RBCC Red Blood Cell Collection

SBDS [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Ribosome maturation protein SBDS (Shwachman-Bodian-Diamond syndrome protein)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q9Y3A5
ID SBDS_HUMAN Reviewed; 250 AA.
AC Q9Y3A5; A8K0P4; Q96FX0; Q9NV53;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 124.
DE RecName: Full=Ribosome maturation protein SBDS;
DE AltName: Full=Shwachman-Bodian-Diamond syndrome protein;
GN Name=SBDS; ORFNames=CGI-97;
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], AND VARIANTS SDS LYS-8; GLY-44; GLU-67;
RP SER-87; THR-126; CYS-169 AND THR-212.
RX PubMed=12496757; DOI=10.1038/ng1062;
RA Boocock G.R.B., Morrison J.A., Popovic M., Richards N., Ellis L.,
RA Durie P.R., Rommens J.M.;
RT "Mutations in SBDS are associated with Shwachman-Diamond syndrome.";
RL Nat. Genet. 33:97-101(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=10810093; DOI=10.1101/gr.10.5.703;
RA Lai C.-H., Chou C.-Y., Ch'ang L.-Y., Liu C.-S., Lin W.-C.;
RT "Identification of novel human genes evolutionarily conserved in
RT Caenorhabditis elegans by comparative proteomics.";
RL Genome Res. 10:703-713(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain cortex, and Ovarian carcinoma;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=PNS;
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 [6]
RP PROTEIN SEQUENCE OF 2-19, CLEAVAGE OF INITIATOR METHIONINE,
RP ACETYLATION AT SER-2, AND MASS SPECTROMETRY.
RC TISSUE=Platelet;
RA Bienvenut W.V., Claeys D.;
RL Submitted (NOV-2005) to UniProtKB.
RN [7]
RP SUBCELLULAR LOCATION.
RX PubMed=15860664; DOI=10.1182/blood-2005-02-0807;
RA Austin K.M., Leary R.J., Shimamura A.;
RT "The Shwachman-Diamond SBDS protein localizes to the nucleolus.";
RL Blood 106:1253-1258(2005).
RN [8]
RP INTERACTION WITH NPM1 AND THE 60S RIBOSOMAL SUBUNIT, AND SUBCELLULAR
RP LOCATION.
RX PubMed=17475909; DOI=10.1182/blood-2007-02-075184;
RA Ganapathi K.A., Austin K.M., Lee C.S., Dias A., Malsch M.M., Reed R.,
RA Shimamura A.;
RT "The human Shwachman-Diamond syndrome protein, SBDS, associates with
RT ribosomal RNA.";
RL Blood 110:1458-1465(2007).
RN [9]
RP FUNCTION, AND INTERACTION WITH NIP7.
RX PubMed=17643419; DOI=10.1016/j.yexcr.2007.06.024;
RA Hesling C., Oliveira C.C., Castilho B.A., Zanchin N.I.;
RT "The Shwachman-Bodian-Diamond syndrome associated protein interacts
RT with HsNip7 and its down-regulation affects gene expression at the
RT transcriptional and translational levels.";
RL Exp. Cell Res. 313:4180-4195(2007).
RN [10]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH RPA1; PRKDC AND
RP THE 60S RIBOSOME SUBUNIT.
RX PubMed=19602484; DOI=10.1093/hmg/ddp316;
RA Ball H.L., Zhang B., Riches J.J., Gandhi R., Li J., Rommens J.M.,
RA Myers J.S.;
RT "Shwachman-Bodian Diamond syndrome is a multi-functional protein
RT implicated in cellular stress responses.";
RL Hum. Mol. Genet. 18:3684-3695(2009).
RN [11]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=19759903; DOI=10.1371/journal.pone.0007084;
RA Orelio C., Verkuijlen P., Geissler J., van den Berg T.K.,
RA Kuijpers T.W.;
RT "SBDS expression and localization at the mitotic spindle in human
RT myeloid progenitors.";
RL PLoS ONE 4:E7084-E7084(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 ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, AND MASS SPECTROMETRY.
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 NMR, AND RNA-BINDING.
RX PubMed=20053358; DOI=10.1016/j.jmb.2009.12.039;
RA de Oliveira J.F., Sforca M.L., Blumenschein T.M., Goldfeder M.B.,
RA Guimaraes B.G., Oliveira C.C., Zanchin N.I., Zeri A.C.;
RT "Structure, dynamics, and RNA interaction analysis of the human SBDS
RT protein.";
RL J. Mol. Biol. 396:1053-1069(2010).
RN [15]
RP STRUCTURE BY NMR, FUNCTION, CHARACTERIZATION OF VARIANT SDS THR-126,
RP AND MUTAGENESIS OF LYS-151.
RX PubMed=21536732; DOI=10.1101/gad.623011;
RA Finch A.J., Hilcenko C., Basse N., Drynan L.F., Goyenechea B.,
RA Menne T.F., Gonzalez Fernandez A., Simpson P., D'Santos C.S.,
RA Arends M.J., Donadieu J., Bellanne-Chantelot C., Costanzo M.,
RA Boone C., McKenzie A.N., Freund S.M., Warren A.J.;
RT "Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes
RT Shwachman-Diamond syndrome.";
RL Genes Dev. 25:917-929(2011).
CC -!- FUNCTION: Required for the assembly of mature ribosomes and
CC ribosome biogenesis. Together with EFTUD1, triggers the GTP-
CC dependent release of EIF6 from 60S pre-ribosomes in the cytoplasm,
CC thereby activating ribosomes for translation competence by
CC allowing 80S ribosome assembly and facilitating EIF6 recycling to
CC the nucleus, where it is required for 60S rRNA processing and
CC nuclear export. Required for normal levels of protein synthesis.
CC May play a role in cellular stress resistance. May play a role in
CC cellular response to DNA damage. May play a role in cell
CC proliferation.
CC -!- SUBUNIT: Associates with the 60S ribosomal subunit. Interacts with
CC NPM1, RPA1 and PRKDC. May interact with NIP7.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus, nucleolus. Nucleus,
CC nucleoplasm. Cytoplasm, cytoskeleton, spindle. Note=Primarily
CC detected in the cytoplasm, and at low levels in nucleus and
CC nucleolus (PubMed:19602484 and PubMed:17475909). Detected in the
CC nucleolus during G1 and G2 phase of the cell cycle, and diffusely
CC distributed in the nucleus during S phase. Detected at the mitotic
CC spindle. Colocalizes with the microtubule organizing center during
CC interphase (PubMed:19759903).
CC -!- TISSUE SPECIFICITY: Widely expressed.
CC -!- DISEASE: Shwachman-Diamond syndrome (SDS) [MIM:260400]: Autosomal
CC recessive disorder characterized by pancreatic exocrine
CC insufficiency, hematologic dysfunction, and skeletal
CC abnormalities. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the SDO1/SBDS family.
CC -!- WEB RESOURCE: Name=SBDSbase; Note=SBDS mutation db;
CC URL="http://bioinf.uta.fi/SBDSbase/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SBDS";
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DR EMBL; AY169963; AAN77490.1; -; mRNA.
DR EMBL; AF151855; AAD34092.1; -; mRNA.
DR EMBL; AK001779; BAA91905.1; -; mRNA.
DR EMBL; AK289609; BAF82298.1; -; mRNA.
DR EMBL; CH471140; EAX07906.1; -; Genomic_DNA.
DR EMBL; BC065700; AAH65700.1; -; mRNA.
DR RefSeq; NP_057122.2; NM_016038.2.
DR UniGene; Hs.110445; -.
DR PDB; 2KDO; NMR; -; A=1-250.
DR PDB; 2L9N; NMR; -; A=1-250.
DR PDBsum; 2KDO; -.
DR PDBsum; 2L9N; -.
DR ProteinModelPortal; Q9Y3A5; -.
DR SMR; Q9Y3A5; 1-250.
DR IntAct; Q9Y3A5; 1.
DR MINT; MINT-3085538; -.
DR STRING; 9606.ENSP00000246868; -.
DR PhosphoSite; Q9Y3A5; -.
DR DMDM; 28380824; -.
DR PaxDb; Q9Y3A5; -.
DR PeptideAtlas; Q9Y3A5; -.
DR PRIDE; Q9Y3A5; -.
DR DNASU; 51119; -.
DR Ensembl; ENST00000246868; ENSP00000246868; ENSG00000126524.
DR GeneID; 51119; -.
DR KEGG; hsa:51119; -.
DR UCSC; uc003tvm.1; human.
DR CTD; 51119; -.
DR GeneCards; GC07M066452; -.
DR HGNC; HGNC:19440; SBDS.
DR HPA; HPA028891; -.
DR MIM; 260400; phenotype.
DR MIM; 607444; gene.
DR neXtProt; NX_Q9Y3A5; -.
DR Orphanet; 88; Idiopathic aplastic anemia.
DR Orphanet; 811; Shwachman-Diamond syndrome.
DR PharmGKB; PA134978742; -.
DR eggNOG; COG1500; -.
DR HOGENOM; HOG000216685; -.
DR HOVERGEN; HBG039762; -.
DR InParanoid; Q9Y3A5; -.
DR KO; K14574; -.
DR OMA; RSGIETD; -.
DR OrthoDB; EOG7XWPPD; -.
DR PhylomeDB; Q9Y3A5; -.
DR ChiTaRS; SBDS; human.
DR EvolutionaryTrace; Q9Y3A5; -.
DR GeneWiki; SBDS; -.
DR GenomeRNAi; 51119; -.
DR NextBio; 53897; -.
DR PRO; PR:Q9Y3A5; -.
DR ArrayExpress; Q9Y3A5; -.
DR Bgee; Q9Y3A5; -.
DR CleanEx; HS_SBDS; -.
DR Genevestigator; Q9Y3A5; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005730; C:nucleolus; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0000922; C:spindle pole; IDA:UniProtKB.
DR GO; GO:0008017; F:microtubule binding; IDA:UniProtKB.
DR GO; GO:0043022; F:ribosome binding; IDA:UniProtKB.
DR GO; GO:0019843; F:rRNA binding; IDA:UniProtKB.
DR GO; GO:0048539; P:bone marrow development; IMP:UniProtKB.
DR GO; GO:0030282; P:bone mineralization; IMP:UniProtKB.
DR GO; GO:0008283; P:cell proliferation; IMP:UniProtKB.
DR GO; GO:0001833; P:inner cell mass cell proliferation; IEA:Ensembl.
DR GO; GO:0030595; P:leukocyte chemotaxis; IDA:UniProtKB.
DR GO; GO:0042256; P:mature ribosome assembly; IDA:UniProtKB.
DR GO; GO:0043148; P:mitotic spindle stabilization; IDA:UniProtKB.
DR GO; GO:0042273; P:ribosomal large subunit biogenesis; IBA:RefGenome.
DR GO; GO:0006364; P:rRNA processing; IMP:UniProtKB.
DR InterPro; IPR018978; Ribosome_mat_SBDS_C.
DR InterPro; IPR018023; Ribosome_mat_SBDS_CS.
DR InterPro; IPR019783; Ribosome_mat_SBDS_N.
DR InterPro; IPR002140; Ribosome_maturation_pr_SBDS.
DR PANTHER; PTHR10927; PTHR10927; 1.
DR Pfam; PF01172; SBDS; 1.
DR Pfam; PF09377; SBDS_C; 1.
DR SUPFAM; SSF89895; SSF89895; 1.
DR TIGRFAMs; TIGR00291; RNA_SBDS; 1.
DR PROSITE; PS01267; UPF0023; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; Disease mutation; Nucleus;
KW Reference proteome; Ribosome biogenesis.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 250 Ribosome maturation protein SBDS.
FT /FTId=PRO_0000123762.
FT MOD_RES 2 2 N-acetylserine.
FT VARIANT 8 8 N -> K (in SDS; dbSNP:rs28942099).
FT /FTId=VAR_015390.
FT VARIANT 44 44 E -> G (in SDS).
FT /FTId=VAR_015391.
FT VARIANT 67 67 K -> E (in SDS).
FT /FTId=VAR_015392.
FT VARIANT 87 87 I -> S (in SDS).
FT /FTId=VAR_015393.
FT VARIANT 126 126 R -> T (in SDS; strongly reduced release
FT of EIF6 from pre-60S ribosome subunits).
FT /FTId=VAR_015394.
FT VARIANT 169 169 R -> C (in SDS).
FT /FTId=VAR_015395.
FT VARIANT 212 212 I -> T (in SDS; dbSNP:rs79344818).
FT /FTId=VAR_015396.
FT MUTAGEN 151 151 K->N: Strongly reduced release of EIF6
FT from pre-60S ribosome subunits.
FT CONFLICT 41 43 SGV -> RAW (in Ref. 2; AAD34092).
FT CONFLICT 89 89 T -> A (in Ref. 2; AAD34092).
FT CONFLICT 105 105 E -> G (in Ref. 2; AAD34092).
FT CONFLICT 114 114 I -> F (in Ref. 2; AAD34092).
FT CONFLICT 126 126 R -> G (in Ref. 2; AAD34092).
FT CONFLICT 143 143 S -> L (in Ref. 2; AAD34092).
FT CONFLICT 146 146 T -> P (in Ref. 2; AAD34092).
FT TURN 6 8
FT STRAND 14 21
FT STRAND 26 35
FT HELIX 36 40
FT HELIX 47 50
FT STRAND 51 55
FT STRAND 56 59
FT TURN 60 63
FT STRAND 64 66
FT HELIX 68 74
FT HELIX 80 89
FT STRAND 90 93
FT STRAND 97 103
FT HELIX 107 116
FT TURN 122 125
FT HELIX 130 140
FT HELIX 150 164
FT STRAND 168 170
FT STRAND 174 177
FT HELIX 180 186
FT TURN 187 189
FT HELIX 190 193
FT STRAND 196 200
FT STRAND 203 205
FT STRAND 208 210
FT HELIX 214 216
FT HELIX 217 227
FT TURN 228 231
FT STRAND 232 236
FT STRAND 240 242
SQ SEQUENCE 250 AA; 28764 MW; D35C43003C05F5A7 CRC64;
MSIFTPTNQI RLTNVAVVRM KRAGKRFEIA CYKNKVVGWR SGVEKDLDEV LQTHSVFVNV
SKGQVAKKED LISAFGTDDQ TEICKQILTK GEVQVSDKER HTQLEQMFRD IATIVADKCV
NPETKRPYTV ILIERAMKDI HYSVKTNKST KQQALEVIKQ LKEKMKIERA HMRLRFILPV
NEGKKLKEKL KPLIKVIESE DYGQQLEIVC LIDPGCFREI DELIKKETKG KGSLEVLNLK
DVEEGDEKFE
//

MIM 260400
*RECORD*
*FIELD* NO
260400
*FIELD* TI
#260400 SHWACHMAN-DIAMOND SYNDROME; SDS
;;PANCREATIC INSUFFICIENCY AND BONE MARROW DYSFUNCTION;;
read moreSHWACHMAN-BODIAN SYNDROME;;
LIPOMATOSIS OF PANCREAS, CONGENITAL
*FIELD* TX
A number sign (#) is used with this entry because the Shwachman-Diamond
syndrome, also known as the Shwachman-Bodian-Diamond syndrome, is caused
by compound heterozygous or homozygous mutations in the SBDS gene
(607444).

Heterozygous mutations in the SBDS gene have been associated with
predisposition to aplastic anemia (609135).

DESCRIPTION

Shwachman-Diamond syndrome is characterized primarily by exocrine
pancreatic insufficiency, hematologic abnormalities, including increased
risk of malignant transformation, and skeletal abnormalities.

For a review of Shwachman-Diamond syndrome, see Dror and Freedman
(2002).

CLINICAL FEATURES

Shwachman et al. (1964) described a syndrome of pancreatic insufficiency
(suggesting cystic fibrosis of the pancreas but with normal sweat
electrolytes and no respiratory difficulties) and pancytopenia. One
sibship contained 2 affected brothers and an affected female. From the
early paper of Bartholomew et al. (1959) it appears that so-called
primary atrophy of the pancreas may be, in some instances, the same
disorder and that manifestations may develop first after the fifth
decade of life. The same syndrome was described by Nezelof and Watchi
(1961) and later by other authors such as Pringle et al. (1968).
Goldstein (1968) and others before him called this condition congenital
lipomatosis of the pancreas. He described one affected fraternal twin
girl. Affected sibs were referred to by Burke et al. (1967). Pringle et
al. (1968) observed associated skeletal changes of the metaphyseal
dysostosis type. These are of interest because of the digestive
abnormalities (not yet well characterized) and hematologic changes in
cartilage-hair hypoplasia (250250), a form of metaphyseal
chondrodysplasia. The exocrine pancreas is replaced by fat, whereas the
islets of Langerhans are normal.

Although dwarfing is usually moderate and becomes apparent only after 1
or 2 years of life, Danks et al. (1976) described 2 pairs of brothers
who showed neonatal respiratory distress, resembling that of Jeune
syndrome (208500), due to abnormally short ribs. The true nature of the
osseous disorder became clear in the second or third year of life.
Susceptibility to infection was marked in 1 family and led to death of 1
of the brothers.

Wulfeck et al. (1991), who referred to this disorder as
Shwachman-Diamond syndrome, evaluated 2 affected sisters, aged 8 and 13
years, in whom the most prominent neurologic abnormality was global
apraxia, which affected their motor skills. Generalized weakness and
hypotonia were also observed.

Mack et al. (1996) reviewed findings in 25 patients. Mean birth weight
was at the 25th percentile; however, by 6 months of age, mean heights
and weights were less than the 5th percentile. After 6 months of age,
growth velocity was normal. Neutropenia was the most common hematologic
abnormality (88%), but leukopenia, thrombocytopenia, and anemia were
also frequently encountered. Eleven patients with hypoplasia of all 3
bone marrow cellular lines had the worst prognosis; 5 patients died, 2
of sepsis and 3 of acute myelogeneous leukemia (AML; 601626).

Ginzberg et al. (1999) collected data from 116 families with Shwachman
syndrome. In 88 patients (33 female, 55 male; median age, 5.2 years),
their predetermined diagnostic criteria were fulfilled; 63 patients
represented isolated cases, and 25 affected sibs were from 12 multiplex
families. Steatorrhea was present in 86% (57 of 66), and 91% (78 of 86)
displayed a low serum trypsinogen concentration. Patients older than 4
years more often had pancreatic sufficiency. Neutropenia occurred in
98%, anemia in 42%, and thrombocytopenia in 34%. Myelodysplasia or
cytogenetic abnormalities were reported in 7 patients. Short stature
with normal nutritional status was a prominent feature. Similarities in
phenotype between isolated cases and affected sib sets supported the
hypothesis that Shwachman syndrome is a single disease entity.

Cipolli et al. (1999) provided long-term follow-up of 13 patients with
Shwachman syndrome diagnosed in infancy. At diagnosis, growth
retardation and pancreatic insufficiency were present in all.
Hematologic features, repeated respiratory infections during the first
years of life, and skeletal abnormalities were frequently observed.
Other associated features included hepatic involvement and occasional
renal dysfunction. One patient died in infancy of respiratory infection.
Six were under observation at other centers. Of the 6 patients followed
up by the authors (mean age of 10 years at the time of study), a
significant growth improvement was observed. In 5, the pancreatic
stimulation test showed values of lipase within reference range outputs,
whereas fat balance or fecal fat losses were normal in all but 1. Of 7
subjects assessed by psychologic evaluation, IQ test results were
markedly abnormal in one and bordered on abnormality in the others. This
study underlined the possibility of improvement or normalization of
exocrine pancreatic function, as well as decreasing the frequency of
infections, with age.

Ip et al. (2002) used a classification and regression tree analysis
(CART) to define a pancreatic phenotype based on serum trypsinogen and
isoamylase measurements in 90 patients confirmed to have SDS compared to
134 controls. They then studied the usefulness of the CART-defined
pancreatic phenotype in determining the diagnosis of SDS in 35 patients
with 'probable' and 39 patients with 'improbable' SDS. All confirmed
patients older than 3 years were classified correctly using the CART
analysis. The CART-defined pancreatic phenotype was found in 82% of
'probable' and 7% of 'improbable' SDS patients older than 3 years. Ip et
al. (2002) concluded that the pancreatic phenotype was diagnostically
useful.

Toiviainen-Salo et al. (2008) investigated brain structures by MRI in 9
patients (7 males, age range 7-37 years) with SDS and mutations in the
SBDS gene and in 18 age- and gender-matched controls. Eight of the 9
SBDS mutation-verified patients reported learning difficulties. Patients
with SDS had smaller occipitofrontal head circumferences than the
controls, and decreased global brain volume; both gray matter and white
matter volumes were reduced. Patients with SDS had no macroscopic brain
malformations, but they had significantly smaller age- and head
size-adjusted areas of posterior fossa, vermis, corpus callosum, and
pons, and significantly larger cerebrum-vermis ratio than the healthy
controls.

- Hematologic Abnormalities and Leukemic Transformation

Patients with Shwachman-Diamond syndrome are predisposed to hematologic
malignancies similar to those that occur with Fanconi anemia (227650)
(Woods et al., 1981).

Smith et al. (1996) reported hematologic abnormalities in 21 children
diagnosed with Shwachman-Diamond syndrome at their institution over 25
years. Anemia was found in 14 patients, thrombocytopenia in 5, and
pancytopenia in 2. Bone marrow cellularity was decreased in 5 and
increased in 3 of 13 patients studied. Cytogenetic examination of the
bone marrow showed clonal abnormalities in 4 of 12 children at the time
of diagnosis, and 1 boy developed a clonal abnormality later in the
course of his illness. Chromosome 7 was involved in rearrangements in 4
children. Myelodysplastic syndrome developed in 7 patients (including
all 5 with clonal bone marrow abnormalities); 5 of these persons
developed acute myeloid leukemia and died. Smith et al. (1996) showed
that the actual risk of leukemic transformation in the patients with
Shwachman-Diamond syndrome is much higher than 5% (as it was previously
considered), and that clonal cytogenetic abnormalities in the bone
marrow predispose to such transformation.

Dokal et al. (1997) described 3 men (2 of whom were brothers) with
Shwachman-Diamond syndrome who presented with acute myeloid leukemia in
adulthood. The brothers were 37 and 43 at time of presentation. The
third patient was 25 years old. Dokal et al. (1997) pointed out that of
the cases of acute myeloid leukemia in Shwachman-Diamond syndrome,
approximately one-quarter (5 in 18) have M6 morphology. They suggested
that the only therapy likely to be successful is allogeneic bone marrow
transplantation, which was reportedly successful in several cases.

In 8 SDS patients who did not have evidence of MDS or AML, Leung et al.
(2006) found increased bone marrow microvessel density compared to
controls. Vessels from SDS patients were more tortuous and showed
collapsed or constricted lumens, whereas control specimens showed more
open and organized vascular architecture. Stromal expression of VEGF
(192240), stromal VEGF secretion, and secretion and serum and marrow
levels of VEGF did not differ between the 2 groups. As increased marrow
angiogenesis and morphologic abnormalities are characteristically
observed in patients MDS and AML, even in the absence of SDS, Leung et
al. (2006) postulated that the marrow changes observed in this study may
be associated with the increased risk for MDS or AML in SDS patients.

DIAGNOSIS

Genieser et al. (1982) demonstrated the usefulness of computed
tomography (CT scan) in the diagnosis.

PATHOGENESIS

Rothbaum et al. (1982) postulated that abnormal polymorphonuclear
chemotaxis reflects defective cytoskeletal integrity in the Shwachman
syndrome. In support of this idea, they demonstrated abnormal
distribution of concanavalin-A receptors on polymorphonuclear
leukocytes.

Dror and Freedman (1999) showed that the bone marrow of patients with
SDS is characterized by a decreased frequency of CD34+ (142230) cells
and that marrow CD34+ cells have a reduced ability to form hematopoietic
colonies in vitro. For these reasons, and because apoptosis is central
in the pathogenesis of bone marrow dysfunction in myelodysplastic
syndrome, Dror and Freedman (2001) studied the role of apoptosis in the
pathogenesis of marrow failure in 11 children with SDS. Compared to
normal controls, the patients' marrow mononuclear cells plated in
clonogenic cultures showed a significantly higher tendency to undergo
apoptosis. The defect was found in patients with and without
myelodysplastic syndrome. They concluded that SDS hematopoietic
progenitors are intrinsically flawed and have faulty proliferative
properties and increased apoptosis. Bone marrow failure is linked to an
increased propensity for apoptosis, which in turn is linked to increased
expression of the Fas antigen (134637) and to hyperactivation of the Fas
signaling pathway.

Although immunologic abnormalities are not traditionally perceived as
part of SDS, patients with the disorder are prone to recurrent
infections even in the face of protective neutrophil counts. Dror et al.
(2001) studied immune function in 11 patients. Seven suffered from
recurrent bacterial infections and 6 from recurrent viral infections.
All patients had neutropenia; total lymphocyte counts, however, were
normal in all but 1 patient. Nine patients had B-cell defects comprising
one or more of the following abnormalities: low IgG or IgG subclasses,
low percentage of circulating B lymphocytes, decreased in vitro
B-lymphocyte proliferation, and a lack of specific antibody production.
Seven of 9 patients studied had at least one T-cell abnormality. Five of
6 patients studied had decreased percentages of circulating natural
killer cells. Moreover, neutrophil chemotaxis was significantly low in
all of the patients studied.

Bone marrow failure is believed to be the underlying condition that
drives the expansion of the paroxysmal nocturnal hemoglobinuria (PNH;
300818) clone. Circulating PNH blood cells have been identified in
patients with acquired aplastic anemia and with hypoplastic
myelodysplasia. To determine whether PNH blood cells are also present in
patients with inherited aplastic anemia, Keller et al. (2002) screened a
large group of patients with Shwachman-Diamond syndrome. None of the
patients analyzed had detectable circulating PNH blood cells, indicating
that bone marrow failure in Shwachman-Diamond syndrome does not select
for PNH progenitor cells.

Thornley et al. (2002) found that telomere length in leukocytes derived
from SDS patients was significantly shortened compared to controls. The
mean telomere length was 1.4-kb shorter than controls and did not differ
according to disease severity. Thornley et al. (2002) suggested that
bone marrow stem cell hyperproliferation is a feature of SDS from the
outset.

Austin et al. (2008) found that primary bone marrow stromal cells and
lymphoblasts from SDS patients exhibited an increased incidence of
abnormal mitoses. Depletion of the SBDS gene using siRNA in normal skin
fibroblasts resulted in increased mitotic abnormalities and aneuploidy
that accumulated over time. Treatment of primary cells from SDS patients
with nocodazole, a microtubule destabilizing agent, led to increased
mitotic arrest and apoptosis compared to treated wildtype cells. In
addition, SDS patient cells were resistant to taxol, a microtubule
stabilizing agent. These findings suggested that spindle instability in
SDS contributes to bone marrow failure and leukemogenesis. In wildtype
human cells, Austin et al. (2008) found that SBDS colocalized with
mitotic spindles and bound to purified microtubules, preventing genomic
instability.

INHERITANCE

Ginzberg et al. (2000) determined estimates of segregation proportion in
a cohort of 84 patients with Shwachman-Diamond syndrome with complete
sibship data under the assumption of complete ascertainment, using the
Li and Mantel estimator (Li and Mantel, 1968), and of single
ascertainment with the Davie modification (Davie, 1979). A third
estimate was computed with the expectation-maximization algorithm. All 3
estimates supported an autosomal recessive mode of inheritance, but
complete ascertainment was found to be unlikely. No consistent
differences were found in levels of serum trypsinogen (to indicate
exocrine pancreatic dysfunction) between parents (presumed
heterozygotes) and a normal control population. Ginzberg et al. (2000)
suggested that although genetic heterogeneity could not be excluded, the
results indicated that a recessive model of inheritance for this
syndrome should be considered.

CYTOGENETICS

Tada et al. (1987) found increased frequencies of spontaneous chromosome
aberrations in a patient's PHA-stimulated circulating lymphocytes;
however, the lymphocytes did not show increased sensitivity to mitomycin
C. In 2 affected sisters, Fraccaro et al. (1988) were unable to confirm
the observation of Tada et al. (1987) of increased chromosome
aberrations.

Masuno et al. (1995) observed a de novo and apparently balanced
reciprocal translocation, t(6;12)(q16.2;q21.2), in an 18-month-old girl
with Shwachman syndrome, characterized by exocrine pancreatic
insufficiency in bone marrow dysfunction. They suggested that the
translocation breakpoints in this patient are candidate regions for a
gene responsible for Shwachman syndrome. Both 6q and 12q were excluded
by linkage studies reported by Goobie et al. (1999). The genetic
analysis was performed on members of 13 Shwachman-Diamond syndrome
families with 2 or 3 affected children.

Smith et al. (1995) described a 5-year-old boy with this disorder in
whom acute monoblastic leukemia developed following a period of
myelodysplasia associated with a clonal cytogenetic abnormality
involving chromosome 7.

Children with SDS are predisposed to myelodysplasia and AML, often with
chromosome 7 abnormalities. Cunningham et al. (2002) reported on 9
children with SDS, 8 of whom had clonal abnormalities of chromosome 7.
They presented evidence suggesting that isochromosome 7q may represent a
separate disease entity in SDS children, which is interesting given that
the SDS gene maps to the centromeric region of chromosome 7. Their
clinical observations suggested that isochromosome 7q is a relatively
benign rearrangement and that it is not advisable to offer allogeneic
transplants to SDS children with isochromosome 7q alone in the absence
of other clinical signs of disease progression.

From an investigation of 14 patients with Shwachman syndrome (SS), using
standard and molecular cytogenetic methods and molecular genetic
techniques, Maserati et al. (2006) made several observations. They
showed that the i(7)(q10) is not, or is not always, an isochromosome but
may arise from a more complex mechanism, retaining part of the short
arm; that the i(7)(q10) has no preferential parental origin; and that
clonal chromosome changes, such as chromosome 7 anomalies and
del(20)(q11), may be present in the bone marrow for a long time without
progressing to myelodysplastic syndrome (MDS)/acute myeloid leukemia
(AML). The del(20)(q11) involves the minimal region of deletion typical
of MDS/AML. The rate of chromosome breaks is not significantly higher
than in controls, from which it can be concluded that SS should not be
considered a breakage syndrome. A specific kind of karyotype instability
is present in SS, with chromosome changes possibly found in single cells
or small clones, often affecting chromosome 7 and 20, in the bone
marrow. Maserati et al. (2006) considered these findings as confirming
their previous hypothesis that the SS mutation itself implies a mutator
effect that is responsible for MDS/AML through these specific chromosome
anomalies. The conclusion supports the practice of including cytogenetic
monitoring in the follow-up of SS patients.

MAPPING

In a genomewide scan of families with SDS, Goobie et al. (2001)
identified chromosome 7 markers that showed linkage with the disorder.
Finer mapping revealed significant linkage across a broad interval that
included the centromere. The maximum 2-point lod score was 8.7, with
D7S473, at a recombination fraction of 0.0. Evidence from all 15 of the
multiplex families analyzed provided support for the linkage, consistent
with a single locus for SDS. However, the presence of several different
mutations was suggested by the heterogeneity of disease-associated
haplotypes in the candidate region.

Popovic et al. (2002) constructed a physical map of the pericentromeric
region of chromosome 7 containing the locus for SDS, by using somatic
cell hybrid, radiation hybrid, and STS-content mapping of YAC and BAC
clones. A total of 34 SDS families of diverse ethnic origin were studied
by linkage disequilibrium analysis, which identified 6 extended
haplotypes to co-segregate with the disease in unrelated families of
common ethnic origin. These observations suggested existence of multiple
founder chromosomes (allelic heterogeneity) in SDS. Detection of
ancestral and intrafamilial recombination events refined the SDS locus
to a 1.9-cM critical interval (predicted size: 3.3 Mb) between markers
D7S2429 and D7S502 at chromosome 7q11.

MOLECULAR GENETICS

Dale et al. (2000) found no mutations in the neutrophil elastase gene
(130130) in 3 patients with Shwachman-Diamond syndrome.

By sequence analysis in 5 SDS patients, Popovic et al. (2002) found no
disease-causing mutations in the tyrosylprotein sulfotransferase 1 gene
(TPST1; 603125). Large-scale gene rearrangements were also excluded by
Southern blot analysis, and RT-PCR analysis failed to detect alterations
in gene expression, thereby excluding TPST1 as the causative gene for
SDS.

Boocock et al. (2003) identified 18 positional candidate genes in 7q11,
the region to which the Shwachman-Diamond syndrome maps. They discovered
mutations associated with a theretofore uncharacterized gene, which they
designated SBDS (607444).

GENOTYPE/PHENOTYPE CORRELATIONS

Kuijpers et al. (2005) sequenced the SBDS gene in 20 unrelated patients
with clinical SDS and identified mutations in 15 (75%), with identical
compound heterozygosity in 11 patients (see 607444.0001 and
607444.0002). The authors examined hematologic parameters over 5 years
of follow-up and observed persistent neutropenia in 43% in the absence
of apoptosis and unrelated to chemotaxis defects or infection rate.
Irrespective of the absolute neutrophil count in vivo, abnormal
granulocyte-monocyte colony formation was observed in all patients with
SDS tested (14 of 14), whereas erythroid and myeloid colony formation
was less often affected (9 of 14). Cytogenetic aberrations occurred in 5
of 19 patients in the absence of myelodysplasia. Kuijpers et al. (2005)
concluded that in patients with genetically proven SDS, a
genotype/phenotype relationship does not exist in clinical and
hematologic terms.

HISTORY

Scott Hamilton, 1984 Olympic Gold Medalist figure skater, was ill as a
child with Shwachman syndrome.

*FIELD* SA
Bodian et al. (1964); McLennan and Steinbach (1974); Saint-Martin
et al. (1969); Saunders et al. (1979); Shmerling et al. (1969); Shwachman
and Holsclaw (1972); Taybi et al. (1969)
*FIELD* RF
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N. M.; Hudson, T. J.; Morgan, K.; Fujiwara, T. M.; Durie, P. R.; Rommens,
J. M.: Shwachman-Diamond syndrome with exocrine pancreatic dysfunction
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23. Ip, W. F.; Dupuis, A.; Ellis, L.; Beharry, S.; Morrison, J.; Stormon,
M. O.; Corey, M.; Rommens, J. M.; Durie, P. R.: Serum pancreatic
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24. Keller, P.; Debaun, M. R.; Rothbaum, R. J.; Bessler, M.: Bone
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25. Kuijpers, T. W.; Alders, M.; Tool, A. T. J.; Mellink, C.; Roos,
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2005.

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29. Maserati, E.; Minelli, A.; Pressato, B.; Valli, R.; Crescenzi,
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*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Height];
Short stature;
[Weight];
Low birth weight;
[Other];
Failure to thrive

CARDIOVASCULAR:
[Heart];
Myocardial necrosis

RESPIRATORY:
[Lung];
Respiratory distress in neonatal period

CHEST:
[External features];
Narrow thorax;
[Ribs, sternum, clavicles, and scapulae];
Costochondral thickening;
Irregular ossification at anterior rib ends

ABDOMEN:
[External features];
[Liver];
Hepatomegaly;
[Pancreas];
Exocrine pancreatic insufficiency;
Pancreatic lipomatosis;
[Gastrointestinal];
Severe fat maldigestion;
Steatorrhea

GENITOURINARY:
[Kidneys];
Nephrocalcinosis

SKELETAL:
Delayed skeletal maturation;
[Spine];
Ovoid vertebral bodies;
[Pelvis];
Coxa vara;
Narrow sacroiliac notch;
[Limbs];
Slipped capital femoral epiphyses;
Metaphyseal chondrodysplasia of long bones

NEUROLOGIC:
[Central nervous system];
Learning disabilities;
Developmental delay;
Mild mental retardation

HEMATOLOGY:
Pancytopenia;
Persistent or intermittent neutropenia;
Anemia;
Thrombocytopenia;
Elevated fetal hemoglobin

NEOPLASIA:
Myelodysplasia;
Acute myelogenous leukemia

LABORATORY ABNORMALITIES:
Abnormal liver function tests;
Abnormal fecal fat;
Decreased serum trypsinogen

MISCELLANEOUS:
Increased susceptibility to infection;
Moderate age-related improvement of pancreatic function;
Broad range in severity of presentation in sibships

MOLECULAR BASIS:
Caused by mutation in the SBDS gene (SBDS, 607444.0001)

*FIELD* CN
Kelly A. Przylepa - updated: 10/6/2004
Kelly A. Przylepa - revised: 9/10/2001

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

*FIELD* ED
joanna: 03/14/2005
joanna: 10/6/2004
joanna: 9/10/2001

*FIELD* CN
Nara Sobreira - updated: 11/20/2009
Cassandra L. Kniffin - updated: 5/18/2009
Cassandra L. Kniffin - updated: 7/14/2008
Cassandra L. Kniffin - updated: 2/25/2008
Victor A. McKusick - updated: 6/9/2006
Marla J. F. O'Neill - updated: 12/12/2005
Natalie E. Krasikov - updated: 8/10/2004
Victor A. McKusick - updated: 2/12/2003
Victor A. McKusick - updated: 1/21/2003
Victor A. McKusick - updated: 12/20/2002
Michael B. Petersen - updated: 11/4/2002
Cassandra L. Kniffin - reorganized: 10/22/2002
Victor A. McKusick - updated: 10/18/2002
Victor A. McKusick - updated: 11/7/2001
Victor A. McKusick - updated: 10/11/2001
Victor A. McKusick - updated: 5/4/2001
Victor A. McKusick - updated: 1/9/2001
Victor A. McKusick - updated: 4/13/2000
Wilson H. Y. Lo - updated: 12/2/1999
Victor A. McKusick - updated: 10/13/1999
Victor A. McKusick - updated: 7/20/1999
Victor A. McKusick - updated: 12/18/1997
Victor A. McKusick - updated: 3/19/1997
Iosif W. Lurie - updated: 1/8/1997

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

*FIELD* ED
carol: 12/30/2013
wwang: 7/22/2010
terry: 7/8/2010
mgross: 7/1/2010
carol: 11/24/2009
terry: 11/20/2009
wwang: 5/21/2009
ckniffin: 5/18/2009
terry: 3/13/2009
wwang: 7/16/2008
ckniffin: 7/14/2008
terry: 6/6/2008
wwang: 3/5/2008
ckniffin: 2/25/2008
alopez: 7/5/2006
terry: 6/9/2006
wwang: 12/12/2005
carol: 8/11/2004
terry: 8/10/2004
carol: 2/27/2003
tkritzer: 2/24/2003
terry: 2/12/2003
cwells: 1/24/2003
tkritzer: 1/21/2003
alopez: 12/23/2002
terry: 12/20/2002
cwells: 11/4/2002
carol: 10/22/2002
ckniffin: 10/22/2002
carol: 10/18/2002
terry: 3/8/2002
carol: 11/28/2001
mcapotos: 11/19/2001
terry: 11/7/2001
carol: 11/5/2001
mcapotos: 10/31/2001
terry: 10/11/2001
mcapotos: 5/17/2001
mcapotos: 5/10/2001
terry: 5/4/2001
mcapotos: 1/22/2001
terry: 1/9/2001
carol: 5/12/2000
terry: 4/13/2000
carol: 12/6/1999
terry: 12/2/1999
carol: 10/13/1999
jlewis: 8/2/1999
terry: 7/20/1999
dholmes: 1/23/1998
mark: 1/10/1998
terry: 12/18/1997
terry: 3/19/1997
terry: 3/12/1997
terry: 3/6/1997
jenny: 3/4/1997
jenny: 1/21/1997
jenny: 1/8/1997
jenny: 1/2/1997
mark: 1/30/1996
terry: 1/24/1996
terry: 1/23/1996
terry: 7/19/1994
davew: 6/6/1994
mimadm: 3/29/1994
carol: 2/9/1994
carol: 3/31/1992
supermim: 3/17/1992

MIM 607444
*RECORD*
*FIELD* NO
607444
*FIELD* TI
*607444 SBDS GENE; SBDS
*FIELD* TX

CLONING

Boocock et al. (2003) screened 18 positional candidate genes in the
read morecritical region on chromosome 7q11 identified by linkage analysis for
the Shwachman-Diamond syndrome (SDS; 260400), an autosomal recessive
disorder with clinical features that include pancreatic exocrine
insufficiency, hematologic dysfunction, and skeletal abnormalities. They
discovered mutations associated with Shwachman-Diamond syndrome (260400)
in an uncharacterized gene represented by the 1.6-kb cDNA clone FLJ10917
(GenBank GENBANK AK001779). They designated the gene SBDS for
'Shwachman-Bodian-Diamond syndrome.' SBDS is a member of a highly
conserved protein family, with orthologs in species ranging from archaea
to vertebrates and plants. Indirect lines of evidence suggested that the
orthologs may function in RNA metabolism. The predicted protein is 28.8
kD with a pI of 8.9.

GENE STRUCTURE

Boocock et al. (2003) determined that the SBDS gene is composed of 5
exons spanning 7.9 kb.

MAPPING

By genomic sequence analysis, Boocock et al. (2003) mapped the SBDS gene
to chromosome 7q11. SBDS and an adjacent gene reside in a block of 305
kb that is locally duplicated. The paralogous duplicon is located 5.8 Mb
distally and contains an unprocessed pseudogene copy of SBDS designated
SBDSP. The pseudogene transcript is 97% identical to SBDS and contains
deletions and nucleotide changes that disrupt coding potential.

GENE FUNCTION

Austin et al. (2005) found that SBDS protein was present in both the
nucleus and the cytoplasm of normal control fibroblasts, but was
particularly concentrated within the nucleolus. SBDS localization was
cell cycle-dependent, with nucleolar localization during G1 and G2 and
diffuse nuclear localization during S phase. The intranucleolar
localization of SBDS provided further supportive evidence for its
postulated role in the processing of ribosomal RNA (rRNA).

Ganapathi et al. (2007) presented in vitro evidence indicating that the
SBDS gene is involved with ribosomal RNA. Nucleolar localization of SBDS
was dependent on active ribosomal RNA transcription. Lymphoblast cell
lines derived from SDS patients showed hypersensitivity to actinomycin
D, which inhibits RNA polymerase I, indicating an underlying impairment
of ribosome biogenesis. SBDS migrated with the 60S ribosomal precursor
protein, and associated with the 28S subunit (see 180450) and
nucleophosmin (see 164040). SBDS knockdown markedly decreased production
of newly synthesized rRNA, although an imbalance of ribosomal subunits
could not be detected.

Menne et al. (2007) identified the function of the yeast SBDS ortholog
Sdo1, showing that it is critical for the release and recycling of the
nucleolar shuttling factor Tif6 from pre-60S ribosomes, a key step in
60S maturation and translational activation of ribosomes. Using
genome-wide synthetic genetic array mapping, they identified multiple
TIF6 gain-of-function alleles that suppressed the pre-60S nuclear export
defects and cytoplasmic mislocalization of Tif6 observed in sdo1-delta
cells. Sdo1 appears to function within a pathway containing elongation
factor-like 1, and together they control translational activation of
ribosomes. The data of Menne et al. (2007) linked defective 60S
ribosomal subunit maturation to an inherited bone marrow failure
syndrome associated with leukemia predisposition.

Austin et al. (2008) found that SBDS colocalized with mitotic spindles
and bound to purified microtubules, thus preventing genomic instability,
in wildtype human bone marrow stromal cells, lymphoblasts, and skin
fibroblasts. Primary bone marrow stromal cells and lymphoblasts from SDS
patients exhibited an increased incidence of abnormal mitoses. Depletion
of the SBDS gene using siRNA in normal skin fibroblasts resulted in
increased mitotic abnormalities and aneuploidy that accumulated over
time. Treatment of primary cells from SDS patients with nocodazole, a
microtubule destabilizing agent, led to increased mitotic arrest and
apoptosis compared to treated wildtype cells. In addition, SDS patient
cells were resistant to taxol, a microtubule stabilizing agent. These
findings suggested that spindle instability in SDS contributes to bone
marrow failure and leukemogenesis.

Vitiello et al. (2010) demonstrated that CLN3 (607042) interacts with
SBDS. The protein-protein interaction was conserved between Btn1 and
Sdo1, the respective S. cerevisiae orthologs of CLN3 and SBDS. It had
been shown that deletion of Btn1 resulted in alterations in vacuolar pH
and vacuolar (H+)-ATPase (V-ATPase)-dependent H+ transport and ATP
hydrolysis. Vitiello et al. (2010) found that an Sdo1 deletion strain
had decreased vacuolar pH and V-ATPase-dependent H+ transport and ATP
hydrolysis; the alterations resulted from decreased V-ATPase subunit
expression. Overexpression of Btn1 or the presence of ionophore carbonyl
cyanide chlorophenil hydrazone (CCCP) caused decreased growth in yeast
lacking Sdo1. In normal cells, overexpression of Btn1 mirrored the
effect of CCCP, with both resulting in increased vacuolar pH due to
alterations in the coupling of V-ATPase-dependent H+ transport and ATP
hydrolysis. Vitiello et al. (2010) proposed that Sdo1 and SBDS work to
regulate Btn1 and CLN3, respectively.

Raaijmakers et al. (2010) demonstrated that deletion of Dicer1 (606241)
specifically in mouse osteoprogenitors, but not in mature osteoblasts,
disrupts the integrity of hematopoiesis. Myelodysplasia resulted and
acute myelogenous leukemia emerged that had acquired several genetic
abnormalities while having intact Dicer1. Examining gene expression
altered in osteoprogenitors as a result of Dicer1 deletion showed
reduced expression of Sbds, the gene mutated in Shwachman-Bodian-Diamond
syndrome, a human bone marrow failure and leukemia predisposition
condition. Deletion of Sbds in mouse osteoprogenitors induced bone
marrow dysfunction with myelodysplasia. Therefore, Raaijmakers et al.
(2010) concluded that perturbation of specific mesenchymal subsets of
stromal cells can disorder differentiation, proliferation, and apoptosis
of heterologous cells, and disrupt tissue homeostasis. Furthermore,
Raaijmakers et al. (2010) concluded that primary stromal dysfunction can
result in secondary neoplastic disease, supporting the concept of
niche-induced oncogenesis.

Using affinity capture and mass spectrometry, Ball et al. (2009)
developed an SBDS interactome and reported SBDS binding partners with
diverse molecular functions, notably components of the large ribosomal
subunit and proteins involved in DNA metabolism. Reciprocal
coimmunoprecipitation confirmed the interaction of SBDS with the large
ribosomal subunit protein RPL4 (180479) and with DNA-PK (PRKDC; 600899)
and RPA70 (RPA1; 179835), 2 proteins with critical roles in DNA repair.
SBDS-depleted HEK293 cells were hypersensitive to multiple types of DNA
damage as well as chemically induced endoplasmic reticulum stress,
suggesting a role for SBDS in response to cellular stress.
SBDS-dependent hypersensitivity of HEK293 cells to UV irradiation could
be distinguished from a role of SBDS in translation.

Finch et al. (2011) showed that GTP and recombinant human SBDS and
elongation factor-like-1 (EFL1, or EFTUD1) cooperated to trigger release
of human EIF6 (602912) from pre60S ribosomes isolated from
Sbds-deficient mouse livers. EFL1 and SBDS independently and
noncooperatively bound to the 60S subunit in vitro. The 60S subunit
activated the GTPase activity of EFL1, but SBDS was required to
stimulate EIF6 release. Two SBDS mutants with different SDS-associated
missense mutations varied in their ability to enhance 60S-dependent
GTPase activity of EFL1, but neither triggered EIF6 release. Finch et
al. (2011) concluded that SBDS and EFL1 catalyze translational
activation and proposed that SDS is a ribosomopathy caused by uncoupling
GTP hydrolysis from EIF6 release.

BIOCHEMICAL FEATURES

Independently, Savchenko et al. (2005) and Shammas et al. (2005)
determined the crystal structure of the Archaeglobus fulgidus ortholog
of SBDS. They found that A. fulgidus Sbds assumes a highly conserved
3-domain structure consisting of an N-terminal domain with a novel
3-dimensional fold structure, a central domain containing a winged
helix-turn-helix motif, and a C-terminal domain that shares structural
homology with RNA-binding proteins.

MOLECULAR GENETICS

Boocock et al. (2003) reported mutations identified in affected
individuals from 158 families. Gene conversion mutations accounted for
74.4% of alleles associated with Shwachman-Diamond syndrome (235 of
316). Observations indicated that gene conversion due to recombination
between SBDS and its pseudogene had occurred. Conversion mutations were
found in 89% of individuals with Shwachman-Diamond syndrome (141 of
158). Boocock et al. (2003) suggested that the conversion events are
confined to a short segment spanning approximately 240 bp in exon 2. In
a study of Japanese patients with SDS, Nakashima et al. (2004) likewise
found mutations in the SBDS gene caused by gene conversion. The sites of
the gene conversion events varied, extending from intron 1 to exon 3.

Abnormalities in chromosome 7 have been reported in association with
Shwachman-Diamond syndrome, especially an isochromosome i(7)(q10). In a
25-year-old patient with SDS who suffered from mild aplastic anemia but
showed no signs of either myelodysplasia or leukemic transformation,
Mellink et al. (2004) identified an isochromosome i(7)(q10) in the bone
marrow and also identified 2 different mutations in the SBDS gene: a
183-184TA-CT mutation (607444.0001) was present in 1 allele and the
splice site mutation 258+2T-C (IVS2DS+2T-C; 607444.0002) was present in
the other. The 2 mutations were the most commonly found in the study of
Boocock et al. (2003). Mellink et al. (2004) concluded that the
isochromosome 7q phenomenon may have a very indirect association with
the pathogenesis of malignant transformation in SDS patients. It may be
the first presentation of chromosome instability that could eventually
result in more significant additional chromosomal aberrations involved
in the clinical manifestation of acute myeloid leukemia and
myelodysplasia syndrome.

Austin et al. (2005) characterized the SBDS protein expression and
intracellular localization in 7 patients with Shwachman-Diamond syndrome
and healthy controls. As predicted by gene mutation, 4 patients with SDS
exhibited no detectable full-length SBDS protein. One patient, who was
homozygous for the IVS2DS+2T-C mutation, expressed scant levels of SBDS
protein. A second patient expressed low levels of SBDS protein harboring
a missense mutation. A third patient who carried no detectable gene
mutations expressed wildtype levels of SBDS protein, adding further
support to the growing body of evidence for additional genes that might
contribute to the pathogenesis of the disease phenotype.

Calado et al. (2007) identified heterozygosity for the IVS2DS+2T-C
mutation in 4 of 91 unrelated patients with aplastic anemia (609135).
These patients were younger on average (5 to 19 years) compared to other
patients with aplastic anemia. Two mothers tested were carriers of the
mutation; these 2 and another mother who was not tested had histories of
subclinical mild anemia. Heterozygous mutation carriers had partial loss
of SBDS protein expression, indicating haploinsufficiency. Although
telomere shortening was observed in patients' granulocytes, lymphocytes
had normal telomere length. None of the patients with aplastic anemia
had pancreatic exocrine failure or skeletal anomalies as seen in SDS.
One of the 4 probands was also heterozygous for a presumed pathogenic
variant in the TERT gene (187270). The outcome of these patients was
poor, with 2 deaths. Calado et al. (2007) concluded that SBDS deficiency
predisposes to marrow failure by causing telomere shortening, thus
indicating a role for SBDS in the maintenance of telomere length.

GENOTYPE/PHENOTYPE CORRELATIONS

Kuijpers et al. (2005) sequenced the SBDS gene in 20 unrelated patients
with clinical SDS and identified mutations in 15 (75%), with identical
compound heterozygosity in 11 patients (see 607444.0001 and
607444.0002). The authors examined hematologic parameters over 5 years
of follow-up and observed persistent neutropenia in 43% in the absence
of apoptosis and unrelated to chemotaxis defects or infection rate.
Irrespective of the absolute neutrophil count in vivo, abnormal
granulocyte-monocyte colony formation was observed in all patients with
SDS tested (14 of 14), whereas erythroid and myeloid colony formation
was less often affected (9 of 14). Cytogenetic aberrations occurred in 5
of 19 patients in the absence of myelodysplasia. Kuijpers et al. (2005)
concluded that in patients with genetically proven SDS, a
genotype/phenotype relationship does not exist in clinical and
hematologic terms.

ANIMAL MODEL

Zhang et al. (2006) reported that loss of the Sbds gene resulted in
early lethality in mice prior to embryonic day 6.5. Heterozygous mutant
mice had a normal phenotype and were indistinguishable from wildtype
littermates.

Finch et al. (2011) also found that Sbds deletion in mice was embryonic
lethal. Sbds -/- mice showed prominent histologic abnormalities in
liver, with disordered architecture between the portal triads and
central veins, degenerative hepatocyte appearance, and scattered
subcapsular areas of hepatocyte necrosis with an associated acute
inflammatory reaction. Sbds-deleted liver extracts showed accumulation
of free cytoplasmic 40S and 60S subunits and 43S initiation complexes
that were stalled at the AUG start codon awaiting binding of 60S
subunits, suggesting a ribosomal subunit-joining defect.

*FIELD* AV
.0001
SHWACHMAN-DIAMOND SYNDROME
SBDS, LYS62TER

In 79 of 141 families with Shwachman-Diamond syndrome (SDS; 260400) with
conversion mutations, Boocock et al. (2003) found that affected
individuals were compound heterozygous for 2 mutations in exon 2 of the
SBDS gene: 183-184TA-CT and 258+2T-C (IVS2DS+2T-C; 607444.0002). The
dinucleotide alteration 183-184TA-CT introduced an in-frame stop codon
(lys62 to ter; K62X). The 258+2T-C mutation was predicted to disrupt the
donor splice site of intron 2; it resulted in an 8-bp deletion
consistent with use of an upstream cryptic splice donor site at position
251-252. The 258+2T-C and the resultant 8-bp deletion caused premature
termination of the encoded protein by frameshift. In 44 families there
was compound heterozygosity of 258+2T-C with another allele. In 7
families there was homozygosity for 258+2T-C. No incidence of
homozygosity for 183-184TA-CT was observed. In 8 alleles of the SBDS
gene found by Boocock et al. (2003) in patients with SDS, both the
183-184TA-CT and the 258+2T-C change were on the same allele.

In 11 patients with SDS, Kuijpers et al. (2005) identified compound
heterozygosity for the K62X and 258+2T-C mutations in the SBDS gene.

.0002
SHWACHMAN-DIAMOND SYNDROME
APLASTIC ANEMIA, SUSCEPTIBILITY TO, INCLUDED
SBDS, IVS2DS, T-C, +2

See 607444.0001. Boocock et al. (2003) referred to this mutation as
258+2T-C. Nakashima et al. (2004) identified this mutation in affected
members of 4 Japanese families, making it the most prevalent mutation.
Recurrent gene conversion was considered the most likely explanation for
the recurrence, rather than founder effect.

See 607444.0001 and Kuijpers et al. (2005).

Calado et al. (2007) identified heterozygosity for the IVS2DS+2T-C
mutation in 4 of 91 unrelated patients with aplastic anemia (609135).
These patients were younger on average (5 to 19 years) compared to other
patients with aplastic anemia. Two mothers tested were carriers of the
mutation; these 2 and another mother who was not tested had histories of
subclinical mild anemia. Heterozygous mutation carriers had partial loss
of SBDS protein expression, indicating haploinsufficiency. Although
telomere shortening was observed in patients' granulocytes, lymphocytes
had normal telomere length. None of the patients with aplastic anemia
had pancreatic exocrine failure or skeletal anomalies as seen in SDS.
One of the 4 probands was also heterozygous for a presumed pathogenic
variant in the TERT gene (187270).

.0003
SHWACHMAN-DIAMOND SYNDROME
SBDS, ASN8LYS

In 1 allele from individuals with Shwachman-Diamond syndrome (260400),
Boocock et al. (2003) found a 24C-A transversion in the SBDS gene,
predicted to result in an asn8-to-lys (N8K) amino acid change.

.0004
SHWACHMAN-DIAMOND SYNDROME
SBDS, 1-BP INS, 96A

In affected members of 4 Japanese families with Shwachman-Diamond
syndrome (260400), Nakashima et al. (2004) found compound heterozygosity
for 2 recurrent mutations in the SBDS gene: IVS2DS+2T-C (607444.0002)
and a 1-bp insertion (96insA) in exon 1.

*FIELD* RF
1. Austin, K. M.; Gupta, M. L., Jr.; Coats, S. A.; Tulpule, A.; Mostoslavsky,
G.; Balazs, A. B.; Mulligan, R. C.; Daley, G.; Pellman, D.; Shimamura,
A.: Mitotic spindle destabilization and genomic instability in Shwachman-Diamond
syndrome. J. Clin. Invest. 118: 1511-1518, 2008.

2. Austin, K. M.; Leary, R. J.; Shimamura, A.: The Shwachman-Diamond
SBDS protein localizes to the nucleolus. Blood 106: 1253-1258, 2005.

3. Ball, H. L.; Zhang, B.; Riches, J. J.; Gandhi, R.; Li, J.; Rommens,
J. M.; Myers, J. S.: Shwachman-Bodian Diamond syndrome is a multi-functional
protein implicated in cellular stress responses. Hum. Molec. Genet. 18:
3684-3695, 2009.

4. Boocock, G. R. B.; Morrison, J. A.; Popovic, M.; Richards, N.;
Ellis, L.; Durie, P. R.; Rommens, J. M.: Mutations in SBDS are associated
with Shwachman-Diamond syndrome. Nature Genet. 33: 97-101, 2003.

5. Calado, R. T.; Graf, S. A.; Wilkerson, K. L.; Kajigaya, S.; Ancliff,
P. J.; Dror, Y.; Chanock, S. J.; Lansdorp, P. M.; Young, N. S.: Mutations
in the SBDS gene in acquired aplastic anemia. Blood 110: 1141-1146,
2007.

6. Finch, A. J.; Hilcenko, C.; Basse, N.; Drynan, L. F.; Goyenechea,
B.; Menne, T. F.; Gonzalez Fernandez, A.; Simpson, P.; D'Santos, C.
S.; Arends, M. J.; Donadieu, J.; Bellanne-Chantelot, C.; Costanzo,
M.; Boone, C.; McKenzie, A. N.; Freund, S. M. V.; Warren, A. J.:
Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes
Shwachman-Diamond syndrome. Genes Dev. 25: 917-929, 2011.

7. Ganapathi, K. A.; Austin, K. M.; Lee, C.-S.; Dias, A.; Malsch,
M. M.; Reed, R.; Shimamura, A.: The human Shwachman-Diamond syndrome
protein, SBDS, associates with ribosomal RNA. Blood 110: 1458-1465,
2007.

8. Kuijpers, T. W.; Alders, M.; Tool, A. T. J.; Mellink, C.; Roos,
D.; Hennekam, R. C. M.: Hematologic abnormalities in Shwachman Diamond
syndrome: lack of genotype-phenotype relationship. Blood 106: 356-361,
2005.

9. Mellink, C. H. M.; Alders, M.; van der Lelie, H.; Hennekam, R.
H. C.; Kuijpers, T. W.: SBDS mutations and isochromosome 7q in a
patient with Shwachman-Diamond syndrome: no predisposition to malignant
transformation? Cancer Genet. Cytogenet. 154: 144-149, 2004.

10. Menne, T. F.; Goyenechea, B.; Sanchez-Puig, N.; Wong, C. C.; Tonkin,
L. M.; Ancliff, P. J.; Brost, R. L.; Costanzo, M.; Boone, C.; Warren,
A. J.: The Shwachman-Bodian-Diamond syndrome protein mediates translational
activation of ribosomes in yeast. Nature Genet. 39: 486-495, 2007.

11. Nakashima, E.; Mabuchi, A.; Makita, Y.; Masuno, M.; Ohashi, H.;
Nishimura, G.; Ikegawa, S.: Novel SBDS mutations caused by gene conversion
in Japanese patients with Shwachman-Diamond syndrome. Hum. Genet. 114:
345-348, 2004.

12. Raaijmakers, M. H. G. P.; Mukherjee, S.; Guo, S.; Zhang, S.; Kobayashi,
T.; Schoonmaker, J. A.; Ebert, B. L.; Al-Shahrour, F.; Hasserjian,
R. P.; Scadden, E. O.; Aung, Z.; Matza, M.; Merkenschlager, M.; Lin,
C.; Rommens, J. M.; Scadden, D. T.: Bone progenitor dysfunction induces
myelodysplasia and secondary leukaemia. Nature 464: 852-857, 2010.

13. Savchenko, A.; Krogan, N.; Cort, J. R.; Evdokimova, E.; Lew, J.
M.; Yee, A. A.; Sanchez-Pulido, L.; Andrade, M. A.; Bochkarev, A.;
Watson, J. D.; Kennedy, M. A.; Greenblatt, J.; Hughes, T.; Arrowsmith,
C. H.; Rommens, J. M.; Edwards, A. M.: The Shwachman-Bodian-Diamond
syndrome protein family is involved in RNA metabolism. J. Biol. Chem. 280:
19213-19220, 2005.

14. Shammas, C.; Menne, T. F.; Hilcenko, C.; Michell, S. R.; Goyenechea,
B.; Boocock, G. R. B.; Durie, P. R.; Rommens, J. M.; Warren, A. J.
: Structural and mutational analysis of the SBDS protein family: insight
into the leukemia-associated Shwachman-Diamond syndrome. J. Biol.
Chem. 280: 19221-19229, 2005.

15. Vitiello, S. P.; Benedict, J. W.; Padilla-Lopez, S.; Pearce, D.
A.: Interaction between Sdo1p and Btn1p in the Saccharomyces cerevisiae
model for Batten disease. Hum. Molec. Genet. 19: 931-942, 2010.

16. Zhang, S.; Shi, M.; Hui, C.; Rommens, J. M.: Loss of the mouse
ortholog of the Shwachman-Diamond syndrome gene (Sbds) results in
early embryonic lethality. Molec. Cell Biol. 26: 6656-6663, 2006.

*FIELD* CN
George E. Tiller - updated: 11/8/2011
Patricia A. Hartz - updated: 5/16/2011
George E. Tiller - updated: 7/8/2010
Ada Hamosh - updated: 5/26/2010
Cassandra L. Kniffin - updated: 7/14/2008
Cassandra L. Kniffin - updated: 2/25/2008
Victor A. McKusick - updated: 4/26/2007
Marla J. F. O'Neill - updated: 12/12/2005
Victor A. McKusick - updated: 12/5/2005
Victor A. McKusick - updated: 1/31/2005
Victor A. McKusick - updated: 4/2/2004

*FIELD* CD
Victor A. McKusick: 12/23/2002

*FIELD* ED
carol: 09/19/2013
alopez: 11/15/2011
terry: 11/8/2011
mgross: 6/10/2011
terry: 5/16/2011
wwang: 7/22/2010
terry: 7/8/2010
alopez: 5/27/2010
terry: 5/26/2010
wwang: 7/16/2008
ckniffin: 7/14/2008
terry: 6/6/2008
wwang: 3/5/2008
ckniffin: 2/25/2008
alopez: 4/30/2007
terry: 4/26/2007
carol: 1/30/2007
wwang: 12/12/2005
alopez: 12/7/2005
terry: 12/5/2005
tkritzer: 2/4/2005
terry: 1/31/2005
tkritzer: 12/13/2004
carol: 8/11/2004
tkritzer: 4/7/2004
terry: 4/2/2004
joanna: 2/26/2004
alopez: 12/23/2002