RBCC

Full text data of VPS45

VPS45 (VPS45A, VPS45B) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Vacuolar protein sorting-associated protein 45; h-VPS45; hlVps45

UniProt Q9NRW7
ID VPS45_HUMAN Reviewed; 570 AA.
AC Q9NRW7; D3DUZ9; Q15715; Q5T4P6; Q9Y4Z6;
DT 19-SEP-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-2000, sequence version 1.
DT 22-JAN-2014, entry version 111.
DE RecName: Full=Vacuolar protein sorting-associated protein 45;
DE Short=h-VPS45;
DE Short=hlVps45;
GN Name=VPS45; Synonyms=VPS45A, VPS45B;
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].
RC TISSUE=Brain;
RX PubMed=8996080; DOI=10.1016/S0378-1119(96)00367-8;
RA Pevsner J., Hsu S.-C., Hyde P.S., Scheller R.H.;
RT "Mammalian homologues of yeast vacuolar protein sorting (vps) genes
RT implicated in Golgi-to-lysosome trafficking.";
RL Gene 183:7-14(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Leukocyte;
RX PubMed=10404641; DOI=10.1016/S1357-2725(99)00017-5;
RA Rajasekariah P., Eyre H.J., Stanley K.K., Walls R.S., Sutherland G.R.;
RT "Molecular cloning and characterization of a cDNA encoding the human
RT leucocyte vacuolar protein sorting (hlVps45).";
RL Int. J. Biochem. Cell Biol. 31:683-694(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Hematopoietic stem cell;
RA Gu J., Huang Q., Yu Y., Xu S., Han Z., Fu G., Zhou J., Wang Y.,
RA Huang C., Ren S., Tu Y., Chen Z.;
RT "Novel genes expressed in hematopoietic stem/progenitor cells from
RT myelodysplastic syndrome patients.";
RL Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon, and Hippocampus;
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 [8]
RP INTERACTION WITH ZFYVE20.
RX PubMed=11062261; DOI=10.1083/jcb.151.3.601;
RA Nielsen E., Christoforidis S., Uttenweiler-Joseph S., Miaczynska M.,
RA Dewitte F., Wilm M., Hoflack B., Zerial M.;
RT "Rabenosyn-5, a novel Rab5 effector, is complexed with hVPS45 and
RT recruited to endosomes through a FYVE finger domain.";
RL J. Cell Biol. 151:601-612(2000).
RN [9]
RP INTERACTION WITH ZFYVE20.
RX PubMed=11788822; DOI=10.1038/ncb744;
RA de Renzis S., Soennichsen B., Zerial M.;
RT "Divalent Rab effectors regulate the sub-compartmental organization
RT and sorting of early endosomes.";
RL Nat. Cell Biol. 4:124-133(2002).
RN [10]
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 [11]
RP VARIANTS SCN5 ASN-224 AND LYS-238.
RX PubMed=23738510; DOI=10.1056/NEJMoa1301296;
RA Vilboux T., Lev A., Malicdan M.C., Simon A.J., Jarvinen P., Racek T.,
RA Puchalka J., Sood R., Carrington B., Bishop K., Mullikin J.,
RA Huizing M., Garty B.Z., Eyal E., Wolach B., Gavrieli R., Toren A.,
RA Soudack M., Atawneh O.M., Babushkin T., Schiby G., Cullinane A.,
RA Avivi C., Polak-Charcon S., Barshack I., Amariglio N., Rechavi G.,
RA van der Werff ten Bosch J., Anikster Y., Klein C., Gahl W.A.,
RA Somech R.;
RT "A congenital neutrophil defect syndrome associated with mutations in
RT VPS45.";
RL N. Engl. J. Med. 369:54-65(2013).
CC -!- FUNCTION: May play a role in vesicle-mediated protein trafficking
CC from the Golgi stack through the trans-Golgi network.
CC -!- SUBUNIT: Interacts with STX6 (By similarity). Interacts with
CC ZFYVE20.
CC -!- SUBCELLULAR LOCATION: Golgi apparatus membrane; Peripheral
CC membrane protein (By similarity). Endosome membrane; Peripheral
CC membrane protein (By similarity). Note=Associated with
CC Golgi/endosomal vesicles and the trans-Golgi network (By
CC similarity).
CC -!- TISSUE SPECIFICITY: Ubiquitous. Expression was highest in testis,
CC heart and brain, intermediate in kidney, spleen, prostate, ovary,
CC small intestine and thymus and low in lung, skeletal muscle,
CC placenta, colon, pancreas, peripheral blood leukocytes and liver.
CC -!- DISEASE: Neutropenia, severe congenital 5, autosomal recessive
CC (SCN5) [MIM:615285]: An autosomal recessive primary
CC immunodeficiency disorder characterized primarily by neutropenia
CC and neutrophil dysfunction, a lack of response to G-CSF, life-
CC threatening infections, bone marrow fibrosis, and renal
CC extramedullary hematopoiesis. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the STXBP/unc-18/SEC1 family.
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DR EMBL; U35246; AAC50931.1; -; mRNA.
DR EMBL; AJ133421; CAB40417.1; -; mRNA.
DR EMBL; AF165513; AAF86643.1; -; mRNA.
DR EMBL; AK023170; BAB14443.1; -; mRNA.
DR EMBL; AL358073; CAI14265.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53584.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53585.1; -; Genomic_DNA.
DR EMBL; BC012932; AAH12932.1; -; mRNA.
DR EMBL; BC028382; AAH28382.1; -; mRNA.
DR PIR; JC5722; JC5722.
DR RefSeq; NP_001266282.1; NM_001279353.1.
DR RefSeq; NP_001266283.1; NM_001279354.1.
DR RefSeq; NP_001266284.1; NM_001279355.1.
DR RefSeq; NP_009190.2; NM_007259.4.
DR UniGene; Hs.443750; -.
DR ProteinModelPortal; Q9NRW7; -.
DR SMR; Q9NRW7; 1-547.
DR STRING; 9606.ENSP00000358126; -.
DR PhosphoSite; Q9NRW7; -.
DR DMDM; 23396937; -.
DR PaxDb; Q9NRW7; -.
DR PRIDE; Q9NRW7; -.
DR DNASU; 11311; -.
DR Ensembl; ENST00000369130; ENSP00000358126; ENSG00000136631.
DR GeneID; 11311; -.
DR KEGG; hsa:11311; -.
DR UCSC; uc001etp.3; human.
DR CTD; 11311; -.
DR GeneCards; GC01P150039; -.
DR HGNC; HGNC:14579; VPS45.
DR HPA; HPA027425; -.
DR HPA; HPA027441; -.
DR MIM; 610035; gene.
DR MIM; 615285; phenotype.
DR neXtProt; NX_Q9NRW7; -.
DR PharmGKB; PA37901; -.
DR eggNOG; COG5158; -.
DR HOGENOM; HOG000200803; -.
DR HOVERGEN; HBG059810; -.
DR InParanoid; Q9NRW7; -.
DR KO; K12479; -.
DR OMA; HSSALQX; -.
DR OrthoDB; EOG7H791T; -.
DR PhylomeDB; Q9NRW7; -.
DR Reactome; REACT_604; Hemostasis.
DR GeneWiki; VPS45; -.
DR GenomeRNAi; 11311; -.
DR NextBio; 42971; -.
DR PRO; PR:Q9NRW7; -.
DR ArrayExpress; Q9NRW7; -.
DR Bgee; Q9NRW7; -.
DR CleanEx; HS_VPS45; -.
DR Genevestigator; Q9NRW7; -.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0005794; C:Golgi apparatus; ISS:BHF-UCL.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral to membrane; ISS:BHF-UCL.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0006886; P:intracellular protein transport; NAS:UniProtKB.
DR GO; GO:0006904; P:vesicle docking involved in exocytosis; IEA:InterPro.
DR Gene3D; 3.40.50.1910; -; 2.
DR InterPro; IPR027482; Sec-1-like_dom2.
DR InterPro; IPR001619; Sec1-like.
DR PANTHER; PTHR11679; PTHR11679; 1.
DR Pfam; PF00995; Sec1; 1.
DR PIRSF; PIRSF005715; VPS45_Sec1; 1.
DR SUPFAM; SSF56815; SSF56815; 1.
PE 1: Evidence at protein level;
KW Complete proteome; Disease mutation; Endosome; Golgi apparatus;
KW Membrane; Protein transport; Reference proteome; Transport.
FT CHAIN 1 570 Vacuolar protein sorting-associated
FT protein 45.
FT /FTId=PRO_0000206312.
FT VARIANT 224 224 T -> N (in SCN5; patient fibroblasts are
FT characterized by impaired motility and
FT increased apoptosis).
FT /FTId=VAR_069865.
FT VARIANT 238 238 E -> K (in SCN5).
FT /FTId=VAR_069866.
FT CONFLICT 81 82 YI -> SL (in Ref. 1; AAC50931).
FT CONFLICT 92 92 T -> S (in Ref. 1; AAC50931).
FT CONFLICT 188 188 A -> G (in Ref. 1; AAC50931).
FT CONFLICT 196 196 T -> S (in Ref. 1; AAC50931).
FT CONFLICT 219 219 C -> L (in Ref. 2; CAB40417).
FT CONFLICT 241 241 G -> D (in Ref. 1; AAC50931).
FT CONFLICT 298 298 K -> R (in Ref. 1; AAC50931).
FT CONFLICT 370 370 I -> V (in Ref. 1; AAC50931).
FT CONFLICT 385 385 A -> V (in Ref. 1; AAC50931).
FT CONFLICT 407 408 MM -> IV (in Ref. 1; AAC50931).
FT CONFLICT 412 412 N -> S (in Ref. 1; AAC50931).
FT CONFLICT 416 416 S -> A (in Ref. 1; AAC50931).
FT CONFLICT 481 481 R -> K (in Ref. 1; AAC50931).
FT CONFLICT 537 537 V -> I (in Ref. 1; AAC50931).
FT CONFLICT 557 557 K -> R (in Ref. 1; AAC50931).
FT CONFLICT 562 562 V -> A (in Ref. 1; AAC50931).
SQ SEQUENCE 570 AA; 65077 MW; 5574F0BE3A7D4EB3 CRC64;
MNVVFAVKQY ISKMIEDSGP GMKVLLMDKE TTGIVSMVYT QSEILQKEVY LFERIDSQNR
EIMKHLKAIC FLRPTKENVD YIIQELRRPK YTIYFIYFSN VISKSDVKSL AEADEQEVVA
EVQEFYGDYI AVNPHLFSLN ILGCCQGRNW DPAQLSRTTQ GLTALLLSLK KCPMIRYQLS
SEAAKRLAEC VKQVITKEYE LFEFRRTEVP PLLLILDRCD DAITPLLNQW TYQAMVHELL
GINNNRIDLS RVPGISKDLR EVVLSAENDE FYANNMYLNF AEIGSNIKNL MEDFQKKKPK
EQQKLESIAD MKAFVENYPQ FKKMSGTVSK HVTVVGELSR LVSERNLLEV SEVEQELACQ
NDHSSALQNI KRLLQNPKVT EFDAARLVML YALHYERHSS NSLPGLMMDL RNKGVSEKYR
KLVSAVVEYG GKRVRGSDLF SPKDAVAITK QFLKGLKGVE NVYTQHQPFL HETLDHLIKG
RLKENLYPYL GPSTLRDRPQ DIIVFVIGGA TYEEALTVYN LNRTTPGVRI VLGGTTVHNT
KSFLEEVLAS GLHSRSKESS QVTSRSASRR
//

MIM 610035
*RECORD*
*FIELD* NO
610035
*FIELD* TI
*610035 VACUOLAR PROTEIN SORTING 45, YEAST, HOMOLOG OF, A; VPS45A
;;VPS45
*FIELD* TX
read more
DESCRIPTION

The VPS45 gene encodes a protein associated with cellular membranes that
functions in protein trafficking and the release of inflammatory
mediators, particularly in leukocytes (summary by Vilboux et al., 2013).

CLONING

By PCR, Pevsner et al. (1996) cloned human VPS45A from a brain cDNA
library. The deduced 570-amino acid protein has a calculated molecular
mass of 65 kD and shares 38% identity with yeast Vps45. Northern blot
analysis detected a 2.3-kb transcript in all tissues examined. Highest
expression was in testis, with progressively lower levels in brain,
kidney, lung, skeletal muscle, spleen, and liver.

Rajasekariah et al. (1999) cloned VPS45A from a human leukocyte cDNA
library. The deduced 570-amino acid protein has a calculated molecular
mass of 67 kD. VPS45A contains a potential N-glycosylation site, an
amidation site close to the C terminus, 2 potential N-myristoylation
sites, and several consensus phosphorylation sites. Northern blot
analysis detected abundant expression in heart, spleen, and testis.
Expression was moderate to low in all other tissues examined except lung
and liver, in which expression was very low. RT-PCR revealed high VPS45A
expression in peripheral blood mononuclear cells and neutrophils, but no
expression in human hepatoma and breast cancer cell lines.

MAPPING

By FISH, Rajasekariah et al. (1999) mapped the VPS45A gene to chromosome
1q21-q22.

MOLECULAR GENETICS

In affected children from 4 consanguineous Palestinian families with
severe congenital neutropenia-5 (SCN5; 615285), Vilboux et al. (2013)
identified a homozygous mutation in the VPS45 gene (T224N; 610035.0001).
The mutation, which was found by homozygosity mapping and whole-exome
sequencing, segregated with the disorder in the families and was not
found in several exome databases or in 250 ethnically matched controls.
Patient neutrophils showed impaired neutrophil chemotaxis, impaired
superoxide production, impaired migration, decreased beta-1 integrin
(ITGB1; 135630) expression, and decreased levels of the
VPS45-interacting proteins rabenosyn-5 (ZFYVE20; 609511) and syntaxin-16
(STX16; 603666). Mutant fibroblasts and bone marrow cells also showed
increased apoptosis compared to controls. Many of these defects were
corrected by transfection of wildtype VPS45.

Stepensky et al. (2013) identified a homozygous T224N mutation in 3
patients from 2 consanguineous Palestinian families with SCN5. The
mutation was found by whole-exome sequencing and confirmed by Sanger
sequencing. It segregated with the disorder in the family and was not
found in 120 Palestinian control individuals or in the Exome Variant
Server. Analysis of the mutation in the yeast ortholog showed that it
caused a decrease in cellular levels of the protein (about 50% compared
to control), suggesting that it destabilizes the protein and abrogates
its function in the endosomal pathway. Patient cells showed severely
decreased levels of mutant VPS45 protein, decreased numbers of
lysosomes, and decreased alpha-granules in platelets. Patient
neutrophils and bone marrow myeloid cells showed accelerated apoptosis.

ANIMAL MODEL

Vilboux et al. (2013) found that morpholino knock-out of the Vps45 gene
in zebrafish resulted in decreased numbers of neutrophils.

*FIELD* AV
.0001
NEUTROPENIA, SEVERE CONGENITAL, 5, AUTOSOMAL RECESSIVE
VPS45, THR224ASN

In affected children from 4 consanguineous Palestinian families with
severe congenital neutropenia-5 (SCN5; 615285), Vilboux et al. (2013)
identified a homozygous c.671C-A transversion in exon 7 of the VPS45
gene, resulting in a thr224-to-asn (T224N) substitution at a highly
conserved residue. The mutation, which was found by homozygosity mapping
and whole-exome sequencing, segregated with the disorder in the families
and was not found in several exome databases or in 250 ethnically
matched controls. Study of 1 patient's cells showed normal mutant mRNA
levels, but decreased amounts of mutant VPS45 protein with altered
intracellular localization. Patient neutrophils showed impaired
neutrophil chemotaxis, impaired superoxide production, and impaired
migration with decreased beta-1 integrin (ITGB1; 135630) expression.
Mutant fibroblasts and bone marrow cells also showed increased apoptosis
compared to controls. Many of these defects were corrected by
transfection of wildtype VPS45.

Stepensky et al. (2013) identified a homozygous T224N mutation in 3
patients from 2 consanguineous Palestinian families with SCN5. The
mutation was found by whole-exome sequencing and confirmed by Sanger
sequencing. It segregated with the disorder in the family and was not
found in 120 Palestinian control individuals or in the Exome Variant
Server. Analysis of the mutation in the yeast ortholog showed that it
caused a decrease in cellular levels of the protein (about 50% compared
to control), suggesting that it destabilizes the protein and abrogates
its function in the endosomal pathway. Patient cells showed severely
decreased levels of mutant VPS45 protein, decreased numbers of
lysosomes, and decreased alpha-granules in platelets. Patient
neutrophils and bone marrow myeloid cells showed accelerated apoptosis.

.0002
NEUTROPENIA, SEVERE CONGENITAL, 5, AUTOSOMAL RECESSIVE
VPS45, GLU238LYS

In 2 sibs, born of consanguineous Moroccan parents, with SCN5 (615285),
Vilboux et al. (2013) identified a homozygous c.712G-A transition in the
VPS45 gene, resulting in a glu238-to-lys (E238K) substitution at a
highly conserved residue. Theses sibs also had neurologic defects, which
may have been unrelated to the immunodeficiency.

*FIELD* RF
1. Pevsner, J.; Hsu, S.-C.; Hyde, P. S.; Scheller, R. H.: Mammalian
homologues of yeast vacuolar protein sorting (vps) genes implicated
in Golgi-to-lysosome trafficking. Gene 183: 7-14, 1996.

2. Rajasekariah, P.; Eyre, H. J.; Stanley, K. K.; Walls, R. S.; Sutherland,
G. R.: Molecular cloning and characterization of a cDNA encoding
the human leucocyte vacuolar protein sorting (hlVps45). Int. J. Biochem.
Cell Biol. 31: 683-694, 1999.

3. Stepensky, P.; Saada, A.; Cowan, M.; Tabib, A.; Fischer, U.; Berkun,
Y.; Saleh, H.; Simanovsky, N.; Kogot-Levin, A.; Weintraub, M.; Ganaiem,
H.; Shaag, A.; Zenvirt, S.; Borkhardt, A.; Elpeleg, O.; Bryant, N.
J.; Mevorach, D.: The Thr224Asn mutation in the VPS45 gene is associated
with the congenital neutropenia and primary myelofibrosis of infancy. Blood 121:
5078-5087, 2013.

4. Vilboux, T.; Lev, A.; Malicdan, M. C. V.; Simon, A. J.; Jarvinen,
P.; Racek, T.; Puchalka, J.; Sood, R.; Carrington, B.; Bishop, K.;
Mullikin, J.; Huizing, M.; and 20 others: A congenital neutrophil
defect syndrome associated with mutations in VPS45. New Eng. J. Med. 369:
54-65, 2013.

*FIELD* CN
Cassandra L. Kniffin - updated: 9/23/2013
Cassandra L. Kniffin - updated: 7/16/2013

*FIELD* CD
Patricia A. Hartz: 4/10/2006

*FIELD* ED
carol: 10/03/2013
ckniffin: 9/23/2013
carol: 7/17/2013
ckniffin: 7/16/2013
mgross: 4/10/2006

MIM 615285
*RECORD*
*FIELD* NO
615285
*FIELD* TI
#615285 NEUTROPENIA, SEVERE CONGENITAL, 5, AUTOSOMAL RECESSIVE; SCN5
*FIELD* TX
A number sign (#) is used with this entry because severe congenital
read moreneutropenia-5 (SCN5) is caused by homozygous mutation in the VPS45 gene
(610035) on chromosome 1q.

DESCRIPTION

Severe congenital neutropenia-5 is an autosomal recessive primary
immunodeficiency disorder characterized primarily by neutropenia and
neutrophil dysfunction, a lack of response to G-CSF, life-threatening
infections, bone marrow fibrosis, and renal extramedullary hematopoiesis
(summary by Vilboux et al., 2013).

For a general phenotypic description and a discussion of genetic
heterogeneity of severe congenital neutropenia, see SCN1 (202700).

CLINICAL FEATURES

Vilboux et al. (2013) reported 5 consanguineous families, 4 of
Palestinian and 1 of Moroccan origin, in which 7 children had severe
congenital neutropenia. All the children presented in infancy with poor
weight gain, hepatomegaly, splenomegaly, and severe infections or
deep-seated abscesses associated with neutropenia. Other features
included poor response to G-CSF, hypergammaglobulinemia, nephromegaly
due to extramedullary hematopoiesis, and nucleated red cells in the
peripheral blood, suggesting bone marrow damage or stress. Two affected
children underwent hematopoietic stem cell transplantation (HSCT) from
matched related donors; both died of infection after failed engraftment.
A third child died of infection before HSCT could be performed, and the
other 2 children were awaiting the procedure. In the Moroccan family,
the 2 affected children also had neurologic abnormalities manifest as
delayed development, cortical blindness, hearing loss, and thin corpus
callosum; both children died of infections before transplantation could
be performed. Bone marrow biopsy showed distortion of hematopoietic
tissue and prominent fibrosis. There were increased numbers of
abnormally hypolobulated neutrophils and numerous apoptotic nuclei.
Peripheral blood neutrophils showed few granules and abundant
mitochondria, suggesting abnormal myeloid differentiation.

Stepensky et al. (2013) reported 3 patients from 2 unrelated
consanguineous Palestinian families with severe congenital neutropenia
and myelofibrosis. Two deceased sibs with a similar disorder were also
described. The patients presented between 1 and 7 months of age with
recurrent bacterial infections, predominantly pneumonia and soft tissue
infections. Laboratory studies showed profound neutropenia, progressive
anemia, and later development of thrombocytopenia. Peripheral blood
smear showed anisocytosis and poikilocytosis, neutropenia, and
thrombocytopenia with few giant platelets. Bone marrow biopsy showed
myeloid hyperplasia and fibrosis. Other features included nephromegaly,
splenomegaly, and osteosclerosis. Two patients died at age 3 months and
3 years, respectively. One patient underwent successful bone marrow
transplant, but was later diagnosed with a pervasive developmental
disorder; none of the other patients had neurologic disorders. Two other
patients were listed for transplant.

INHERITANCE

The transmission pattern in the families with SCN5 reported by Vilboux
et al. (2013) was consistent with autosomal recessive inheritance.

MOLECULAR GENETICS

In affected children from 4 consanguineous Palestinian families with
severe congenital neutropenia-5, Vilboux et al. (2013) identified a
homozygous mutation in the VPS45 gene (T224N; 610035.0001). The
mutation, which was found by homozygosity mapping and whole-exome
sequencing, segregated with the disorder in the families and was not
found in several exome databases or in 250 ethnically matched controls.
Affected Moroccan sibs with the disorder had a different homozygous
mutation (E238K; 610035.0002). Study of 1 patient's cells showed normal
mRNA levels, but decreased amounts of VPS45 protein with altered
intracellular localization. Patient neutrophils showed impaired
neutrophil chemotaxis, impaired superoxide production, impaired
migration, decreased beta-1 integrin (ITGB1; 135630) expression, and
decreased levels of the VPS45-interacting proteins rabenosyn-5 (ZFYVE20;
609511) and syntaxin-16 (STX16; 603666). Mutant fibroblasts and bone
marrow cells also showed increased apoptosis compared to controls. Many
of these defects were corrected by transfection of wildtype VPS45. A
zebrafish model of Vps45 deficiency showed a marked paucity of
neutrophils.

Stepensky et al. (2013) identified a homozygous T224N mutation in the
VPS45 gene in 3 patients from 2 consanguineous Palestinian families with
SCN5. The mutation was found by whole-exome sequencing and confirmed by
Sanger sequencing. It segregated with the disorder in the family and was
not found in 120 Palestinian control individuals or in the Exome Variant
Server. Analysis of the mutation in the yeast ortholog showed that it
caused a decrease in cellular levels of the protein (about 50% compared
to control), suggesting that it destabilizes the protein and abrogates
its function in the endosomal pathway. Patient cells showed severely
decreased levels of mutant VPS45 protein, decreased numbers of
lysosomes, and decreased alpha-granules in platelets. Patient
neutrophils and bone marrow myeloid cells showed accelerated apoptosis.

*FIELD* RF
1. Stepensky, P.; Saada, A.; Cowan, M.; Tabib, A.; Fischer, U.; Berkun,
Y.; Saleh, H.; Simanovsky, N.; Kogot-Levin, A.; Weintraub, M.; Ganaiem,
H.; Shaag, A.; Zenvirt, S.; Borkhardt, A.; Elpeleg, O.; Bryant, N.
J.; Mevorach, D.: The Thr224Asn mutation in the VPS45 gene is associated
with the congenital neutropenia and primary myelofibrosis of infancy. Blood 121:
5078-5087, 2013.

2. Vilboux, T.; Lev, A.; Malicdan, M. C. V.; Simon, A. J.; Jarvinen,
P.; Racek, T.; Puchalka, J.; Sood, R.; Carrington, B.; Bishop, K.;
Mullikin, J.; Huizing, M.; and 20 others: A congenital neutrophil
defect syndrome associated with mutations in VPS45. New Eng. J. Med. 369:
54-65, 2013.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Weight];
Poor weight gain

ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly

GENITOURINARY:
[Kidneys];
Enlarged kidneys due to extramedullary hematopoiesis

NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development (in 1 family)

HEMATOLOGY:
Extramedullary hematopoiesis;
Anemia;
Thrombocytopenia;
Nucleated red cells in peripheral blood;
Bone marrow fibrosis;
Bone marrow shows abnormal development of neutrophils

IMMUNOLOGY:
Recurrent infections, bacterial and fungal;
Leukopenia;
Neutropenia;
Neutrophil dysfunction;
Hypergammaglobulinemia

MISCELLANEOUS:
Onset in infancy;
Early death from infection may occur

MOLECULAR BASIS:
Caused by mutation in the homolog of the yeast vacuolar protein sorting
45 gene (VPS45, 610035.0001)

*FIELD* CD
Cassandra L. Kniffin: 7/16/2013

*FIELD* ED
ckniffin: 09/23/2013
joanna: 8/21/2013
ckniffin: 7/16/2013

*FIELD* CN
Cassandra L. Kniffin - updated: 9/23/2013

*FIELD* CD
Cassandra L Kniffin: 6/25/2013

*FIELD* ED
carol: 10/03/2013
ckniffin: 9/23/2013
carol: 7/17/2013
ckniffin: 7/16/2013
ckniffin: 6/25/2013

RBCC Red Blood Cell Collection

Full text data of VPS45