias and/or complications after heart transplantation.
Brauch, K. M., Karst, M. L., Herron, K. J., de Andrade, M., Pellikka, P. A., Rodeheffer, R. J., Michels, V. V., Olson, T. M. Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. J. Am. Coll. Cardiol. 54: 930-941, 2009. [PubMed: 19712804] [Full Text: https://doi.org/10.1016/j.jacc.2009.05.038]
Li, D., Morales, A., Gonzalez-Quintana, J., Norton, N., Siegfried, J. D., Hofmeyer, M., Hershberger, R. E. Identification of novel mutations in RBM20 in patients with dilated cardiomyopathy. Clin. Transl. Sci. 3: 90-97, 2010. [PubMed: 20590677] [Full Text: https://doi.org/10.1111/j.1752-8062.2010.00198.x]