* 603474

RIBOSOMAL PROTEIN S19; RPS19


HGNC Approved Gene Symbol: RPS19

Cytogenetic location: 19q13.2     Genomic coordinates (GRCh38): 19:41,860,255-41,872,925 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
19q13.2 Diamond-Blackfan anemia 1 105650 AD 3

TEXT

Description

The mammalian ribosome is composed of 4 RNA species (see 180450) and approximately 80 different proteins, including RPS19. The RPS19 protein is a component of the 40S ribosomal subunit (Gregory et al., 2007).


Cloning and Expression

Kondoh et al. (1992) cloned a cDNA encoding ribosomal protein S19 from a colon tumor-enriched subtraction cDNA library. Northern blot analysis showed that the 0.6-kb RPS19 mRNA was expressed at higher levels in 6 of 7 primary colon carcinomas than in matched normal colon tissues. The deduced human and rat RPS19 proteins differ by 1 amino acid.

By Northern blot analysis, Draptchinskaia et al. (1999) found that the RPS19 gene is expressed in several human adult tissues including bone marrow, peripheral blood, spleen, and liver, as well as nonhematopoietic tissues. Ribosomal protein S19 consists of 145 amino acids with a predicted molecular mass of 16 kD and an isoelectric point of 10.3. The protein lacks cysteine residues and the hydropathy profile predicts the presence of hydrophobic domains.


Gene Function

Using wildtype and mutant RPS19 cDNA, Da Costa et al. (2003) explored the subcellular distribution of normal and mutant proteins in a fibroblast cell line (COS-7 cells). RPS19 was detected primarily in the nucleus, and more specifically in the nucleoli, where RPS19 colocalized with the nucleolar protein nucleolin (NCL; 164035). Using various N-terminal and C-terminal deletion constructs, they identified 2 nucleolar localization signals in RPS19: the first comprising amino acids met1 to arg16 in the NH2 terminus and the second comprising gly120 to asn142 in the COOH terminus. Importantly, 2 mutations identified in Diamond-Blackfan anemia (DBA; 105650) patients, val15 to phe (603474.0007) and gly127 to glu (603474.0008), each of which localized to 1 of the 2 nucleolar localization signals, failed to localize RPS19 to the nucleolus. In addition to their mislocalization, there was a dramatic decrease in the expression of the 2 mutant proteins compared to the wildtype. This decrease in protein expression was specific for the mutant RPS19, since expression of other proteins was normal.

Using small interfering RNA (siRNA), Flygare et al. (2007) showed that reduced expression of RPS19 in a human erythroleukemia cell line led to a defect in maturation of the 40S ribosomal subunits, affected erythroid differentiation, and increased apoptosis. Cells expressing siRNA targeting RPS19 failed to efficiently cleave 21S pre-rRNAs at the E site within internal transcribed sequence-1, which would normally lead to formation of the mature 3-prime end of the 18S rRNA. CD34 (142230)-negative and CD34-positive bone marrow cells from DBA patients with mutations in RPS19 showed an increased ratio of 21S to 18SE pre-rRNA compared with healthy controls, and the defect was more pronounced in CD34-negative patient cells. Flygare et al. (2007) concluded that RPS19 is required for efficient E site cleavage and maturation of 40S ribosomal subunits.


Gene Structure

Draptchinskaia et al. (1999) found that the RPS19 gene is 11 kb long with 6 exons. The first exon is untranslated and the ATG, which corresponds with the start codon (AUG) in the cDNA, is located at the beginning of exon 2. No TATA or CAAT boxes were identified.


Biochemical Features

Crystal Structure

Gregory et al. (2007) determined the crystal structure of Rps19 from Pyrococcus abyssi. The protein forms a 5 alpha-helix bundle organized around a central amphipathic alpha-helix.


Mapping

By somatic cell hybrid and radiation hybrid mapping analyses, Kenmochi et al. (1998) mapped the RPS19 gene to 19q13.2 (GenBank AB007155).


Cytogenetics

Draptchinskaia et al. (1999) found that the RPS19 gene was interrupted in its third intron in a female patient with a de novo balanced translocation t(X;19)(p21;q13) associated with DBA.


Molecular Genetics

In a screen for mutations of the RPS19 gene in 40 unrelated individuals with Diamond-Blackfan anemia (105650), Draptchinskaia et al. (1999) found 9 different mutations in 10 probands. Six of the patients with mutations had a family history of the disorder. No mutations were found in the 5-prime untranslated region or in the sequence encoding the 5 translated exons in 30 other probands. All patients with mutations were heterozygous for the alterations and no additional sequence variations in the protein-coding region of the gene were found.

Willig et al. (1999) analyzed 190 DBA patients and found alterations in RPS19 sequences in about 24% of the cases.

Tentler et al. (2000) reported a 12-year-old male with moderate psychomotor retardation, anemia, and skeletal changes. He was found to have a heterozygous microdeletion of 19q13.2 over a 3.2-Mb region that included the RPS19 gene. Tentler et al. (2000) suggested that this combination of features was due to a contiguous gene defect at that locus.

Gazda et al. (2004) presented RNA and protein evidence that the DBA phenotype caused by mutations in the RPS19 gene results from haploinsufficiency of the protein.

It is well established that mutated mRNA containing a premature stop codon or lacking a stop codon can be rapidly degraded by specific mechanisms called, respectively, nonsense-mediated decay and nonstop decay. To study the involvement of such mechanisms in Diamond-Blackfan anemia, Chatr-aryamontri et al. (2004) immortalized lymphoblastoid cells and primary fibroblasts from patients presenting different kinds of mutations in the RPS19 gene, generating allelic deletion, missense, nonsense, and nonstop messengers. They found that RPS19 mRNA levels were decreased in the cells with allelic deletion and, to a variable extent, also in all the cells lines with premature stop codon or nonstop mutations. Further analysis showed that translation inhibition causes a stabilization of the mutated RPS19 mRNA.

Gregory et al. (2007) used the crystal structure of Rps19 derived from Pyrococcus abyssi to classify DBA mutations relative to their respective impact on protein folding, structure, and stability (class I) or on surface properties (class II) that did not affect protein stability. Class II mutations clustered into 2 conserved basic patches, and studies in yeast demonstrated an essential role for class II residues in the function of RPS19 and its incorporation into pre-40S ribosomal particles. The data indicated that missense mutations in DBA primarily affect the capacity of the protein to be incorporated into pre-ribosomes, thus blocking maturation of the pre-40Sa central particles. Most missense mutations clustered within or around alpha-helix-3 (residues 52 to 67 in humans).

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 in the RPS19 gene (603474.0009) in a steroid-dependent male patient.


Animal Model

Matsson et al. (2004) found that homozygous disruption of the mouse Rps19 gene was lethal before the blastocyst stage. In contrast, heterozygous mice showed normal growth and organ development, including that of the hematopoietic system.

McGowan et al. (2008) reported 2 mouse 'dark skin' loci, Dsk3 and Dsk4, caused by mutations in Rps19 and Rps20 (603682), respectively. These mice have dark paws, tail skin, and ears, with melanocytosis limited to the epidermis. In the model proposed by McGowan et al. (2008), reduced dosage of Rps6 (180460), Rps19, or Rps20 triggers stabilization and/or activation of p53 (191170), which gives rise to a pleiotropic phenotype whose components depend on the sensitivity and response of individual cell types and on specific downstream targets of p53. Stabilization of p53 stimulates Kit ligand (KITLG; 184745) expression and, consequently, epidermal melanocytosis via a paracrine mechanism. Increased apoptosis causes erythrocyte hypoplasia and anemia, and activation of p53 causes reduced growth and decreased body size. McGowan et al. (2008) concluded that their results provide a mechanistic explanation for the diverse collection of phenotypes that accompany reduced dosage of genes encoding ribosomal proteins, and have implications for understanding normal human variation and human disease.


ALLELIC VARIANTS ( 9 Selected Examples):

.0001 DIAMOND-BLACKFAN ANEMIA 1

RPS19, ARG94TER
  
RCV000033182...

In 2 sisters and their mother with Diamond-Blackfan anemia (DBA1; 105650), Draptchinskaia et al. (1999) found a heterozygous C-to-T transition in the RPS19 gene causing an arg94-to-ter (R94X) substitution. The sisters were discordant for associated malformations: one of them presented with limb malformations and duplicated ureter, whereas the other had congenital glaucoma. The mother had normal hemoglobin levels and no malformations.


.0002 DIAMOND-BLACKFAN ANEMIA 1

RPS19, ARG62TRP
  
RCV000033183...

In 2 unrelated patients of Swedish and Italian origin with Diamond-Blackfan anemia (105650), Draptchinskaia et al. (1999) identified a 184C-T transition in the RPS19 gene, resulting in an arg62-to-trp (R62W) substitution. The mutation was found to segregate with the 2 affected individuals of a Swedish family, whereas the mutation in the Italian family occurred de novo. The patients did not share a flanking haplotype, suggesting recurrent mutation events. The mutation was present in heterozygous state.


.0003 DIAMOND-BLACKFAN ANEMIA 1

RPS19, TRP33TER
  
RCV000033184...

In a sporadic case of Diamond-Blackfan anemia (105650), Matsson et al. (1999) identified a heterozygous 120G-A transition in the RPS19 gene, resulting in a trp33-to-ter (W33X) substitution.


.0004 DIAMOND-BLACKFAN ANEMIA 1

RPS19, ARG84TER
  
RCV000033185

In a patient with Diamond-Blackfan anemia (105650), Matsson et al. (1999) identified a heterozygous 302C-T transition in the RPS19 gene, resulting in an arg84-to-ter (R84X) substitution.


.0005 DIAMOND-BLACKFAN ANEMIA 1

RPS19, 1-BP DEL, 329G
  
RCV000033186

In a patient with Diamond-Blackfan anemia (105650), Matsson et al. (1999) identified a 1-bp deletion (329delG) in the RPS19 gene, resulting in a frameshift starting at codon 103.


.0006 DIAMOND-BLACKFAN ANEMIA 1

RPS19, LEU45GLN AND 2-BP INS, 160CT
   RCV000033187

Matsson et al. (1999) identified a complex mutation of the RPS19 gene in 3 members of a family with variable phenotypes of Diamond-Blackfan anemia (105650). The mutation was a TT-to-AA transversion at nucleotides 157-158, resulting in a leu45-to-gln (L45Q) substitution, and a 2-bp insertion (160insCT), resulting in a frameshift at codon 46. The father and elder sister were diagnosed with mild anemia at 35 years of age and 5 years of age, respectively. The proband was diagnosed at 15 months of age and initially required transfusions every third week. At age 18 years she still required transfusions every third month. The father and sister did not require therapy, and both had hemoglobin levels within the normal range.


.0007 DIAMOND-BLACKFAN ANEMIA 1

RPS19, VAL15PHE AND THR55MET
  
RCV000033188...

In a girl with sporadic Diamond-Blackfan anemia (105650) who was small for gestational age, Da Costa et al. (2003) found a double mutation, val15-to-phe (V15F) and thr55- to-met (T55M), in the RPS19 gene on the same chromosome. The V15F mutation alone was shown to interfere with nucleolar localization of the RPS19 protein.


.0008 DIAMOND-BLACKFAN ANEMIA 1

RPS19, GLY127GLU
  
RCV000033189...

Angelini et al. (2007) noted that this mutation is a 380G-A transition in the RPS19 gene, resulting in a gly127-to-glu (G127E) substitution.

In a female child in whom the diagnosis of Diamond-Blackfan anemia (105650) had been made at the age of 1 month, Willig et al. (1999) identified a 380G-A transition in the RPS19 gene, which they reported to result in a gly127-to-gln substitution. Da Costa et al. (2003) noted that the patient was small for gestational age and showed deafness and hip hypoplasia. They found that the mutation resulted in failure of the RPS19 protein to localize to the nucleolus.


.0009 DIAMOND-BLACKFAN ANEMIA 1

RPS19, 5,070-BP DEL
   RCV000074476

In a steroid-dependent male patient with Diamond-Blackfan anemia (105650), Landowski et al. (2013) identified heterozygosity for a 5,070-bp deletion at chr19:47,056,452-47,061,521 (NCBI36), containing exons 2 and 3 of the RPS19 gene. The patient also had a webbed neck.


REFERENCES

  1. Angelini, M., Cannata, S., Mercaldo, V., Gibello, L., Santoro, C., Dianzani, I., Loreni, F. Missense mutations associated with Diamond-Blackfan anemia affect the assembly of ribosomal protein S19 into the ribosome. Hum. Molec. Genet. 16: 1720-1727, 2007. [PubMed: 17517689, related citations] [Full Text]

  2. Chatr-aryamontri, A., Angelini, M., Garelli, E., Tchernia, G., Ramenghi, U., Dianzani, I., Loreni, F. Nonsense-mediated and nonstop decay of ribosomal protein S19 mRNA in Diamond-Blackfan anemia. Hum. Mutat. 24: 526-533, 2004. [PubMed: 15523650, related citations] [Full Text]

  3. Da Costa, L., Tchernia, G., Gascard, P., Lo, A., Meerpohl, J., Niemeyer, C., Chasis, J.-A., Fixler, J., Mohandas, N. Nucleolar localization of RPS19 protein in normal cells and mislocalization due to mutations in the nucleolar localization signals in 2 Diamond-Blackfan anemia patients: potential insights into pathophysiology. Blood 101: 5039-5045, 2003. [PubMed: 12586610, related citations] [Full Text]

  4. Draptchinskaia, N., Gustavsson, P., Andersson, B., Pettersson, M., Willig, T.-N., Dianzani, I., Ball, S., Tchernia, G., Klar, J., Matsson, H., Tentler, D., Mohandas, N., Carlsson, B., Dahl, N. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nature Genet. 21: 169-175, 1999. [PubMed: 9988267, related citations] [Full Text]

  5. Flygare, J., Aspesi, A., Bailey, J. C., Miyake, K., Caffrey, J. M., Karlsson, S., Ellis, S. R. Human RPS19, the gene mutated in Diamond-Blackfan anemia, encodes a ribosomal protein required for the maturation of 40S ribosomal subunits. Blood 109: 980-986, 2007. [PubMed: 16990592, images, related citations] [Full Text]

  6. Gazda, H. T., Zhong, R., Long, L., Niewiadomska, E., Lipton, J. M., Ploszynska, A., Zaucha, J. M., Vlachos, A., Atsidaftos, E., Viskochil, D. H., Niemeyer, C. M., Meerpohl, J. J., Rokicka-Milewska, R., Pospisilova, D., Wiktor-Jedrzejczak, W., Nathan, D. G., Beggs, A. H., Sieff, C. A. RNA and protein evidence for haplo-insufficiency in Diamond-Blackfan anaemia patients with RPS19 mutations. Brit. J. Haemat. 127: 105-113, 2004. [PubMed: 15384984, related citations] [Full Text]

  7. Gregory, L. A., Aguissa-Toure, A.-H., Pinaud, N., Legrand, P., Gleizes, P.-E., Fribourg, S. Molecular basis of Diamond-Blackfan anemia: structure and function analysis of RPS19. Nucleic Acids Res. 35: 5913-5921, 2007. [PubMed: 17726054, images, related citations] [Full Text]

  8. 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, related citations] [Full Text]

  9. Kondoh, N., Schweinfest, C. W., Henderson, K. W., Papas, T. S. Differential expression of S19 ribosomal protein, laminin-binding protein, and human lymphocyte antigen class I messenger RNAs associated with colon carcinoma progression and differentiation. Cancer Res. 52: 791-796, 1992. [PubMed: 1339304, related citations]

  10. 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, images, related citations] [Full Text]

  11. Matsson, H., Davey, E. J., Draptchinskaia, N., Hamaguchi, I., Ooka, A., Leveen, P., Forsberg, E., Karlsson, S., Dahl, N. Targeted disruption of the ribosomal protein S19 gene is lethal prior to implantation. Molec. Cell. Biol. 24: 4032-4037, 2004. [PubMed: 15082795, images, related citations] [Full Text]

  12. Matsson, H., Klar, J., Draptchinskaia, N., Gustavsson, P., Carlsson, B., Bowers, D., de Bont, E., Dahl, N. Truncating ribosomal protein S19 mutations and variable clinical expression in Diamond-Blackfan anemia. Hum. Genet. 105: 496-500, 1999. [PubMed: 10598818, related citations] [Full Text]

  13. McGowan, K. A., Li, J. Z., Park, C. Y., Beaudry, V., Tabor, H. K., Sabnis, A. J., Zhang, W., Fuchs, H., de Angelis, M. H., Myers, R. M., Attardi, L. D., Barsh, G. S. Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects. Nature Genet. 40: 963-970, 2008. [PubMed: 18641651, images, related citations] [Full Text]

  14. Tentler, D., Gustavsson, P., Elinder, G., Eklof, O., Gordon, L., Mandel, A., Dahl, N. A microdeletion in 19q13.2 associated with mental retardation, skeletal malformations, and Diamond-Blackfan anaemia suggests a novel contiguous gene syndrome. J. Med. Genet. 37: 128-131, 2000. [PubMed: 10662814, related citations] [Full Text]

  15. Willig, T.-N., Draptchinskaia, N., Dianzani, I., Ball, S., Niemeyer, C., Ramenghi, U., Orfali, K., Gustavsson, P., Garelli, E., Brusco, A., Tiemann, C., Perignon, J. L., Bouchier, C., Cicchiello, L., Dahl, N., Mohandas, N., Tchernia, G. Mutations in ribosomal protein S19 gene and Diamond Blackfan anemia: wide variations in phenotypic expression. Blood 94: 4294-4306, 1999. [PubMed: 10590074, related citations]


Marla J. F. O'Neill - updated : 11/27/2013
Cassandra L. Kniffin - updated : 3/11/2009
Patricia A. Hartz - updated : 12/31/2008
Ada Hamosh - updated : 10/24/2008
Cassandra L. Kniffin -updated : 6/15/2005
Victor A. McKusick - updated : 1/10/2005
Patricia A. Hartz - updated : 6/25/2004
Victor A. McKusick - updated : 9/4/2003
Victor A. McKusick - updated : 12/6/1999
Patti M. Sherman - updated : 3/30/1999
Creation Date:
Victor A. McKusick : 2/2/1999
alopez : 10/17/2016
carol : 04/01/2015
joanna : 3/31/2015
carol : 12/2/2013
mcolton : 11/27/2013
wwang : 3/19/2009
ckniffin : 3/11/2009
mgross : 1/5/2009
mgross : 1/5/2009
terry : 12/31/2008
alopez : 11/10/2008
terry : 10/24/2008
carol : 6/23/2005
ckniffin : 6/15/2005
alopez : 2/15/2005
terry : 2/7/2005
wwang : 1/25/2005
terry : 1/10/2005
mgross : 7/1/2004
terry : 6/25/2004
cwells : 9/8/2003
terry : 9/4/2003
cwells : 8/10/2001
cwells : 8/2/2001
mgross : 12/10/1999
terry : 12/6/1999
psherman : 4/5/1999
carol : 4/2/1999
carol : 4/1/1999
alopez : 2/2/1999

* 603474

RIBOSOMAL PROTEIN S19; RPS19


HGNC Approved Gene Symbol: RPS19

Cytogenetic location: 19q13.2     Genomic coordinates (GRCh38): 19:41,860,255-41,872,925 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
19q13.2 Diamond-Blackfan anemia 1 105650 Autosomal dominant 3

TEXT

Description

The mammalian ribosome is composed of 4 RNA species (see 180450) and approximately 80 different proteins, including RPS19. The RPS19 protein is a component of the 40S ribosomal subunit (Gregory et al., 2007).


Cloning and Expression

Kondoh et al. (1992) cloned a cDNA encoding ribosomal protein S19 from a colon tumor-enriched subtraction cDNA library. Northern blot analysis showed that the 0.6-kb RPS19 mRNA was expressed at higher levels in 6 of 7 primary colon carcinomas than in matched normal colon tissues. The deduced human and rat RPS19 proteins differ by 1 amino acid.

By Northern blot analysis, Draptchinskaia et al. (1999) found that the RPS19 gene is expressed in several human adult tissues including bone marrow, peripheral blood, spleen, and liver, as well as nonhematopoietic tissues. Ribosomal protein S19 consists of 145 amino acids with a predicted molecular mass of 16 kD and an isoelectric point of 10.3. The protein lacks cysteine residues and the hydropathy profile predicts the presence of hydrophobic domains.


Gene Function

Using wildtype and mutant RPS19 cDNA, Da Costa et al. (2003) explored the subcellular distribution of normal and mutant proteins in a fibroblast cell line (COS-7 cells). RPS19 was detected primarily in the nucleus, and more specifically in the nucleoli, where RPS19 colocalized with the nucleolar protein nucleolin (NCL; 164035). Using various N-terminal and C-terminal deletion constructs, they identified 2 nucleolar localization signals in RPS19: the first comprising amino acids met1 to arg16 in the NH2 terminus and the second comprising gly120 to asn142 in the COOH terminus. Importantly, 2 mutations identified in Diamond-Blackfan anemia (DBA; 105650) patients, val15 to phe (603474.0007) and gly127 to glu (603474.0008), each of which localized to 1 of the 2 nucleolar localization signals, failed to localize RPS19 to the nucleolus. In addition to their mislocalization, there was a dramatic decrease in the expression of the 2 mutant proteins compared to the wildtype. This decrease in protein expression was specific for the mutant RPS19, since expression of other proteins was normal.

Using small interfering RNA (siRNA), Flygare et al. (2007) showed that reduced expression of RPS19 in a human erythroleukemia cell line led to a defect in maturation of the 40S ribosomal subunits, affected erythroid differentiation, and increased apoptosis. Cells expressing siRNA targeting RPS19 failed to efficiently cleave 21S pre-rRNAs at the E site within internal transcribed sequence-1, which would normally lead to formation of the mature 3-prime end of the 18S rRNA. CD34 (142230)-negative and CD34-positive bone marrow cells from DBA patients with mutations in RPS19 showed an increased ratio of 21S to 18SE pre-rRNA compared with healthy controls, and the defect was more pronounced in CD34-negative patient cells. Flygare et al. (2007) concluded that RPS19 is required for efficient E site cleavage and maturation of 40S ribosomal subunits.


Gene Structure

Draptchinskaia et al. (1999) found that the RPS19 gene is 11 kb long with 6 exons. The first exon is untranslated and the ATG, which corresponds with the start codon (AUG) in the cDNA, is located at the beginning of exon 2. No TATA or CAAT boxes were identified.


Biochemical Features

Crystal Structure

Gregory et al. (2007) determined the crystal structure of Rps19 from Pyrococcus abyssi. The protein forms a 5 alpha-helix bundle organized around a central amphipathic alpha-helix.


Mapping

By somatic cell hybrid and radiation hybrid mapping analyses, Kenmochi et al. (1998) mapped the RPS19 gene to 19q13.2 (GenBank AB007155).


Cytogenetics

Draptchinskaia et al. (1999) found that the RPS19 gene was interrupted in its third intron in a female patient with a de novo balanced translocation t(X;19)(p21;q13) associated with DBA.


Molecular Genetics

In a screen for mutations of the RPS19 gene in 40 unrelated individuals with Diamond-Blackfan anemia (105650), Draptchinskaia et al. (1999) found 9 different mutations in 10 probands. Six of the patients with mutations had a family history of the disorder. No mutations were found in the 5-prime untranslated region or in the sequence encoding the 5 translated exons in 30 other probands. All patients with mutations were heterozygous for the alterations and no additional sequence variations in the protein-coding region of the gene were found.

Willig et al. (1999) analyzed 190 DBA patients and found alterations in RPS19 sequences in about 24% of the cases.

Tentler et al. (2000) reported a 12-year-old male with moderate psychomotor retardation, anemia, and skeletal changes. He was found to have a heterozygous microdeletion of 19q13.2 over a 3.2-Mb region that included the RPS19 gene. Tentler et al. (2000) suggested that this combination of features was due to a contiguous gene defect at that locus.

Gazda et al. (2004) presented RNA and protein evidence that the DBA phenotype caused by mutations in the RPS19 gene results from haploinsufficiency of the protein.

It is well established that mutated mRNA containing a premature stop codon or lacking a stop codon can be rapidly degraded by specific mechanisms called, respectively, nonsense-mediated decay and nonstop decay. To study the involvement of such mechanisms in Diamond-Blackfan anemia, Chatr-aryamontri et al. (2004) immortalized lymphoblastoid cells and primary fibroblasts from patients presenting different kinds of mutations in the RPS19 gene, generating allelic deletion, missense, nonsense, and nonstop messengers. They found that RPS19 mRNA levels were decreased in the cells with allelic deletion and, to a variable extent, also in all the cells lines with premature stop codon or nonstop mutations. Further analysis showed that translation inhibition causes a stabilization of the mutated RPS19 mRNA.

Gregory et al. (2007) used the crystal structure of Rps19 derived from Pyrococcus abyssi to classify DBA mutations relative to their respective impact on protein folding, structure, and stability (class I) or on surface properties (class II) that did not affect protein stability. Class II mutations clustered into 2 conserved basic patches, and studies in yeast demonstrated an essential role for class II residues in the function of RPS19 and its incorporation into pre-40S ribosomal particles. The data indicated that missense mutations in DBA primarily affect the capacity of the protein to be incorporated into pre-ribosomes, thus blocking maturation of the pre-40Sa central particles. Most missense mutations clustered within or around alpha-helix-3 (residues 52 to 67 in humans).

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 in the RPS19 gene (603474.0009) in a steroid-dependent male patient.


Animal Model

Matsson et al. (2004) found that homozygous disruption of the mouse Rps19 gene was lethal before the blastocyst stage. In contrast, heterozygous mice showed normal growth and organ development, including that of the hematopoietic system.

McGowan et al. (2008) reported 2 mouse 'dark skin' loci, Dsk3 and Dsk4, caused by mutations in Rps19 and Rps20 (603682), respectively. These mice have dark paws, tail skin, and ears, with melanocytosis limited to the epidermis. In the model proposed by McGowan et al. (2008), reduced dosage of Rps6 (180460), Rps19, or Rps20 triggers stabilization and/or activation of p53 (191170), which gives rise to a pleiotropic phenotype whose components depend on the sensitivity and response of individual cell types and on specific downstream targets of p53. Stabilization of p53 stimulates Kit ligand (KITLG; 184745) expression and, consequently, epidermal melanocytosis via a paracrine mechanism. Increased apoptosis causes erythrocyte hypoplasia and anemia, and activation of p53 causes reduced growth and decreased body size. McGowan et al. (2008) concluded that their results provide a mechanistic explanation for the diverse collection of phenotypes that accompany reduced dosage of genes encoding ribosomal proteins, and have implications for understanding normal human variation and human disease.


ALLELIC VARIANTS 9 Selected Examples):

.0001   DIAMOND-BLACKFAN ANEMIA 1

RPS19, ARG94TER
SNP: rs61762293, gnomAD: rs61762293, ClinVar: RCV000033182, RCV000272977, RCV002433445

In 2 sisters and their mother with Diamond-Blackfan anemia (DBA1; 105650), Draptchinskaia et al. (1999) found a heterozygous C-to-T transition in the RPS19 gene causing an arg94-to-ter (R94X) substitution. The sisters were discordant for associated malformations: one of them presented with limb malformations and duplicated ureter, whereas the other had congenital glaucoma. The mother had normal hemoglobin levels and no malformations.


.0002   DIAMOND-BLACKFAN ANEMIA 1

RPS19, ARG62TRP
SNP: rs104894711, ClinVar: RCV000033183, RCV000497714, RCV001065746, RCV003415668

In 2 unrelated patients of Swedish and Italian origin with Diamond-Blackfan anemia (105650), Draptchinskaia et al. (1999) identified a 184C-T transition in the RPS19 gene, resulting in an arg62-to-trp (R62W) substitution. The mutation was found to segregate with the 2 affected individuals of a Swedish family, whereas the mutation in the Italian family occurred de novo. The patients did not share a flanking haplotype, suggesting recurrent mutation events. The mutation was present in heterozygous state.


.0003   DIAMOND-BLACKFAN ANEMIA 1

RPS19, TRP33TER
SNP: rs104894716, ClinVar: RCV000033184, RCV001237459

In a sporadic case of Diamond-Blackfan anemia (105650), Matsson et al. (1999) identified a heterozygous 120G-A transition in the RPS19 gene, resulting in a trp33-to-ter (W33X) substitution.


.0004   DIAMOND-BLACKFAN ANEMIA 1

RPS19, ARG84TER
SNP: rs121908649, ClinVar: RCV000033185

In a patient with Diamond-Blackfan anemia (105650), Matsson et al. (1999) identified a heterozygous 302C-T transition in the RPS19 gene, resulting in an arg84-to-ter (R84X) substitution.


.0005   DIAMOND-BLACKFAN ANEMIA 1

RPS19, 1-BP DEL, 329G
SNP: rs786200935, ClinVar: RCV000033186

In a patient with Diamond-Blackfan anemia (105650), Matsson et al. (1999) identified a 1-bp deletion (329delG) in the RPS19 gene, resulting in a frameshift starting at codon 103.


.0006   DIAMOND-BLACKFAN ANEMIA 1

RPS19, LEU45GLN AND 2-BP INS, 160CT
ClinVar: RCV000033187

Matsson et al. (1999) identified a complex mutation of the RPS19 gene in 3 members of a family with variable phenotypes of Diamond-Blackfan anemia (105650). The mutation was a TT-to-AA transversion at nucleotides 157-158, resulting in a leu45-to-gln (L45Q) substitution, and a 2-bp insertion (160insCT), resulting in a frameshift at codon 46. The father and elder sister were diagnosed with mild anemia at 35 years of age and 5 years of age, respectively. The proband was diagnosed at 15 months of age and initially required transfusions every third week. At age 18 years she still required transfusions every third month. The father and sister did not require therapy, and both had hemoglobin levels within the normal range.


.0007   DIAMOND-BLACKFAN ANEMIA 1

RPS19, VAL15PHE AND THR55MET
SNP: rs104894717, rs147508369, gnomAD: rs104894717, rs147508369, ClinVar: RCV000033188, RCV000471188, RCV000482973, RCV001331478, RCV001507957, RCV001843501

In a girl with sporadic Diamond-Blackfan anemia (105650) who was small for gestational age, Da Costa et al. (2003) found a double mutation, val15-to-phe (V15F) and thr55- to-met (T55M), in the RPS19 gene on the same chromosome. The V15F mutation alone was shown to interfere with nucleolar localization of the RPS19 protein.


.0008   DIAMOND-BLACKFAN ANEMIA 1

RPS19, GLY127GLU
SNP: rs786200936, ClinVar: RCV000033189, RCV002512845

Angelini et al. (2007) noted that this mutation is a 380G-A transition in the RPS19 gene, resulting in a gly127-to-glu (G127E) substitution.

In a female child in whom the diagnosis of Diamond-Blackfan anemia (105650) had been made at the age of 1 month, Willig et al. (1999) identified a 380G-A transition in the RPS19 gene, which they reported to result in a gly127-to-gln substitution. Da Costa et al. (2003) noted that the patient was small for gestational age and showed deafness and hip hypoplasia. They found that the mutation resulted in failure of the RPS19 protein to localize to the nucleolus.


.0009   DIAMOND-BLACKFAN ANEMIA 1

RPS19, 5,070-BP DEL
ClinVar: RCV000074476

In a steroid-dependent male patient with Diamond-Blackfan anemia (105650), Landowski et al. (2013) identified heterozygosity for a 5,070-bp deletion at chr19:47,056,452-47,061,521 (NCBI36), containing exons 2 and 3 of the RPS19 gene. The patient also had a webbed neck.


REFERENCES

  1. Angelini, M., Cannata, S., Mercaldo, V., Gibello, L., Santoro, C., Dianzani, I., Loreni, F. Missense mutations associated with Diamond-Blackfan anemia affect the assembly of ribosomal protein S19 into the ribosome. Hum. Molec. Genet. 16: 1720-1727, 2007. [PubMed: 17517689] [Full Text: https://doi.org/10.1093/hmg/ddm120]

  2. Chatr-aryamontri, A., Angelini, M., Garelli, E., Tchernia, G., Ramenghi, U., Dianzani, I., Loreni, F. Nonsense-mediated and nonstop decay of ribosomal protein S19 mRNA in Diamond-Blackfan anemia. Hum. Mutat. 24: 526-533, 2004. [PubMed: 15523650] [Full Text: https://doi.org/10.1002/humu.20117]

  3. Da Costa, L., Tchernia, G., Gascard, P., Lo, A., Meerpohl, J., Niemeyer, C., Chasis, J.-A., Fixler, J., Mohandas, N. Nucleolar localization of RPS19 protein in normal cells and mislocalization due to mutations in the nucleolar localization signals in 2 Diamond-Blackfan anemia patients: potential insights into pathophysiology. Blood 101: 5039-5045, 2003. [PubMed: 12586610] [Full Text: https://doi.org/10.1182/blood-2002-12-3878]

  4. Draptchinskaia, N., Gustavsson, P., Andersson, B., Pettersson, M., Willig, T.-N., Dianzani, I., Ball, S., Tchernia, G., Klar, J., Matsson, H., Tentler, D., Mohandas, N., Carlsson, B., Dahl, N. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nature Genet. 21: 169-175, 1999. [PubMed: 9988267] [Full Text: https://doi.org/10.1038/5951]

  5. Flygare, J., Aspesi, A., Bailey, J. C., Miyake, K., Caffrey, J. M., Karlsson, S., Ellis, S. R. Human RPS19, the gene mutated in Diamond-Blackfan anemia, encodes a ribosomal protein required for the maturation of 40S ribosomal subunits. Blood 109: 980-986, 2007. [PubMed: 16990592] [Full Text: https://doi.org/10.1182/blood-2006-07-038232]

  6. Gazda, H. T., Zhong, R., Long, L., Niewiadomska, E., Lipton, J. M., Ploszynska, A., Zaucha, J. M., Vlachos, A., Atsidaftos, E., Viskochil, D. H., Niemeyer, C. M., Meerpohl, J. J., Rokicka-Milewska, R., Pospisilova, D., Wiktor-Jedrzejczak, W., Nathan, D. G., Beggs, A. H., Sieff, C. A. RNA and protein evidence for haplo-insufficiency in Diamond-Blackfan anaemia patients with RPS19 mutations. Brit. J. Haemat. 127: 105-113, 2004. [PubMed: 15384984] [Full Text: https://doi.org/10.1111/j.1365-2141.2004.05152.x]

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  8. 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]

  9. Kondoh, N., Schweinfest, C. W., Henderson, K. W., Papas, T. S. Differential expression of S19 ribosomal protein, laminin-binding protein, and human lymphocyte antigen class I messenger RNAs associated with colon carcinoma progression and differentiation. Cancer Res. 52: 791-796, 1992. [PubMed: 1339304]

  10. 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]

  11. Matsson, H., Davey, E. J., Draptchinskaia, N., Hamaguchi, I., Ooka, A., Leveen, P., Forsberg, E., Karlsson, S., Dahl, N. Targeted disruption of the ribosomal protein S19 gene is lethal prior to implantation. Molec. Cell. Biol. 24: 4032-4037, 2004. [PubMed: 15082795] [Full Text: https://doi.org/10.1128/MCB.24.9.4032-4037.2004]

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  13. McGowan, K. A., Li, J. Z., Park, C. Y., Beaudry, V., Tabor, H. K., Sabnis, A. J., Zhang, W., Fuchs, H., de Angelis, M. H., Myers, R. M., Attardi, L. D., Barsh, G. S. Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects. Nature Genet. 40: 963-970, 2008. [PubMed: 18641651] [Full Text: https://doi.org/10.1038/ng.188]

  14. Tentler, D., Gustavsson, P., Elinder, G., Eklof, O., Gordon, L., Mandel, A., Dahl, N. A microdeletion in 19q13.2 associated with mental retardation, skeletal malformations, and Diamond-Blackfan anaemia suggests a novel contiguous gene syndrome. J. Med. Genet. 37: 128-131, 2000. [PubMed: 10662814] [Full Text: https://doi.org/10.1136/jmg.37.2.128]

  15. Willig, T.-N., Draptchinskaia, N., Dianzani, I., Ball, S., Niemeyer, C., Ramenghi, U., Orfali, K., Gustavsson, P., Garelli, E., Brusco, A., Tiemann, C., Perignon, J. L., Bouchier, C., Cicchiello, L., Dahl, N., Mohandas, N., Tchernia, G. Mutations in ribosomal protein S19 gene and Diamond Blackfan anemia: wide variations in phenotypic expression. Blood 94: 4294-4306, 1999. [PubMed: 10590074]


Contributors:
Marla J. F. O'Neill - updated : 11/27/2013
Cassandra L. Kniffin - updated : 3/11/2009
Patricia A. Hartz - updated : 12/31/2008
Ada Hamosh - updated : 10/24/2008
Cassandra L. Kniffin -updated : 6/15/2005
Victor A. McKusick - updated : 1/10/2005
Patricia A. Hartz - updated : 6/25/2004
Victor A. McKusick - updated : 9/4/2003
Victor A. McKusick - updated : 12/6/1999
Patti M. Sherman - updated : 3/30/1999

Creation Date:
Victor A. McKusick : 2/2/1999

Edit History:
alopez : 10/17/2016
carol : 04/01/2015
joanna : 3/31/2015
carol : 12/2/2013
mcolton : 11/27/2013
wwang : 3/19/2009
ckniffin : 3/11/2009
mgross : 1/5/2009
mgross : 1/5/2009
terry : 12/31/2008
alopez : 11/10/2008
terry : 10/24/2008
carol : 6/23/2005
ckniffin : 6/15/2005
alopez : 2/15/2005
terry : 2/7/2005
wwang : 1/25/2005
terry : 1/10/2005
mgross : 7/1/2004
terry : 6/25/2004
cwells : 9/8/2003
terry : 9/4/2003
cwells : 8/10/2001
cwells : 8/2/2001
mgross : 12/10/1999
terry : 12/6/1999
psherman : 4/5/1999
carol : 4/2/1999
carol : 4/1/1999
alopez : 2/2/1999