Alternative titles; symbols
HGNC Approved Gene Symbol: RERE
Cytogenetic location: 1p36.23 Genomic coordinates (GRCh38) : 1:8,352,404-8,817,640 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.23 | Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart | 616975 | Autosomal dominant | 3 |
The RERE gene encodes a nuclear receptor coregulator that positively regulates retinoic acid signaling (summary by Fregeau et al., 2016).
Yanagisawa et al. (2000) isolated the RERE gene as one sharing the arginine-glutamic acid (RE) dipeptide repeat motif also present in the DRPLA gene (607462), in which expansion of CAG/glutamine repeats cause dentatorubral-pallidoluysian atrophy (DRPLA; 125370). The RERE gene has an open reading frame of 1,566 amino acids, of which the C-terminal portion has 67% homology to DRPLA, whereas the N-terminal portion is distinctive. RERE also contains arginine-aspartic acid (RD) dipeptide repeats and putative nuclear localization signal sequences, but no polyglutamine tracts. Northern blot analysis detected 2 RERE transcripts: one of 9 kb, expressed exclusively in pancreas and testis; and one of 7 kb, expressed most strongly in skeletal muscle with weaker expression in other tissues tested, including brain. The RERE protein migrated at an apparent molecular weight of 212 kD in SDS-PAGE. An RERE fusion protein localized predominantly in the nucleus. Immunoprecipitation and in vitro binding assays demonstrated that the DRPLA and RERE proteins bind each other, which is facilitated by one of the RE repeats, and that extension of the DRPLA polyglutamine tract enhances the binding. Moreover, when RERE is overexpressed, the distribution of endogenous DRPLA protein alters from a diffuse to a speckled pattern in the nucleus so as to colocalize with RERE. More RERE protein is recruited into nuclear aggregates of the DRPLA protein with extended polyglutamine than into those of pure polyglutamine. The authors suggested a function for the DRPLA protein in the nucleus and the RE repeat in the protein-protein interaction.
Vilhais-Neto et al. (2010) showed that a mutation in Rere leads to the formation of symmetrical somites in mouse embryos, similar to embryos deprived of retinoic acid. Furthermore, Vilhais-Neto et al. (2010) also demonstrated that Rere controls retinoic acid signaling, which is required to maintain somite symmetry by interacting with Fgf8 (600483) in a left-right signaling pathway. Rere forms a complex with Nr2f2 (107773), p300 (602700), and a retinoic acid receptor, which is recruited to the retinoic acid regulatory element of retinoic acid targets, such as the Rarb (180220) promoter. Furthermore, the knockdown of Nr2f2 and/or Rere decreases retinoic acid signaling, suggesting that this complex is required to promote transcriptional activation of retinoic acid targets. The symmetrical expression of Nr2f2 in the presomitic mesoderm overlaps with the symmetry of the retinoic acid signaling response, supporting its implication in the control of somitic symmetry. Vilhais-Neto et al. (2010) suggested that misregulation of this mechanism could be involved in symmetry defects of the human spine, such as those observed in patients with scoliosis.
By study of a YAC spanning a translocation/duplication breakpoint within the minimally defined loss of heterozygosity region at 1p36.2-p36.1 in a neuroblastoma cell line, Amler et al. (2000) identified the RERE gene, which they designated DNB1/ARP (deleted in neuroblastoma-1/atrophin-related protein).
Fregeau et al. (2016) reported 10 unrelated patients with neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH; 616975) who carried a heterozygous mutation in the RERE gene (see, e.g., 605226.0001-605226.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, occurred de novo in all cases in which parental DNA was available. The mutations clustered throughout the gene and included both missense and truncating mutations; functional studies of the variants and studies of patient cells were not performed. However, Fregeau et al. (2016) noted that mice with Rere mutations showed a similar phenotype (see ANIMAL MODEL). The phenotype was reminiscent of that observed in patients with 1p36 deletion syndrome (607872); RERE is located in the proximal 1p36 critical region.
Of 9 unrelated patients with NEDBEH, Jordan et al. (2018) identified heterozygous mutations in the RERE gene (see, e.g., 605226.0005-605226.0006) in 8 and a heterozygous, approximately 317-kb deletion that included exons 1-10 of the RERE gene in 1. The sequence variants, which were found by exome sequencing and confirmed by Sanger sequencing, included missense mutations and 2 small duplications. Parental studies were done in all but the patient with the large deletion, and all of the variants occurred de novo.
Jordan et al. (2018) reviewed all 19 patients reported with NEDBEH and found that 6 (31%) carried putative loss-of-function variants (partial deletions, nonsense variants and frameshift variants) and 12 (63%) had point mutations in the atrophin-1 domain. A high proportion of the RERE pathogenic variants involved a 21-amino acid histidine-rich region of the atrophin-1 domain (amino acids 1425-1445). The authors noted a genotype/phenotype correlation, with patients with point mutations in the atrophin-1 domain having a more severe presentation than that seen in patients with putative loss-of-function variants.
Kim et al. (2013) noted that mice homozygous for a null Rere allele died between E9.5 and E11.5 from failure of cardiac looping and subsequent cardiac failure. These embryos also had defects in somitogenesis, fusion of the telencephalic vesicles, defects of the optic vesicles and failure of anterior neural tube closure, and were given the name 'openmind' (om). Studies of these mice indicated that loss of Rere interfered with retinoic acid signaling and embryonic development. Kim et al. (2013) generated an allelic series of Rere-deficient mice using the 'om' allele and a hypomorphic Rere allele, termed 'eyes3' because it resulted in autosomal recessive microphthalmia. Mice compound heterozygous for both mutations had a high level of perinatal mortality, postnatal growth deficiency, brain hypoplasia, decreased numbers of hippocampal neurons, hearing loss, cardiovascular malformations, spontaneous development of cardiac fibrosis in adulthood, and renal agenesis. These findings suggested that Rere plays a critical role in the development and function of multiple organs including the eye, brain, inner ear, heart, and kidney. Kim et al. (2013) suggested that haploinsufficiency of RERE may contribute to the development of many of the phenotypes seen in human patients with 1p36 deletions. In a follow-up report, Fregeau et al. (2016) observed that om/eye3 compound heterozygous mice also had ventriculomegaly and incomplete closure of the optic fissure, suggestive of coloboma.
Kim and Scott (2014) specifically examined cerebellar development in the compound heterozygous Rere hypomorphic mice originally studied by Kim et al. (2013). Mutant mice showed pre- and postnatal delayed development of the principal fissures in the cerebellum, which was associated with decreased proliferative activity of granule cell precursors and delayed maturation and migration of Purkinje cells. These abnormalities were associated with a decrease in the expression of SHH (600725), which is secreted from Purkinje cells and is required for normal proliferation.
In a 3-year-old boy (patient 1) of European descent with neurodevelopmental disorder with anomalies of the brain, eye, and heart (NEDBEH; 616975), Fregeau et al. (2016) identified a de novo heterozygous c.3466G-A (c.3466G-A, NM_012102.3) transition in the RERE gene, resulting in a gly1156-to-arg (G1156R) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database, but was found at a low frequency in the ExAC database (2 of 66,082 European alleles). Functional studies of the variant and studies of patient cells were not performed.
In a 2-year-old Hispanic boy (patient 3) with neurodevelopmental disorder with anomalies of the brain, eye, and heart (NEDBEH; 616975), Fregeau et al. (2016) identified a de novo heterozygous c.3785C-G transversion (c.3785C-G, NM_012102.3) transition in the RERE gene, resulting in a pro1262-to-arg (P1262R) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server or ExAC databases. Functional studies of the variant and studies of patient cells were not performed.
In a 12-year-old Dutch boy (patient 5) with neurodevelopmental disorder with anomalies of the brain and eye (NEBDEH; 616975), previously reported by Bosch et al. (2016) as patient 22, Fregeau et al. (2016) identified a de novo heterozygous c.4293C-A transversion (c.4293C-A, NM_012102.3) in the RERE gene, resulting in a his1431-to-gln (H1431Q) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server or ExAC databases. Functional studies of the variant and studies of patient cells were not performed.
In a 7-year-old Dutch boy (patient 9) with neurodevelopmental disorder with anomalies of the brain and heart (NEBDEH; 616975), Fregeau et al. (2016) identified a de novo heterozygous 22-bp duplication (c.2249_2270dup, NM_012102.3) in the RERE gene, resulting in a frameshift and premature termination (Thr758SerfsTer36). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server or ExAC databases. Functional studies of the variant and studies of patient cells were not performed.
In a 22-year-old woman (S5) of Japanese and European ancestry with neurodevelopmental disorder with anomalies of the brain and heart (NEDBEH; 616975), Jordan et al. (2018) identified heterozygosity for a de novo c.4304A-G transition (c.4304A-G, NM_012102.3) in the RERE gene, resulting in a his1435-to-arg (H1435R) substitution. The variant was not present in the ExAC or gnomAD databases. No functional studies were reported.
In 2 unrelated patients, an 8-year-old girl (S7) and a boy (S8) who died at 33 days of age, Jordan et al. (2018) identified a de novo heterozygous 6-bp duplication (c.4313_4318dupTCCACC, NM_012102.3) in the RERE gene, resulting in duplication of 2 amino acids (Leu1438_His1439dup). The duplication occurs in the atrophin-1 domain of RERE and affects a highly conserved histidine-rich region. The variant was not present in the ExAC or gnomAD databases. No functional studies were reported. Features in the female patient included truncus arteriosus, choanal atresia, chorioretinal and iris coloboma, and progressive sensorineural hearing loss. A temporal bone CT scan showed bilateral cochlear dysplasia. She also has developmental delay, intellectual disability, growth delay, and dysmorphic features. The male patient had dysmorphic features, choanal atresia, atrial septal defect, ventricular septal defect, and a mildly dilated right ventricle. Head ultrasound showed diffuse white matter changes, and brain MRI showed a simplified gyral pattern with unusually large ventricles. The features in these patients fulfilled the diagnostic criteria for CHARGE syndrome (214800), but neither patient had a pathogenic variant in the CHD7 gene (608892). Jordan et al. (2018) noted that the same 6-bp duplication had been reported in a patient with NEDBEH by Fregeau et al. (2016); this patient also met diagnostic criteria for CHARGE syndrome.
Amler, L. C., Bauer, A., Corvi, R., Dihlmann, S., Praml, C., Cavenee, W. K., Schwab, M., Hampton, G. M. Identification and characterization of novel genes located at the t(1;15)(p36.2;q24) translocation breakpoint in the neuroblastoma cell line NGP. Genomics 64: 195-202, 2000. [PubMed: 10729226] [Full Text: https://doi.org/10.1006/geno.1999.6097]
Bosch, D. G. M., Boonstra, F. N., de Leeuw, N., Pfundt, R., Nillesen, W. M., de Ligt, J., Gilissen, C., Jhangiani, S., Lupski, J. R., Cremers, F. P. M., de Vries, B. B. A. Novel genetic causes for cerebral visual impairment. Europ. J. Hum. Genet. 24: 660-665, 2016. [PubMed: 26350515] [Full Text: https://doi.org/10.1038/ejhg.2015.186]
Fregeau, B., Kim, B. J., Hernandez-Garcia, A., Jordan, V. K., Cho, M. T., Schnur, R. E., Monaghan, K. G., Juusola, J., Rosenfeld, J. A., Bhoj, E., Zackai, E. H., Sacharow, S., and 14 others. De novo mutations of RERE cause a genetic syndrome with features that overlap those associated with proximal 1p36 deletions. Am. J. Hum. Genet. 98: 963-970, 2016. [PubMed: 27087320] [Full Text: https://doi.org/10.1016/j.ajhg.2016.03.002]
Jordan, V. K., Fregeau, B., Ge, X., Giordano, J., Wapner, R. J., Balci, T. B., Carter, M. T., Bernat, J. A., Moccia, A. N., Srivastava, A., Martin, D. M., Bielas, S. L., and 19 others. Genotype-phenotype correlations in individuals with pathogenic RERE variants. Hum. Mutat. 39: 666-675, 2018. [PubMed: 29330883] [Full Text: https://doi.org/10.1002/humu.23400]
Kim, B. J., Scott, D. A. Mouse model reveals the role of RERE in cerebellar foliation and the migration and maturation of Purkinje cells. PLoS One 9: e87518, 2014. Note: Electronic Article. [PubMed: 24466353] [Full Text: https://doi.org/10.1371/journal.pone.0087518]
Kim, B. J., Zaveri, H. P., Shchelochkov, O. A., Yu, Z., Hernandez-Garcia, A., Seymour, M. L., Oghalai, J. S., Pereira, F. A., Stockton, D. W., Justice, M. J., Lee, B., Scott, D. A. An allelic series of mice reveals a role for RERE in the development of multiple organs affected in chromosome 1p36 deletions. PLoS One 8: e57460, 2013. Note: Electronic Article. [PubMed: 23451234] [Full Text: https://doi.org/10.1371/journal.pone.0057460]
Vilhais-Neto, G. C., Maruhashi, M., Smith, K. T., Vasseur-Cognet, M., Peterson, A. S., Workman, J. L., Pourquie, O. Rere controls retinoic acid signalling and somite bilateral symmetry. Nature 463: 953-957, 2010. [PubMed: 20164929] [Full Text: https://doi.org/10.1038/nature08763]
Yanagisawa, H., Bundo, M., Miyashita, T., Okamura-Oho, Y., Tadokoro, K., Tokunaga, K., Yamada, M. Protein binding of a DRPLA family through arginine-glutamic acid dipeptide repeats is enhanced by extended polyglutamine. Hum. Molec. Genet. 9: 1433-1442, 2000. [PubMed: 10814707] [Full Text: https://doi.org/10.1093/hmg/9.9.1433]