RBCC Red Blood Cell Collection

RPS19 [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
40S ribosomal protein S19
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P39019
ID RS19_HUMAN Reviewed; 145 AA.
AC P39019;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 137.
DE RecName: Full=40S ribosomal protein S19;
GN Name=RPS19;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1339304;
RA Kondoh N., Schweinfest C.W., Henderson K.W., Papas T.S.;
RT "Differential expression of S19 ribosomal protein, laminin-binding
RT protein, and human lymphocyte antigen class I messenger RNAs
RT associated with colon carcinoma progression and differentiation.";
RL Cancer Res. 52:791-796(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS DBA1 ARG-52 AND
RP TRP-62.
RX PubMed=9988267; DOI=10.1038/5951;
RA Draptchinskaia N., Gustavsson P., Andersson B., Pettersson M.,
RA Willig T.-N.D., Dianzani I., Ball S., Tchernia G., Klar J.,
RA Matsson H., Tentler D., Mohandas N., Carlsson B., Dahl N.;
RT "The gene encoding ribosomal protein S19 is mutated in Diamond-
RT Blackfan anaemia.";
RL Nat. Genet. 21:169-175(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon, Eye, and Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP PROTEIN SEQUENCE OF 2-11.
RC TISSUE=Placenta;
RX PubMed=8706699; DOI=10.1111/j.1432-1033.1996.0144u.x;
RA Vladimirov S.N., Ivanov A.V., Karpova G.G., Musolyamov A.K.,
RA Egorov T.A., Thiede B., Wittmann-Liebold B., Otto A.;
RT "Characterization of the human small-ribosomal-subunit proteins by N-
RT terminal and internal sequencing, and mass spectrometry.";
RL Eur. J. Biochem. 239:144-149(1996).
RN [5]
RP PROTEIN SEQUENCE OF 2-24; 30-38; 83-94; 102-111 AND 134-145, CLEAVAGE
RP OF INITIATOR METHIONINE, LACK OF N-TERMINAL ACETYLATION, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma, and Mammary carcinoma;
RA Bienvenut W.V., Calvo F., Kolch W., Lourenco F., Olson M.F.;
RL Submitted (DEC-2009) to UniProtKB.
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 120-137.
RX PubMed=9582194;
RA Kenmochi N., Kawaguchi T., Rozen S., Davis E., Goodman N.,
RA Hudson T.J., Tanaka T., Page D.C.;
RT "A map of 75 human ribosomal protein genes.";
RL Genome Res. 8:509-523(1998).
RN [7]
RP REVIEW ON DBA1 VARIANTS.
RX PubMed=15075082;
RA Campagnoli M.F., Garelli E., Quarello P., Carando A., Varotto S.,
RA Nobili B., Longoni D., Pecile V., Zecca M., Dufour C., Ramenghi U.,
RA Dianzan I.;
RT "Molecular basis of Diamond-Blackfan anemia: new findings from the
RT Italian registry and a review of the literature.";
RL Haematologica 89:480-489(2004).
RN [8]
RP FUNCTION.
RX PubMed=16990592; DOI=10.1182/blood-2006-07-038232;
RA Flygare J., Aspesi A., Bailey J.C., Miyake K., Caffrey J.M.,
RA Karlsson S., Ellis S.R.;
RT "Human RPS19, the gene mutated in Diamond-Blackfan anemia, encodes a
RT ribosomal protein required for the maturation of 40S ribosomal
RT subunits.";
RL Blood 109:980-986(2007).
RN [9]
RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS DBA1 PHE-15;
RP PRO-18; LEU-47; ARG-52; GLN-56; PRO-57; GLU-61; GLN-62; TRP-62;
RP HIS-101 AND ARG-120.
RX PubMed=17517689; DOI=10.1093/hmg/ddm120;
RA Angelini M., Cannata S., Mercaldo V., Gibello L., Santoro C.,
RA Dianzani I., Loreni F.;
RT "Missense mutations associated with Diamond-Blackfan anemia affect the
RT assembly of ribosomal protein S19 into the ribosome.";
RL Hum. Mol. Genet. 16:1720-1727(2007).
RN [10]
RP REVIEW ON VARIANTS DBA1.
RX PubMed=18412286; DOI=10.1002/humu.20752;
RA Campagnoli M.F., Ramenghi U., Armiraglio M., Quarello P., Garelli E.,
RA Carando A., Avondo F., Pavesi E., Fribourg S., Gleizes P.E.,
RA Loreni F., Dianzani I.;
RT "RPS19 mutations in patients with Diamond-Blackfan anemia.";
RL Hum. Mutat. 29:911-920(2008).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-23 AND LYS-111, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [14]
RP STRUCTURE BY ELECTRON MICROSCOPY (5.0 ANGSTROMS) OF 80S RIBOSOME.
RX PubMed=23636399; DOI=10.1038/nature12104;
RA Anger A.M., Armache J.P., Berninghausen O., Habeck M., Subklewe M.,
RA Wilson D.N., Beckmann R.;
RT "Structures of the human and Drosophila 80S ribosome.";
RL Nature 497:80-85(2013).
RN [15]
RP VARIANTS DBA1 PHE-15; GLN-56; GLU-61; TRP-62; HIS-101 AND ARG-120.
RX PubMed=10590074;
RA Willig T.-N.D., Draptchinskaia N., Dianzani I., Ball S., Niemeyer C.,
RA Ramenghi U., Orfali K., Gustavsson P., Garelli E., Brusco A.,
RA Tiemann C., Perignon J.L., Bouchier C., Cicchiello L., Dahl N.,
RA Mohandas N., Tchernia G.;
RT "Mutations in ribosomal protein S19 gene and Diamond Blackfan anemia:
RT wide variations in phenotypic expression.";
RL Blood 94:4294-4306(1999).
RN [16]
RP VARIANTS DBA1 PRO-18; LEU-47 AND TRP-62.
RX PubMed=11112378; DOI=10.1006/bcmd.2000.0324;
RA Ramenghi U., Campagnoli M.F., Garelli E., Carando A., Brusco A.,
RA Bagnara G.P., Strippoli P., Izzi G.C., Brandalise S., Riccardi R.,
RA Dianzani I.;
RT "Diamond-Blackfan anemia: report of seven further mutations in the
RT RPS19 gene and evidence of mutation heterogeneity in the Italian
RT population.";
RL Blood Cells Mol. Dis. 26:417-422(2000).
RN [17]
RP VARIANTS DBA1 PHE-15 AND MET-55, AND SUBCELLULAR LOCATION.
RX PubMed=12586610; DOI=10.1182/blood-2002-12-3878;
RA Da Costa L., Tchernia G., Gascard P., Lo A., Meerpohl J., Niemeyer C.,
RA Chasis J.-A., Fixler J., Mohandas N.;
RT "Nucleolar localization of RPS19 protein in normal cells and
RT mislocalization due to mutations in the nucleolar localization signals
RT in 2 Diamond-Blackfan anemia patients: potential insights into
RT pathophysiology.";
RL Blood 101:5039-5045(2003).
RN [18]
RP VARIANTS DBA1 GLN-62 AND PRO-131.
RX PubMed=12750732; DOI=10.1038/sj.thj.6200230;
RA Proust A., Da Costa L., Rince P., Landois A., Tamary H., Zaizov R.,
RA Tchernia G., Delaunay J.;
RT "Ten novel Diamond-Blackfan anemia mutations and three polymorphisms
RT within the rps19 gene.";
RL Hematol. J. 4:132-136(2003).
RN [19]
RP VARIANTS DBA1 ARG-18; GLN-56; 58-ALA--THR-60 DEL; PHE-59; GLN-62;
RP HIS-101 AND ARG-131.
RX PubMed=15384984; DOI=10.1111/j.1365-2141.2004.05152.x;
RA Gazda H.T., Zhong R., Long L., Niewiadomska E., Lipton J.M.,
RA Ploszynska A., Zaucha J.M., Vlachos A., Atsidaftos E., Viskochil D.H.,
RA Niemeyer C.M., Meerpohl J.J., Rokicka-Milewska R., Pospisilova D.,
RA Wiktor-Jedrzejczak W., Nathan D.G., Beggs A.H., Sieff C.A.;
RT "RNA and protein evidence for haplo-insufficiency in Diamond-Blackfan
RT anaemia patients with RPS19 mutations.";
RL Br. J. Haematol. 127:105-113(2004).
RN [20]
RP ERRATUM, AND VARIANT DBA1 PRO-17.
RA Pereira J.C., Fiskerstrand T., Ribeiro M.L.;
RL Hum. Genet. 115:349-349(2004).
CC -!- FUNCTION: Required for pre-rRNA processing and maturation of 40S
CC ribosomal subunits.
CC -!- SUBUNIT: Interacts with RPS19BP1 (By similarity).
CC -!- INTERACTION:
CC P11309:PIM1; NbExp=7; IntAct=EBI-354451, EBI-696621;
CC -!- SUBCELLULAR LOCATION: Nucleus. Note=Located more specifically in
CC the nucleoli.
CC -!- TISSUE SPECIFICITY: Higher level expression is seen in the colon
CC carcinoma tissue than normal colon tissue.
CC -!- DISEASE: Diamond-Blackfan anemia 1 (DBA1) [MIM:105650]: A form of
CC Diamond-Blackfan anemia, a congenital non-regenerative hypoplastic
CC anemia that usually presents early in infancy. Diamond-Blackfan
CC anemia is characterized by a moderate to severe macrocytic anemia,
CC erythroblastopenia, and an increased risk of developing leukemia.
CC 30 to 40% of Diamond-Blackfan anemia patients present with short
CC stature and congenital anomalies, the most frequent being
CC craniofacial (Pierre-Robin syndrome and cleft palate), thumb and
CC urogenital anomalies. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the ribosomal protein S19e family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/RPS19";
CC -!- WEB RESOURCE: Name=Diamond-Blackfan Anemia mutation database;
CC URL="http://www.dbagenes.unito.it/home.php?select_db=RPS19";
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DR EMBL; M81757; AAA89070.1; -; mRNA.
DR EMBL; AF092907; AAD13668.1; -; Genomic_DNA.
DR EMBL; AF092906; AAD13668.1; JOINED; Genomic_DNA.
DR EMBL; BC000023; AAH00023.1; -; mRNA.
DR EMBL; BC007615; AAH07615.1; -; mRNA.
DR EMBL; BC018616; AAH18616.1; -; mRNA.
DR EMBL; AB007155; BAA28593.1; -; Genomic_DNA.
DR PIR; I52692; I52692.
DR RefSeq; NP_001013.1; NM_001022.3.
DR RefSeq; XP_005259198.1; XM_005259141.1.
DR RefSeq; XP_005278448.1; XM_005278391.1.
DR RefSeq; XP_005278449.1; XM_005278392.1.
DR UniGene; Hs.438429; -.
DR PDB; 3J3A; EM; 5.00 A; T=1-145.
DR PDBsum; 3J3A; -.
DR ProteinModelPortal; P39019; -.
DR SMR; P39019; 4-144.
DR IntAct; P39019; 16.
DR MINT; MINT-189322; -.
DR STRING; 9606.ENSP00000221975; -.
DR PhosphoSite; P39019; -.
DR DMDM; 730640; -.
DR PaxDb; P39019; -.
DR PeptideAtlas; P39019; -.
DR PRIDE; P39019; -.
DR DNASU; 6223; -.
DR Ensembl; ENST00000593863; ENSP00000470004; ENSG00000105372.
DR Ensembl; ENST00000598742; ENSP00000470972; ENSG00000105372.
DR GeneID; 6223; -.
DR KEGG; hsa:6223; -.
DR UCSC; uc002ort.3; human.
DR CTD; 6223; -.
DR GeneCards; GC19P042363; -.
DR HGNC; HGNC:10402; RPS19.
DR MIM; 105650; phenotype.
DR MIM; 603474; gene.
DR neXtProt; NX_P39019; -.
DR Orphanet; 124; Blackfan-Diamond anemia.
DR PharmGKB; PA34803; -.
DR eggNOG; COG2238; -.
DR HOVERGEN; HBG000240; -.
DR InParanoid; P39019; -.
DR KO; K02966; -.
DR OMA; CQSLEKI; -.
DR OrthoDB; EOG74J99M; -.
DR PhylomeDB; P39019; -.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_1762; 3' -UTR-mediated translational regulation.
DR Reactome; REACT_21257; Metabolism of RNA.
DR Reactome; REACT_71; Gene Expression.
DR ChiTaRS; RPS19; human.
DR GeneWiki; Ribosomal_protein_S19; -.
DR GenomeRNAi; 6223; -.
DR NextBio; 24159; -.
DR PRO; PR:P39019; -.
DR ArrayExpress; P39019; -.
DR Bgee; P39019; -.
DR CleanEx; HS_RPS19; -.
DR Genevestigator; P39019; -.
DR GO; GO:0022627; C:cytosolic small ribosomal subunit; IDA:UniProtKB.
DR GO; GO:0005730; C:nucleolus; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0003735; F:structural constituent of ribosome; IDA:UniProtKB.
DR GO; GO:0030218; P:erythrocyte differentiation; IMP:HGNC.
DR GO; GO:0000462; P:maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA); IMP:UniProtKB.
DR GO; GO:0002548; P:monocyte chemotaxis; IDA:UniProtKB.
DR GO; GO:0060266; P:negative regulation of respiratory burst involved in inflammatory response; IDA:UniProtKB.
DR GO; GO:0000184; P:nuclear-transcribed mRNA catabolic process, nonsense-mediated decay; TAS:Reactome.
DR GO; GO:0007000; P:nucleolus organization; IMP:UniProtKB.
DR GO; GO:0051272; P:positive regulation of cellular component movement; TAS:HGNC.
DR GO; GO:0060265; P:positive regulation of respiratory burst involved in inflammatory response; IDA:UniProtKB.
DR GO; GO:0051262; P:protein tetramerization; IDA:UniProtKB.
DR GO; GO:0009991; P:response to extracellular stimulus; TAS:HGNC.
DR GO; GO:0000028; P:ribosomal small subunit assembly; IMP:UniProtKB.
DR GO; GO:0006614; P:SRP-dependent cotranslational protein targeting to membrane; TAS:Reactome.
DR GO; GO:0006414; P:translational elongation; TAS:Reactome.
DR GO; GO:0006413; P:translational initiation; TAS:Reactome.
DR GO; GO:0006415; P:translational termination; TAS:Reactome.
DR GO; GO:0019083; P:viral transcription; TAS:Reactome.
DR InterPro; IPR001266; Ribosomal_S19e.
DR InterPro; IPR018277; Ribosomal_S19e_CS.
DR PANTHER; PTHR11710; PTHR11710; 1.
DR Pfam; PF01090; Ribosomal_S19e; 1.
DR ProDom; PD003854; Ribosomal_S19e; 1.
DR PROSITE; PS00628; RIBOSOMAL_S19E; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Diamond-Blackfan anemia;
KW Direct protein sequencing; Disease mutation; Nucleus;
KW Reference proteome; Ribonucleoprotein; Ribosomal protein.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 145 40S ribosomal protein S19.
FT /FTId=PRO_0000153810.
FT SITE 2 2 Not acetylated.
FT MOD_RES 23 23 N6-acetyllysine.
FT MOD_RES 111 111 N6-acetyllysine.
FT VARIANT 9 14 Missing (in DBA1).
FT /FTId=VAR_055436.
FT VARIANT 15 15 V -> F (in DBA1; affects protein
FT stability; does not localize to the
FT nucleolus).
FT /FTId=VAR_018438.
FT VARIANT 17 17 A -> P (in DBA1).
FT /FTId=VAR_046145.
FT VARIANT 18 19 LA -> E (in DBA1).
FT /FTId=VAR_055437.
FT VARIANT 18 18 L -> P (in DBA1; affects protein
FT stability; does not localize to the
FT nucleolus; affects assembly into a
FT functional ribosomal subunit).
FT /FTId=VAR_018439.
FT VARIANT 18 18 L -> R (in DBA1).
FT /FTId=VAR_046146.
FT VARIANT 21 21 F -> S (in DBA1).
FT /FTId=VAR_055438.
FT VARIANT 47 47 P -> L (in DBA1; affects assembly into a
FT functional ribosomal subunit).
FT /FTId=VAR_018440.
FT VARIANT 52 52 W -> C (in DBA1).
FT /FTId=VAR_055439.
FT VARIANT 52 52 W -> R (in DBA1; affects assembly into a
FT functional ribosomal subunit).
FT /FTId=VAR_018441.
FT VARIANT 55 55 T -> M (in DBA1).
FT /FTId=VAR_018442.
FT VARIANT 56 56 R -> Q (in DBA1; affects assembly into a
FT functional ribosomal subunit).
FT /FTId=VAR_018437.
FT VARIANT 57 57 A -> P (in DBA1; affects protein
FT stability; does not localize to the
FT nucleolus; affects assembly into a
FT functional ribosomal subunit).
FT /FTId=VAR_055440.
FT VARIANT 58 60 Missing (in DBA1).
FT /FTId=VAR_046147.
FT VARIANT 59 59 S -> F (in DBA1).
FT /FTId=VAR_046148.
FT VARIANT 61 61 A -> E (in DBA1; does not localize to the
FT nucleolus; affects assembly into a
FT functional ribosomal subunit).
FT /FTId=VAR_018443.
FT VARIANT 62 62 R -> Q (in DBA1; affects assembly into a
FT functional ribosomal subunit).
FT /FTId=VAR_018444.
FT VARIANT 62 62 R -> W (in DBA1; increased protein
FT degradation; affects assembly into a
FT functional ribosomal subunit).
FT /FTId=VAR_006924.
FT VARIANT 64 64 L -> P (in DBA1).
FT /FTId=VAR_055441.
FT VARIANT 76 76 T -> P (in DBA1).
FT /FTId=VAR_055442.
FT VARIANT 78 83 IYGGRQ -> R (in DBA1).
FT /FTId=VAR_055443.
FT VARIANT 101 101 R -> H (in DBA1; increased protein
FT degradation; affects assembly into a
FT functional ribosomal subunit).
FT /FTId=VAR_018445.
FT VARIANT 120 120 G -> R (in DBA1).
FT /FTId=VAR_018446.
FT VARIANT 127 127 G -> E (in DBA1; affects protein
FT stability; does not localize to the
FT nucleolus; affects assembly into a
FT functional ribosomal subunit).
FT /FTId=VAR_055444.
FT VARIANT 131 131 L -> P (in DBA1).
FT /FTId=VAR_018447.
FT VARIANT 131 131 L -> R (in DBA1).
FT /FTId=VAR_046149.
FT VARIANT 135 135 A -> T (in DBA1).
FT /FTId=VAR_055445.
SQ SEQUENCE 145 AA; 16060 MW; 181F2DB898E56E41 CRC64;
MPGVTVKDVN QQEFVRALAA FLKKSGKLKV PEWVDTVKLA KHKELAPYDE NWFYTRAAST
ARHLYLRGGA GVGSMTKIYG GRQRNGVMPS HFSRGSKSVA RRVLQALEGL KMVEKDQDGG
RKLTPQGQRD LDRIAGQVAA ANKKH
//

MIM 105650
*RECORD*
*FIELD* NO
105650
*FIELD* TI
#105650 DIAMOND-BLACKFAN ANEMIA 1; DBA1
;;DBA;;
BLACKFAN-DIAMOND SYNDROME; BDS;;
ANEMIA, CONGENITAL HYPOPLASTIC, OF BLACKFAN AND DIAMOND;;
read moreANEMIA, CONGENITAL ERYTHROID HYPOPLASTIC;;
RED CELL APLASIA, PURE, HEREDITARY;;
AREGENERATIVE ANEMIA, CHRONIC CONGENITAL;;
ERYTHROGENESIS IMPERFECTA;;
AASE-SMITH SYNDROME II;;
AASE SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
Diamond-Blackfan anemia-1 (DBA1) is caused by heterozygous mutation in
the gene encoding ribosomal protein S19 (RPS19; 603474) on chromosome
19q13.

DESCRIPTION

Diamond-Blackfan anemia (DBA) is an inherited red blood cell aplasia
that usually presents in the first year of life. The main features are
normochromic macrocytic anemia, reticulocytopenia, and nearly absent
erythroid progenitors in the bone marrow. Patients show growth
retardation, and approximately 30 to 50% have craniofacial, upper limb,
heart, and urinary system congenital malformations. The majority of
patients have increased mean corpuscular volume, elevated erythrocyte
adenosine deaminase activity, and persistence of hemoglobin F. However,
some DBA patients do not exhibit these findings, and even in the same
family, symptoms can vary between affected family members (summary by
Landowski et al., 2013).

- Genetic Heterogeneity of Diamond-Blackfan Anemia

A locus for DBA (DBA2; 606129) has been mapped to chromosome 8p23-p22.
Other forms of DBA include DBA3 (610629), caused by mutation in the
RPS24 gene (602412) on chromosome 10q22-q23; DBA4 (612527), caused by
mutation in the RPS17 gene (180472) on 15q; DBA5 (612528), caused by
mutation in the RPL35A gene (180468) on 3q29-qter; DBA6 (612561), caused
by mutation in the RPL5 gene (603634) on 1p22.1; DBA7 (612562), caused
by mutation in the RPL11 gene (604175) on 1p36.1-p35; DBA8 (612563),
caused by mutation in the RPS7 gene (603658) on 2p25; DBA9 (613308),
caused by mutation in the RPS10 gene (603632) on 6p; DBA10 (613309),
caused by mutation in the RPS26 (603701) gene on chromosome 12q; DBA11
(614900), caused by mutation in the RPL26 gene (603704) on 17p13; and
DBA12 (615550), caused by mutation in the RPL15 gene (604174) on
chromosome 3p24.

Boria et al. (2010) provided a review of the molecular basis of
Diamond-Blackfan anemia, emphasizing that it is a disorder of defective
ribosome synthesis.

Gazda et al. (2012) completed a large-scale screen of 79 ribosomal
protein genes in families with Diamond-Blackfan anemia and stated that
of the 10 known DBA-associated genes, RPS19 accounts for approximately
25% of patients; RPS24, 2%; RPS17, 1%; RPL35A, 3.5%; RPL5, 6.6%; RPL11,
4.8%; RPS7, 1%; RPS10, 6.4%; RPS26, 2.6%; and RPL26, 1%. Gazda et al.
(2012) stated that in total these mutations account for approximately
54% of all DBA patients.

CLINICAL FEATURES

Diamond et al. (1961) observed triphalangeal thumbs in 1 of 30 patients
with congenital erythroid hypoplastic anemia. Alter (1978) pointed out
that triphalangeal thumbs occurred in 6 of 133 cases of congenital
hypoplastic anemia. In all, 45 of the 133 cases (34%) had associated
hand anomalies of some kind.

Cathie (1950) described a similar facial appearance in 4 unrelated
affected children with erythrogenesis imperfecta, including snub noses,
thick upper lips, and widely separated eyes.

A propensity for the development of leukemia has been reported (Krishnan
et al., 1978; Wasser et al., 1978).

Ball et al. (1996) analyzed retrospective data from 80 cases of DBA (33
male, 47 female) born in the U.K. in a 20-year period (1975-1994),
representing an annual incidence of 5 per million live births. Ten
children from 7 families had an apparently familial disorder. Thirteen
percent were anemic at birth, and 72.5% had presented by the age of 3
months. Sixty-seven percent had macrocytosis at presentation, 72%
responded initially to steroids, and at the time of study, 61% were
transfusion-dependent, 45% were steroid-dependent, and 39% required
regular transfusions. Unequivocal physical anomalies, predominantly
craniofacial, were present in 37%, and were more likely in boys (52%)
than girls (25%). Eighteen percent had thumb anomalies. Height was below
the third centile for age in 28%; 31% had neither short stature nor
physical anomalies. In 4 children without physical abnormalities, red
cell indices were normal and steroid-independent remission was achieved,
suggesting transient erythroblastopenia of childhood (227050) rather
than DBA. The birth month distribution of children with sporadic DBA and
craniofacial dysmorphism suggested a possible seasonality, consistent
with a viral etiology. In the familial cases, affected males had
unequivocal anomalies, whereas females had only short stature or
equivocal anomalies. In 3 families, 2 generations were affected; in 1
family, 3 generations were affected.

Willig et al. (1999) reported 42 probands with DBA caused by mutation in
the RPS19 gene. The mean age at presentation was 2 months, and
approximately 40% had associated physical anomalies, including
triphalangeal thumb, duplication of thumb, short stature, ventricular
septal defects, kidney hypoplasia, low hairline, and congenital
glaucoma.

INHERITANCE

Willig et al. (1999) stated that although the majority of DBA cases are
sporadic, approximately 10 to 25% are familial, with most showing
autosomal dominant inheritance.

Gazda et al. (2012) stated that approximately 40 to 50% of DBA cases are
familial and show autosomal and commonly dominant inheritance.

Familial cases of congenital erythroid hypoplastic anemia were reported
by Burgert et al. (1954) and by Diamond et al. (1961). Wallman (1956)
described a father and daughter with erythroid hypoplasia, but the ages
of onset (34 and 6 years, respectively) were beyond the usual limits of
the Diamond-Blackfan syndrome. Forare (1963) observed affected brother
and sister with the same father but different mothers. Although he
referred to them as 'step-sibs,' they are actually half-sibs. Mott et
al. (1969) reported a similar situation of 3 affected children from 2
mothers and the same father. Falter and Robinson (1972) described
affected mother and daughter. Only the mother had aminoaciduria,
suggesting that it was unrelated to the hematologic disorder. Lawton et
al. (1974) described father and son with documented erythroid anemia
from infancy. The father's anemia remitted at age 6 years, but he
continued to have macrocytosis, reticulocytosis, and raised fetal
hemoglobin. Hamilton et al. (1974) described affected mother and
daughter. Other families with possible autosomal dominant transmission
were reported by Hunter and Hakami (1972), Wang et al. (1978), and Gray
(1982).

Sensenbrenner (1972) described affected brother and sister. Pallor was
first noted in the male at age 4 months and heart failure from anemia
occurred at 10 months. Prednisone effectively controlled the anemia, but
the brother developed aseptic necrosis of the left hip. Both patients
had height below the 3rd percentile; at age 16, the brother was 147 cm
tall, and at age 11, the sister was 127 cm tall. Both patients showed
appropriate sexual maturation.

Viskochil et al. (1990) reported a kindred with 7 affected members in 4
sibships spanning 3 generations, with several instances of male-to-male
transmission. Hurst et al. (1991) described a mother and son with
congenital erythroid hypoplastic anemia; the son had a right radial club
hand with absent thumb and conjoined radius and ulna on the right with
small, useless thumb on the left. Gojic et al. (1994) reported a family
in which 4 males in 3 successive generations had congenital hypoplastic
anemia. None of these individuals had malformations; specifically, the
thumbs and radii were normal. Two brothers were of short stature: 162
and 156 cm.

Of 6 pedigrees presented by Gustavsson et al. (1997), 2 families
suggested autosomal recessive inheritance, and 4 families showed
dominant inheritance with variable expressivity. In 1 family, the
disease was evident in 3 generations with 2 instances of male-to-male
transmission. In 2 families, the mother showed a mild anemia. In a
fourth family, no phenotype was detected in the parents but the
segregation of haplotypes indicated dominant inheritance from the
mother.

Among 38 multiplex families with DBA collected from multiple geographic
areas, Gazda et al. (2001) found a pedigree pattern consistent with
autosomal dominant inheritance in all but 3. The 3 exceptions were small
pedigrees consisting of 2 affected children and unaffected parents.

DIAGNOSIS

- Prenatal Diagnosis

McLennan et al. (1996) made the prenatal diagnosis of congenital
hypoplastic anemia causing hydrops fetalis in a child born to a
26-year-old woman with steroid-dependent Blackfan-Diamond syndrome. The
diagnosis of BDS had been made in the mother at the age of 2 years
following investigation of short stature and failure to thrive. From the
age of 4 years, she had been treated with steroids, titrated to maintain
a hemoglobin level between 7 and 8.5 g/dl. There was no relevant family
history. Her first pregnancy ended in a spontaneous abortion at 8 weeks.
In the second pregnancy, failure to visualize cardiac structures
adequately at 22 weeks led to referral to a tertiary center.
Cardiomegaly and a small pericardial effusion with structurally normal
heart were demonstrated. By 33 weeks, the mother developed severe
ascites and enlargement of the heart, which occupied nearly the entire
chest. Cordocentesis at that time confirmed severe fetal anemia, and
transfusion of packed red cells was undertaken. The infant was delivered
by cesarean section at 34 weeks. No physical anomalies were found except
for proximal and superior displacement of the first metatarsophalangeal
joint of an otherwise normal left great toe. Mild cardiac failure had
resolved by day 14. Bone marrow at 3 months of age showed a cellular
marrow with normal megakaryocytes and myeloid differentiation but
virtual absence of red cell precursors. Prednisolone was introduced at
that stage without any significant response over the next 2 months. At
14 months of age, the baby was being managed with intermittent
transfusions and continued steroid administration.

CLINICAL MANAGEMENT

Pfeiffer and Ambs (1983) reported a patient in whom, as in other
reported patients, treatment with prednisone was effective.

In 2 out of 6 patients, Dunbar et al. (1991) observed sustained
remission following treatment with interleukin-3 (IL3; 147740).

Willig et al. (1999) assembled a registry of 229 DBA patients, including
151 from France, 70 from Germany, and 8 from other countries. Of 222
available for long-term follow-up analysis, 62.6% initially responded to
steroid therapy. Initial steroid responsiveness was significantly and
independently associated with older age at presentation, family history
of DBA, and normal platelet count at the time of diagnosis. Severe
evolution of the disease, transfusion dependence or death, was
significantly and independently associated with a younger age at
presentation and with a history of premature birth. In contrast,
patients with a family history of the disease experienced a better
outcome. The authors found that reassessing steroid responsiveness
during the course of the disease for initially nonresponsive patients
was useful. Bone marrow transplantation was successful in 11 of 13
cases. They suggested that HLA typing of probands and sibs should be
performed early if patients are transfusion-dependent, and cord blood
should be preserved. In families with dominant inheritance, no parental
imprinting effect or anticipation phenomenon could be demonstrated.

PATHOGENESIS

Nathan et al. (1978) suggested that Diamond-Blackfan anemia may be a
'congenital abnormality of erythropoietin (EPO; 133170) responsiveness
that causes a functional, if not absolute, deficiency of erythroid
precursors.'

Halperin and Freedman (1989) noted that erythroid stem cells in DBA are
partly or completely refractory to EPO. However, they noted that
patients have normal EPO structure and no anti-EPO antibodies,
suggesting that there may be an abnormality in EPO receptor expression,
EPO binding, or EPO signal transduction.

Glader et al. (1983) found increased adenosine deaminase (ADA; 608958)
activity in red cells of patients with DBS. Whitehouse et al. (1984)
found heterogeneity in DBS with respect to erythrocyte ADA activity and
concluded that increased ADA activity was not limited to erythroid
cells. Two sibs in 1 family showed increased red cell ADA activity over
4 months of multiple blood sampling. Both patients had the ADA 2-1
electrophoretic pattern and both allelozymes showed hyperactivity,
indicating that there was not a mutation at the ADA locus.

Abkowitz et al. (1991) cultured marrow and blood mononuclear cells from
10 Diamond-Blackfan patients with various hematopoietic growth factors
in the presence or absence of stem cell factor (SCF; mast cell growth
factor; Steel factor; SF; 184745). Because of erythroid bursts observed
in cultures containing SCF, the authors speculated that the SCF axis may
be involved in the pathogenesis of Diamond-Blackfan anemia, and
suggested that a therapeutic trial of SCF in patients would be
worthwhile. Similar results were obtained by Bagnara et al. (1991) and
by Carow et al. (1991). Sieff et al. (1992) investigated whether DBA was
due to hyporesponsiveness to or hypoproduction of Steel factor. By
studying long-term bone marrow cultures, they found that the DBA
patients studied responded to SCF and produced SCF mRNA normally,
indicating that SCF itself was not involved in DBA pathophysiology.
Olivieri et al. (1991) found no gross abnormalities in the structure of
either stem cell factor or its tyrosine kinase receptor (KIT; 164920) in
10 DBA patients. Spritz and Freedman (1993) found no mutations in either
the SCF or KIT genes in patients with DBA.

Dianzani et al. (1996) stated that there was neither molecular nor
clinical evidence for the involvement of stem cell factor or
interleukin-3 (IL3; 147740) in the pathogenesis of DBA. Dianzani et al.
(1996) also found no abnormality of the coding sequence of the EPOR gene
(133171) in 23 DBA patients using SSCP. A Southern blot hybridization
with an EPOR probe was negative in 7 patients. Furthermore, linkage
studies showed that the disorder did not segregate with the EPOR gene in
2 informative DBA families.

Using gene expression profiling, Gazda et al. (2006) found that
erythroid precursors of 3 patients with RPS19-association DBA in
remission showed downregulation of multiple ribosomal protein genes, as
well as downregulation of genes involved in transcription and
translation compared to cells from 6 control individuals. DBA cells also
showed upregulation of several proapoptotic genes, including TNFRSF10B
(603612) and TNFRSF6 (134637). In addition, DBA cells showed
downregulation of MYB (189990) and changes in expression of other
cancer-related genes. Some of these changes were validated by RT-PCR
studies. Gazda et al. (2006) concluded that DBA results from impaired
ribosome biogenesis and decreased protein translation.

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. The findings indicated that
RPS19 is required for efficient maturation of 40S ribosomal subunits.
The results showed that cells from patients with DFA have a defect in
pre-rRNA processing, and Flygare et al. (2007) concluded that the
disorder results from defects in ribosome synthesis.

MAPPING

Gustavsson et al. (1997) reported a female patient with a de novo
balanced translocation t(X;19)(p21;q13) who presented with
constitutional erythroblastopenia as well as short stature and left
kidney hypoplasia. By analysis of 26 families with DBA, Gustavsson et
al. (1997) found linkage to chromosome 19q13 with a peak lod score at
D19S197 (maximum lod = 7.08, theta = 0.00). Within this region, a
submicroscopic de novo deletion of 3.3 Mb was identified in a patient
with DBA. The deletion coincided with the translocation breakpoint
observed in the patient mentioned earlier and, together with key
recombinations, restricted the DBA gene to a 1.8-Mb region.

Using polymorphic 19q13 markers, including a short-tandem repeat in the
critical DBA locus region, Gustavsson et al. (1998) studied 29 multiplex
DBA families and 50 families with sporadic DBA cases. In 26 of the 29
multiplex families, DNA analysis yielded results consistent with a DBA
gene on 19q within a 4.1-cM interval restricted by D19S200 and D19S178;
however, in 3 multiplex families, the DBA candidate region on 19q13 was
excluded from the segregation of marker alleles. This result suggested
genetic heterogeneity for DBA, but indicated that the gene region on 19q
segregates with the majority of familial cases. Among the 50 families
comprising sporadic DBA cases, Gustavsson et al. (1998) identified 2 de
novo and overlapping microdeletions on 19q13. In combination, the 3
known microdeletions associated with DBA restricted the critical gene
region to approximately 1 Mb.

- Genetic Heterogeneity

In 5 of 12 Italian families with DBA, Ramenghi et al. (1999) excluded
the locus on 19q.

Costa et al. (2002) described piebaldism in a patient with DBA who did
not have a mutation in the RPS19, KIT, or SCF genes. RPS19 is involved
in approximately 25% of patients with DBA, KIT is a basis for piebald
trait, and SCF is the KIT ligand. Costa et al. (2002) suggested that DBA
with piebaldism may represent a novel phenotype due to mutation in a
gene not previously identified.

MOLECULAR GENETICS

In 10 of 40 probands with DBA, Draptchinskaia et al. (1999) identified 9
different heterozygous mutations in the RPS19 gene (see, e.g.,
603474.0001-603474.0002). Twenty-one patients had a family history of
the disorder and 19 were sporadic cases. Six of the patients with
mutations had a family history of the disorder. No mutations were found
in the 5-prime untranslated region sequence or in the coding sequence in
the 30 other probands.

Willig et al. (1999) identified heterozygous mutations in the RPS19 gene
in 42 (24.4%) of 172 index patients with DBA. Mutations in the RPS19
gene were also found in some apparently unaffected individuals from DBA
families who presented only with increased ADA levels. The authors found
no genotype/phenotype correlations. For example, in 1 family, a pair of
monozygotic twins had the same mutation, but only 1 of them had a thumb
malformation.

Gazda et al. (2006) stated that mutation in the RPS19 gene occurs in an
estimated 25% of probands with DBA. The authors identified de novo
nonsense and splice site mutations in another ribosomal protein, RPS24
(602412), in 3 families with DBA. This finding strongly suggests that
DBA is a disorder of ribosome synthesis and that mutations in other
ribosomal proteins or associated genes that lead to disrupted ribosomal
biogenesis and/or function may also cause 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 large
deletions in 6 (7%) of the patients, including a deletion in the RPS19
gene (603474.0009) in a steroid-dependent male patient with a webbed
neck. Large deletions were also identified in the RPS24, RPS17, RPS26,
and RPL15 genes; Landowski et al. (2013) proposed screening of all 80
ribosomal protein genes for copy number changes in DBA patients.

GENOTYPE/PHENOTYPE CORRELATIONS

Gazda et al. (2008) screened 196 probands with DBA for mutations in 25
genes encoding ribosomal proteins and identified mutations in the RPL5
(603634), RPL11 (604175), and RPS7 (603658) genes that segregated with
disease in multiplex families and were associated with defects in the
maturation of ribosomal RNAs in vitro. Mutations in RPL5 were associated
with craniofacial abnormalities, particularly cleft lip and/or palate,
in 9 of 14 patients with known malformations; the authors noted that
none of the 12 DBA patients with RPL11 mutations and associated
malformations had craniofacial abnormalities (p = 0.007) nor did any of
the 35 previously reported DBA patients with RPS19 mutations and
associated malformations (p = 9.745 x 10(-7)). In addition, mutations in
RPL5 appeared to cause a more severe phenotype compared to mutations in
RPL11 or RPS19, with RPL11 mutations being predominantly associated with
thumb abnormalities.

POPULATION GENETICS

In France, Willig et al. (1999) estimated the incidence of DBA to be 7.3
cases per million live births.

Landowski et al. (2013) stated that the incidence of DBA is estimated to
be 5 to 7 per million live births, equally distributed between genders.

HISTORY

Mentzer (2003) provided a biographic sketch of Louis Diamond (1902-1999)
and a review of his contributions to pediatric hematology. Diamond and
Blackfan (1938) described 'their' syndrome in an article on hypoplastic
anemia. They reported 4 children with hypoplastic anemia beginning in
infancy and requiring red cell transfusions at regular intervals.
Similar cases had been reported earlier by Josephs (1936) at Johns
Hopkins. Diamond's name is also associated with that of Shwachman in the
syndrome of pancreatic insufficiency and bone marrow dysfunction,
Shwachman-Diamond syndrome (260400).

'Congenital (erythroid) hypoplastic anemia' was the term used by Diamond
et al. (1961) for the disorder subsequently called Diamond-Blackfan
anemia. Confusingly, Estren and Dameshek (1947) had used the designation
'familial hypoplastic anemia' for the disorder in 2 families that were
later shown to have Fanconi anemia (FA; 227650) (Li and Potter, 1978).

*FIELD* SA
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(1974); van Weel-Sipman et al. (1977)
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by array-comparative genomic hybridization in Diamond-Blackfan anemia. Hum.
Genet. 132: 1265-1274, 2013.

43. Lawton, J. W. M.; Aldrich, J. E.; Turner, T. L.: Congenital erythroid
hypoplastic anemia: autosomal dominant transmission. Scand. J. Haemat. 13:
276-280, 1974.

44. Li, F. P.; Potter, N. U.: Classical Fanconi anemia in a family
with hypoplastic anemia. J. Pediat. 92: 943-944, 1978.

45. McLennan, A. C.; Chitty, L. S.; Rissik, J.; Maxwell, D. J.: Prenatal
diagnosis of Blackfan-Diamond syndrome: case report and review of
the literature. Prenatal Diag. 16: 349-353, 1996.

46. Mentzer, W. C.: Louis Diamond and his contribution to haematology. Brit.
J. Haemat. 123: 389-395, 2003.

47. Mott, M. G.; Apley, J.; Raper, A. B.: Congenital (erythroid)
hypoplastic anaemia: modified expression in males. Arch. Dis. Child. 44:
757-760, 1969.

48. Muis, N.; Beemer, F. A.; van Dijken, P.; Klep-de Pater, J. M.
: The Aase syndrome: case report and review of the literature. Europ.
J. Pediat. 145: 153-157, 1986.

49. Murphy, S.; Lubin, B.: Triphalangeal thumbs and congenital erythroid
hypoplasia: report of a case with unusual features. J. Pediat. 81:
987-989, 1972.

50. Nathan, D. G.; Clarke, B. J.; Hillman, D. G.; Alter, B. P.; Housman,
D. E.: Erythroid precursors in congenital hypoplastic (Diamond-Blackfan)
anemia. J. Clin. Invest. 61: 489-498, 1978.

51. Olivieri, N. F.; Grunberger, T.; Ben-David, Y.; Ng, J.; Williams,
D. E.; Lyman, S.; Anderson, D. M.; Axelrad, A. A.; Correa, P.; Bernstein,
A.; Freedman, M. H.: Diamond-Blackfan anemia: heterogenous response
of hematopoietic progenitor cells in vitro to the protein product
of the Steel locus. Blood 78: 2211-2215, 1991.

52. Pearson, H. A.; Cone, T. E., Jr.: Congenital hypoplastic anemia. Pediatrics 19:
192-200, 1957.

53. Pfeiffer, R. A.; Ambs, E.: Das Aase-Syndrom: autosomal-rezessiv
vererbte, konnatal insuffiziente Erythropoese und Triphalangie der
Daumen. Mschr. Kinderheilk. 131: 235-237, 1983.

54. Ramenghi, U.; Garelli, E.; Valtolina, S.; Campagnoli, M. F.; Timeus,
F.; Crescenzio, N.; Mair, M.; Varotto, S.; D'Avanzo, M.; Nobili, B.;
Massolo, F.; Mori, P. G.; Locatelli, F.; Gustavsson, P.; Dahl, N.;
Dianzani, I.: Diamond-Blackfan anaemia in the Italian population. Brit.
J. Haemat. 104: 841-848, 1999.

55. Sensenbrenner, J. A.: Congenital hypoplastic anemia of Blackfan
and Diamond in sibs. Birth Defects Orig. Art. Ser. 8(3): 166-170,
1972.

56. Sieff, C. A.; Yokoyama, C. T.; Zsebo, K. M.; Trammell, J.; Andersen,
J. W.; Nathan, D. G.; Williams, D. A.: The production of Steel factor
mRNA in Diamond-Blackfan anaemia long-term cultures and interactions
of Steel factor with erythropoietin and interleukin-3. Brit. J. Haemat. 82:
640-647, 1992.

57. Spritz, R. A.; Freedman, M. H.: Lack of mutations of the MGF
and KIT genes in Diamond-Blackfan anemia. (Letter) Blood 81: 3165,
1993.

58. Terheggen, H. G.: Hypoplastic anemia accompanied by triphalangeal
thumbs. Z. Kinderheilk. 118: 71-80, 1974.

59. van Weel-Sipman, M.; van de Kamp, J. J. P.; de Koning, J.: A
female patient with 'Aase syndrome.'. J. Pediat. 91: 753-755, 1977.

60. Viskochil, D. H.; Carey, J. C.; Glader, B. E.; Rothstein, G.;
Christensen, R. D.: Congenital hypoplastic (Diamond-Blackfan) anemia
in seven members of one kindred. Am. J. Med. Genet. 35: 251-256,
1990.

61. Wallman, I. S.: Hereditary red cell aplasia. Med. J. Aust. 2:
488-490, 1956.

62. Wang, W. C.; Mentzer, W.; Alter, B.: Congenital hypoplastic anemia:
Diamond-Blackfan syndrome: comments and additional data on clinical
aspects of Diamond-Blackfan syndrome. Blood Cells 4: 215-218, 1978.

63. Wasser, J. S.; Yolken, R.; Miller, D. R.; Diamond, L.: Congenital
hypoplastic anemia (Diamond-Blackfan syndrome) terminating in acute
myelogenous leukemia. Blood 51: 991-995, 1978.

64. Whitehouse, D. B.; Hopkinson, D. A.; Evans, D. I. K.: Adenosine
deaminase activity in Diamond-Blackfan syndrome. (Letter) Lancet 324:
1398-1399, 1984. Note: Originally Volume II.

65. 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.

66. Willig, T.-N.; Niemeyer, C. M.; Leblanc, T.; Tiemann, C.; Robert,
A.; Budde, J.; Lambiliotte, A.; Kohne, E.; Souillet, G.; Eber, S.;
Stephan, J. L.; Girot, R.; Bordigoni, P.; Cornu, G.; Blanche, S; Guillard,
J. M.; Mohandas, N.; Tchernia, G.: Identification of new prognosis
factors from the clinical and epidemiologic analysis of a registry
of 229 Diamond-Blackfan anemia patients. Pediat. Res. 46: 553-561,
1999.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Height];
Short stature;
[Other];
Intrauterine growth retardation, mild;
Failure to thrive

HEAD AND NECK:
[Head];
Microcephaly;
Delayed closure of fontanel;
[Face];
Micrognathia;
Retrognathia;
[Eyes];
Downslanting palpebral fissures;
Hypertelorism;
Strabismus;
[Nose];
Flat nose;
[Mouth];
Cleft lip;
Cleft palate;
High-arched palate;
[Neck];
Webbed neck;
Short neck

CARDIOVASCULAR:
[Heart];
Atrial septal defect;
Ventricular septal defect;
[Vascular];
Coarctation of the aorta;
Absent radial pulse

CHEST:
[External features];
Narrow shoulders;
[Ribs, sternum, clavicles, and scapulae];
11 pairs of ribs;
Clavicle agenesis

SKELETAL:
[Skull];
Parietal foramina;
[Spine];
Bifid thoracic vertebrae;
Hypoplastic sacral vertebrae;
Hypoplastic coccygeal vertebrae;
[Pelvis];
Hypoplastic ilia;
[Limbs];
Mild radial hypoplasia;
[Hands];
Triphalangeal thumbs;
Bifid thumbs;
Hypoplastic thumbs;
Absent thumbs

SKIN, NAILS, HAIR:
[Skin];
Pallor

NEUROLOGIC:
[Central nervous system];
Mental retardation (in some patients)

HEMATOLOGY:
Anemia, congenital hypoplastic, moderate-severe (normochromic, macrocytic);
Reticulocytopenia;
Neutropenia, mild;
Thrombocytosis;
Thrombocytopenia;
Elevated fetal hemoglobin (HbF);
Presence of i erythrocyte antigen;
Increased myeloid to erythroid ratio (M:E ratio) 10:1-200:1

NEOPLASIA:
Osteogenic sarcoma;
Myelodysplastic syndrome;
Colon cancer

PRENATAL MANIFESTATIONS:
[Delivery];
Premature birth

LABORATORY ABNORMALITIES:
Elevated erythrocyte adenine deaminase (eADA)

MISCELLANEOUS:
Onset in infancy;
Age at diagnosis 2-4 months;
40% patients have associated abnormalities;
Variable expressivity in families;
Most cases are sporadic

MOLECULAR BASIS:
Caused by mutation in the ribosomal protein S19 gene (RPS19, 603474.0001)

*FIELD* CN
Marla J. F. O'Neill - updated: 03/26/2010
Kelly A. Przylepa - revised: 8/13/2002

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 03/26/2010
joanna: 3/26/2010
joanna: 3/14/2005
joanna: 8/15/2002
joanna: 8/13/2002

*FIELD* CN
Marla J. F. O'Neill - updated: 12/2/2013
Cassandra L. Kniffin - updated: 2/20/2013
Marla J. F. O'Neill - updated: 11/1/2012
Cassandra L. Kniffin - updated: 3/16/2011
Marla J. F. O'Neill - updated: 3/18/2010
Cassandra L. Kniffin - updated: 3/11/2009
Marla J. F. O'Neill - updated: 1/26/2009
Marla J. F. O'Neill - updated: 1/13/2009
Victor A. McKusick - updated: 11/28/2006
Cassandra L. Kniffin - reorganized: 6/23/2005
Victor A. McKusick - updated: 7/17/2001
Victor A. McKusick - updated: 10/26/1999
Victor A. McKusick - updated: 1/28/1999

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 12/02/2013
carol: 12/2/2013
mcolton: 11/27/2013
carol: 11/4/2013
carol: 2/20/2013
ckniffin: 2/20/2013
ckniffin: 2/19/2013
carol: 11/1/2012
terry: 11/1/2012
ckniffin: 9/25/2012
carol: 8/10/2011
wwang: 3/24/2011
ckniffin: 3/16/2011
carol: 3/18/2010
wwang: 3/19/2009
ckniffin: 3/11/2009
wwang: 1/29/2009
terry: 1/26/2009
carol: 1/13/2009
terry: 1/13/2009
terry: 1/7/2009
alopez: 12/5/2006
terry: 11/28/2006
terry: 3/22/2006
carol: 6/23/2005
ckniffin: 6/15/2005
terry: 4/18/2005
terry: 6/25/2004
terry: 6/2/2004
carol: 7/20/2001
terry: 7/17/2001
carol: 10/27/1999
terry: 10/26/1999
alopez: 2/2/1999
terry: 1/28/1999
carol: 8/22/1996
marlene: 8/2/1996
terry: 7/29/1996
jason: 6/7/1994
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 9/27/1991
supermim: 3/20/1990
supermim: 2/28/1990

MIM 603474
*RECORD*
*FIELD* NO
603474
*FIELD* TI
*603474 RIBOSOMAL PROTEIN S19; RPS19
*FIELD* TX

DESCRIPTION

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

CLONING

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 gln (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 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.

*FIELD* AV
.0001
DIAMOND-BLACKFAN ANEMIA 1
RPS19, ARG94TER

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

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

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

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

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

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, THR55MET

In a girl with Diamond-Blackfan anemia (105650), 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, GLY127GLN

Da Costa et al. (2003) reported a gly127-to-gln (G127N) missense
mutation in the RPS19 gene in a female child in whom the diagnosis of
Diamond-Blackfan anemia (105650) had been made at the age of 1 month.
The patient was small for gestational age and showed deafness and hip
hypoplasia. Her mutation was found to result in failure of the RPS19
protein to localize to the nucleolus.

.0009
DIAMOND-BLACKFAN ANEMIA 1
RPS19, 5,070-BP DEL

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.

*FIELD* RF
1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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
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*FIELD* CN
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

*FIELD* CD
Victor A. McKusick: 2/2/1999

*FIELD* ED
carol: 12/02/2013
mcolton: 11/27/2013
wwang: 3/19/2009
ckniffin: 3/11/2009
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