Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 603701

RIBOSOMAL PROTEIN S26; RPS26

HGNC Approved Gene Symbol: RPS26

Cytogenetic location: 12q13.2 Genomic coordinates (GRCh38) : 12:56,041,918-56,044,697 (from NCBI)

Gene-Phenotype Relationships

TEXT

Description

The eukaryotic ribosome is composed of 4 RNA species (see 180450) and approximately 80 different proteins. The ribosomal protein genes appear to be members of multigene families, most of which contain multiple processed pseudogenes and 1 intron-containing functional gene.

Cloning and Expression

Vincent et al. (1993) isolated a HeLa cell cDNA encoding ribosomal protein S26 (RPS26). Northern blot analysis demonstrated that the 600- to 700-bp RPS26 transcript is expressed at high and comparable levels in various human adult tissues. The deduced RPS26 protein has 115 amino acids (SWISS-PROT Q06722).

Gene Structure

Filipenko et al. (1998) isolated the genomic sequence of the functional RPS26 gene using PCR. The RPS26 gene has 4 exons which span 2,027 bp and result in an mRNA of 438 bp, plus the poly(A) tail. Like other vertebrate ribosomal protein genes, the RPS26 gene has a transcription start site that is located within a polypyrimidine tract, and a short 5-prime untranslated region.

Mapping

By analysis of somatic cell hybrids, Filipenko et al. (1998) mapped the intron-containing RPS26 gene to chromosome 12. Kenmochi et al. (1998) mapped the RPS26 gene to 12q using somatic cell hybrid and radiation hybrid mapping analyses.

Gene Function

Using siRNA knockdown in HeLa cells to analyze the role of RPS26 in pre-rRNA processing, Doherty et al. (2010) found that depletion of RPS26 led to decreased levels of 18S rRNA, indicating that RPS26 is necessary for production of the small subunit. RNA blot analysis showed accumulation of 43S, 26S, and 18S-E pre-rRNAs, consistent with defects in cleavage at both ends of the 18S rRNA.

Molecular Genetics

Doherty et al. (2010) sequenced 35 ribosomal protein genes in a cohort of 117 patients with Diamond-Blackfan anemia (see DBA10, 613309) and identified 9 different mutations in the RPS26 gene in 12 patients (see, e.g., 603701.0001-603701.0005). None of the mutations were found in at least 520 chromosomes from a control population of similar, largely European origin. Six probands had a mutation in the first codon, changing met to leu, val, or arg, suggesting that the translation initiation codon may be a hotspot in RPS26. Doherty et al. (2010) noted that 1 of the mutation-positive patients (603701.0002) had cleft lip and palate, making RPS26 the third DBA gene in which mutation is associated with clefting in DBA.

Landowski et al. (2013) performed array CGH for copy number variation in 87 probands with Diamond-Blackfan anemia who were negative for mutation in 10 known DBA-associated ribosomal protein genes and identified a large deletion encompassing all 4 exons of the RPS26 gene (603701.0006) in a transfusion-dependent female patient.

ALLELIC VARIANTS 8 Selected Examples):

.0001 DIAMOND-BLACKFAN ANEMIA 10

RPS26, MET1VAL
SNP: rs143951267, ClinVar: RCV000006496, RCV002415402, RCV003225019

In 6 patients with Diamond-Blackfan anemia-10 (DBA10; 613309) from 4 families, Doherty et al. (2010) identified heterozygosity for a 1A-G transition in exon 1 of the RPS26 gene, causing a met1-to-val (M1V) substitution that eliminates the start codon and is predicted to result in an untranslated protein. The mutation was not found in the unaffected parents of 2 of the probands or in at least 520 control chromosomes. Of the 6 patients with the M1V mutation, 3 were responsive to initial steroid therapy and 3 were unresponsive; in 1 father-daughter pair, the father was responsive and the daughter was unresponsive. Three of the patients were receiving red blood cell transfusions, 2 were on steroid therapy, and 1 required no therapy. One of the male patients, who was diagnosed at 7 weeks of age, also had duplicated pelvis and calyx of the right kidney.

.0002 DIAMOND-BLACKFAN ANEMIA 10

RPS26, MET1LEU
SNP: rs143951267, ClinVar: RCV000006497, RCV001310994

In a male patient with Diamond-Blackfan anemia-10 (DBA10; 613309), Doherty et al. (2010) identified heterozygosity for a 1A-T transversion in exon 1 of the RPS26 gene, causing a met1-to-leu (M1L) substitution that eliminates the start codon and is predicted to result in an untranslated protein. The mutation was not found in his unaffected parents and sister or in at least 520 control chromosomes. The patient, who was responsive to steroid therapy, also had cleft lip and palate.

.0003 DIAMOND-BLACKFAN ANEMIA 10

RPS26, ASP33ASN
SNP: rs267607023, ClinVar: RCV000006498

In a male patient who was diagnosed at 8 months of age with Diamond-Blackfan anemia (DBA10; 613309), Doherty et al. (2010) identified heterozygosity for a 97G-A transition in exon 2 of the RPS26 gene, resulting in an asp33-to-asn (D33N) substitution. The mutation was not found in his unaffected parents or sister, or in at least 520 control chromosomes. Other features in this patient included inguinal hernia, unilaterally absent vas deferens, abnormal epididymis, and pronounced bony prominence of a cervical spinous process.

.0004 DIAMOND-BLACKFAN ANEMIA 10

RPS26, 1-BP INS, 31G
SNP: rs786200892, ClinVar: RCV000006499

In a female patient with Diamond-Blackfan anemia-10 (DBA10; 613309), Doherty et al. (2010) identified heterozygosity for a 1-bp insertion (31insG) in exon 2 of the RPS26 gene, causing a frameshift and resulting in a termination sequence at codon 25. The mutation was not found in at least 520 control chromosomes. The patient, who had no associated malformations, had been unresponsive to initial steroid therapy and was deceased.

.0005 DIAMOND-BLACKFAN ANEMIA 10

RPS26, IVS1DS, G-A, +1
SNP: rs148622862, ClinVar: RCV000006500

In a male patient with Diamond-Blackfan anemia-10 (DBA10; 613309), Doherty et al. (2010) identified heterozygosity for a splice site mutation (+1G-A) in intron 1 of the RPS26 gene. The de novo mutation was not found in either of his parents or an unaffected sister and brother, or in at least 520 control chromosomes. The patient, who had been unresponsive to initial steroid therapy, was deceased.

.0006 DIAMOND-BLACKFAN ANEMIA 10

RPS26, 20,456-BP DEL
ClinVar: RCV000074477

In a transfusion-dependent female patient with Diamond-Blackfan anemia (DBA10; 613309), Landowski et al. (2013) identified heterozygosity for a 20,456-bp deletion at chr12:54,711,095-54,731,551, encompassing all 4 exons of the RPS26 gene. Validation by mPCR showed that PCR product from all 4 exons was significantly decreased; mPCR in her unaffected parents showed ratios similar to controls, indicating that the mutation arose de novo in the patient.

.0007 DIAMOND-BLACKFAN ANEMIA 10

RPS26, ARG87TER ({dbSNP rs148942765})
SNP: rs148942765, gnomAD: rs148942765, ClinVar: RCV000167574, RCV000191914, RCV002433720

In 3 members of a family (family 2) with Diamond-Blackfan anemia-10 (DBA10; 613309), Gripp et al. (2014) identified a heterozygous c.259C-T transition in the RPS26 gene, resulting in an arg87-to-ter (R87X) substitution. The proband had been reported by Handler et al. (2009). The mutation, which was found by sequencing of candidate ribosomal protein genes, segregated with the disorder in the family. The mutation was found in the dbSNP database (rs148942765) but not in the 1000 Genomes Project or Exome Sequencing Project databases. In addition to DBA, the proband also had mandibulofacial dysostosis, thus expanding the phenotype associated with DBA10. Functional studies of the variant were not performed.

.0008 DIAMOND-BLACKFAN ANEMIA 10

RPS26, IV1AS, A-T, -2
SNP: rs786203998, ClinVar: RCV000167575, RCV000191913

In a girl (patient 3) with Diamond-Blackfan anemia-10 (DBA10; 613309) associated with mandibular dysostosis originally reported by McFarren et al. (2007), Gripp et al. (2014) identified a de novo heterozygous A-to-T transversion (c.4-2A-T) in intron 1 of the RPS26 gene, resulting in the skipping of exon 2, a frameshift, and premature termination. RT-PCR analysis of patient cells confirmed the effect of the mutation.

REFERENCES

1. Doherty, L., Sheen, M. R., Vlachos, A., Choesmel, V., O'Donohue, M.-F., Clinton, C., Schneider, H. E., Sieff, C. A., Newburger, P. E., Ball, S. E., Niewiadomska, E., Matysiak, M., Glader, B., Arceci, R. J., Farrar, J. E., Atsidaftos, E., Lipton, J. M., Gleizes, P.-E., Gazda, H. T.Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. Am. J. Hum. Genet. 86: 222-228, 2010. Note: Erratum: Am. J. Hum. Genet 86: 655-656, 2010. [PubMed: 20116044] [Full Text: https://doi.org/10.1016/j.ajhg.2009.12.015\]
2. Filipenko, M. L., Vinichenko, N. A., Karpova, G. G., Mertvetsov, N. P., Amaldi, F.Isolation, structural analysis and mapping of the functional gene of human ribosomal protein S26. Gene 211: 287-292, 1998. [PubMed: 9602156] [Full Text: https://doi.org/10.1016/s0378-1119(98)00108-5\]
3. Gripp, K. W., Curry, C., Olney, A. H., Sandoval, C., Fisher, J., Chong, J. X.-L., UW Center for Mendelian Genomics, Pilchman, L., Sahraoui, R., Stabley, D. L., Sol-Church, K.Diamond-Blackfan anemia with mandibulofacial dystostosis (sic) is heterogeneous, including the novel DBA genes TSR2 and RPS28. Am. J. Med. Genet. 164A: 2240-2249, 2014. [PubMed: 24942156] [Full Text: https://doi.org/10.1002/ajmg.a.36633\]
4. Handler, M. Z., Alabi, O., Miller, J.Curvilinear mandibular distraction in a patient with mandibulofacial dysostosis associated with Diamond-Blackfan anemia. J. Craniofac. Surg. 20: 1417-1419, 2009. [PubMed: 19816270] [Full Text: https://doi.org/10.1097/SCS.0b013e3181aee34e\]
5. Kenmochi, N., Kawaguchi, T., Rozen, S., Davis, E., Goodman, N., Hudson, T. J., Tanaka, T., Page, D. C.A map of 75 human ribosomal protein genes. Genome Res. 8: 509-523, 1998. [PubMed: 9582194] [Full Text: https://doi.org/10.1101/gr.8.5.509\]
6. Landowski, M., O'Donohue, M.-F., Buros, C., Ghazvinian, R., Montel-Lehry, N., Vlachos, A., Sieff, C. A., Newburger, P. E., Niewiadomska, E., Matysiak, M., Glader, B., Atsidaftos, E., Lipton, J. M., Beggs, A. H., Gleizes, P.-E., Gazda, H. T.Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia. Hum. Genet. 132: 1265-1274, 2013. [PubMed: 23812780] [Full Text: https://doi.org/10.1007/s00439-013-1326-z\]
7. McFarren, A., Jayabose, S., Ozkaynak, M. F., Tugal, O., Sandoval, C.Cleft palate, bilateral external auditory canal atresia, and other midline defects associated with Diamond-Blackfan anemia: case report. J. Pediat. Hemat. Oncol. 29: 338-340, 2007. [PubMed: 17483715] [Full Text: https://doi.org/10.1097/MPH.0b013e31805d8f45\]
8. Vincent, S., Marty, L., Fort, P.S26 ribosomal protein RNA: an invariant control for gene regulation experiments in eukaryotic cells and tissues. Nucleic Acids Res. 21: 1498 only, 1993. [PubMed: 8464749] [Full Text: https://doi.org/10.1093/nar/21.6.1498\]

Contributors:

Cassandra L. Kniffin - updated : 3/23/2015
Marla J. F. O'Neill - updated : 12/2/2013
Marla J. F. O'Neill - updated : 3/18/2010

Creation Date:

Patti M. Sherman : 4/6/1999

Edit History:

carol : 05/16/2017
carol : 05/15/2017
carol : 05/26/2015
alopez : 4/8/2015
alopez : 3/24/2015
mcolton : 3/23/2015
ckniffin : 3/23/2015
carol : 12/2/2013
mcolton : 12/2/2013
alopez : 6/18/2010
alopez : 6/18/2010
wwang : 5/12/2010
wwang : 5/12/2010
carol : 3/18/2010
psherman : 4/20/1999
carol : 4/16/1999