Full text data of CAPN5
CAPN5
(NCL3)
[Confidence: high (present in two of the MS resources)]
Calpain-5; 3.4.22.- (Calpain htra-3; New calpain 3; nCL-3)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Calpain-5; 3.4.22.- (Calpain htra-3; New calpain 3; nCL-3)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
O15484
ID CAN5_HUMAN Reviewed; 640 AA.
AC O15484; O00263;
DT 12-FEB-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 12-FEB-2003, sequence version 2.
DT 22-JAN-2014, entry version 111.
DE RecName: Full=Calpain-5;
DE EC=3.4.22.-;
DE AltName: Full=Calpain htra-3;
DE AltName: Full=New calpain 3;
DE Short=nCL-3;
GN Name=CAPN5; Synonyms=NCL3;
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=9367857; DOI=10.1006/bbrc.1997.7571;
RA Mugita N., Kimura Y., Ogawa M., Saya H., Nakao M.;
RT "Identification of a novel, tissue-specific calpain htra-3; a human
RT homologue of the Caenorhabditis elegans sex determination gene.";
RL Biochem. Biophys. Res. Commun. 239:845-850(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas;
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 [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-633.
RC TISSUE=Hippocampus;
RX PubMed=9339374; DOI=10.1006/geno.1997.4870;
RA Dear T.N., Matena K., Vingron M., Boehm T.;
RT "A new subfamily of vertebrate calpains lacking a calmodulin-like
RT domain: implications for calpain regulation and evolution.";
RL Genomics 45:175-184(1997).
RN [4]
RP TISSUE SPECIFICITY, VARIANTS VRNI LEU-243 AND PRO-244, AND
RP CHARACTERIZATION OF VARIANTS VRNI LEU-243 AND PRO-244.
RX PubMed=23055945; DOI=10.1371/journal.pgen.1003001;
RA Mahajan V.B., Skeie J.M., Bassuk A.G., Fingert J.H., Braun T.A.,
RA Daggett H.T., Folk J.C., Sheffield V.C., Stone E.M.;
RT "Calpain-5 mutations cause autoimmune uveitis, retinal
RT neovascularization, and photoreceptor degeneration.";
RL PLoS Genet. 8:E1003001-E1003001(2012).
CC -!- CATALYTIC ACTIVITY: Broad endopeptidase specificity.
CC -!- TISSUE SPECIFICITY: Expressed in many tissues. Strong expression
CC in the photoreceptor cells of the retina, with a punctate pattern
CC of labeling over the nuclei and inner segments with less
CC expression along the other segments and outer plexiform layer.
CC -!- DISEASE: Vitreoretinopathy, neovascular inflammatory (VRNI)
CC [MIM:193235]: An autoimmune condition of the eye that sequentially
CC mimics uveitis, retinitis pigmentosa, and proliferative diabetic
CC retinopathy as it progresses to complete blindness. Patients
CC present during the second or third decade of life with posterior
CC uveitis and reduction of the electroretinogram b-wave. They become
CC more symptomatic when cataracts, cystoid macular edema, and disk
CC edema diminish visual acuity during the second stage. Severe
CC vision loss begins during the third stage when proliferative
CC retinal neovascularization and epiretinal membranes appear. There
CC is an ongoing pigmentary retinal degeneration and peripheral
CC visual field loss during all stages. In the fourth stage,
CC proliferative vitreoretinopathy causes tractional retinal
CC detachments at the macula and vitreous base. The fifth or end-
CC stage disease is marked by phthisis. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase C2 family.
CC -!- SIMILARITY: Contains 1 C2 domain.
CC -!- SIMILARITY: Contains 1 calpain catalytic domain.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; U94346; AAC51869.1; -; mRNA.
DR EMBL; BC018123; AAH18123.1; -; mRNA.
DR EMBL; Y10552; CAA71584.1; -; mRNA.
DR PIR; JC5772; JC5772.
DR RefSeq; NP_004046.2; NM_004055.4.
DR UniGene; Hs.248153; -.
DR ProteinModelPortal; O15484; -.
DR SMR; O15484; 8-490.
DR IntAct; O15484; 1.
DR STRING; 9606.ENSP00000278559; -.
DR MEROPS; C02.011; -.
DR PhosphoSite; O15484; -.
DR PaxDb; O15484; -.
DR PRIDE; O15484; -.
DR DNASU; 726; -.
DR Ensembl; ENST00000278559; ENSP00000278559; ENSG00000149260.
DR Ensembl; ENST00000529629; ENSP00000432332; ENSG00000149260.
DR Ensembl; ENST00000571230; ENSP00000461719; ENSG00000262875.
DR Ensembl; ENST00000576267; ENSP00000458516; ENSG00000262875.
DR GeneID; 726; -.
DR KEGG; hsa:726; -.
DR UCSC; uc001oxx.3; human.
DR CTD; 726; -.
DR GeneCards; GC11P076777; -.
DR HGNC; HGNC:1482; CAPN5.
DR HPA; CAB033237; -.
DR MIM; 193235; phenotype.
DR MIM; 602537; gene.
DR neXtProt; NX_O15484; -.
DR PharmGKB; PA26062; -.
DR eggNOG; NOG258770; -.
DR HOGENOM; HOG000232036; -.
DR HOVERGEN; HBG001095; -.
DR InParanoid; O15484; -.
DR KO; K08574; -.
DR PhylomeDB; O15484; -.
DR GeneWiki; CAPN5; -.
DR GenomeRNAi; 726; -.
DR NextBio; 2956; -.
DR PRO; PR:O15484; -.
DR ArrayExpress; O15484; -.
DR Bgee; O15484; -.
DR CleanEx; HS_CAPN5; -.
DR Genevestigator; O15484; -.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005622; C:intracellular; IEA:InterPro.
DR GO; GO:0004198; F:calcium-dependent cysteine-type endopeptidase activity; TAS:ProtInc.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR022684; Calpain_cysteine_protease.
DR InterPro; IPR022682; Calpain_domain_III.
DR InterPro; IPR022683; Calpain_III.
DR InterPro; IPR000169; Pept_cys_AS.
DR InterPro; IPR001300; Peptidase_C2_calpain_cat.
DR Pfam; PF00168; C2; 1.
DR Pfam; PF01067; Calpain_III; 1.
DR Pfam; PF00648; Peptidase_C2; 1.
DR PRINTS; PR00704; CALPAIN.
DR SMART; SM00239; C2; 1.
DR SMART; SM00720; calpain_III; 1.
DR SMART; SM00230; CysPc; 1.
DR SUPFAM; SSF49562; SSF49562; 1.
DR SUPFAM; SSF49758; SSF49758; 1.
DR PROSITE; PS50004; C2; FALSE_NEG.
DR PROSITE; PS50203; CALPAIN_CAT; 1.
DR PROSITE; PS00640; THIOL_PROTEASE_ASN; FALSE_NEG.
DR PROSITE; PS00139; THIOL_PROTEASE_CYS; 1.
DR PROSITE; PS00639; THIOL_PROTEASE_HIS; FALSE_NEG.
PE 1: Evidence at protein level;
KW Complete proteome; Disease mutation; Hydrolase; Protease;
KW Reference proteome; Thiol protease.
FT CHAIN 1 640 Calpain-5.
FT /FTId=PRO_0000207713.
FT DOMAIN 26 343 Calpain catalytic.
FT DOMAIN 518 619 C2.
FT REGION 344 496 Domain III.
FT ACT_SITE 81 81 By similarity.
FT ACT_SITE 252 252 By similarity.
FT ACT_SITE 284 284 By similarity.
FT VARIANT 243 243 R -> L (in VRNI; largely mislocalized to
FT the cytoplasm whereas the wild-type
FT protein is localized near the cell
FT surface).
FT /FTId=VAR_069277.
FT VARIANT 244 244 L -> P (in VRNI; largely mislocalized to
FT the cytoplasm whereas the wild-type
FT protein is localized near the cell
FT surface).
FT /FTId=VAR_069278.
FT CONFLICT 18 18 R -> Q (in Ref. 1; AAC51869).
FT CONFLICT 51 51 W -> R (in Ref. 3; CAA71584).
FT CONFLICT 112 115 EKPN -> RKAQ (in Ref. 1; AAC51869).
FT CONFLICT 128 131 FGEW -> LGM (in Ref. 1; AAC51869).
FT CONFLICT 138 138 D -> E (in Ref. 1; AAC51869).
FT CONFLICT 502 502 E -> K (in Ref. 1; AAC51869).
SQ SEQUENCE 640 AA; 73169 MW; 7A3A9A1A920410BC CRC64;
MFSCVKPYED QNYSALRRDC RRRKVLFEDP LFPATDDSLY YKGTPGPAVR WKRPKGICED
PRLFVDGISS HDLHQGQVGN CWFVAACSSL ASRESLWQKV IPDWKEQEWD PEKPNAYAGI
FHFHFWRFGE WVDVVIDDRL PTVNNQLIYC HSNSRNEFWC ALVEKAYAKL AGCYQALDGG
NTADALVDFT GGVSEPIDLT EGDFANDETK RNQLFERMLK VHSRGGLISA SIKAVTAADM
EARLACGLVK GHAYAVTDVR KVRLGHGLLA FFKSEKLDMI RLRNPWGERE WNGPWSDTSE
EWQKVSKSER EKMGVTVQDD GEFWMTFEDV CRYFTDIIKC RVINTSHLSI HKTWEEARLH
GAWTLHEDPR QNRGGGCINH KDTFFQNPQY IFEVKKPEDE VLICIQQRPK RSTRREGKGE
NLAIGFDIYK VEENRQYRMH SLQHKAASSI YINSRSVFLR TDQPEGRYVI IPTTFEPGHT
GEFLLRVFTD VPSNCRELRL DEPPHTCWSS LCGYPQLVTQ VHVLGAAGLK DSPTGANSYV
IIKCEGDKVR SAVQKGTSTP EYNVKGIFYR KKLSQPITVQ VWNHRVLKDE FLGQVHLKAD
PDNLQALHTL HLRDRNSRQP SNLPGTVAVH ILSSTSLMAV
//
ID CAN5_HUMAN Reviewed; 640 AA.
AC O15484; O00263;
DT 12-FEB-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 12-FEB-2003, sequence version 2.
DT 22-JAN-2014, entry version 111.
DE RecName: Full=Calpain-5;
DE EC=3.4.22.-;
DE AltName: Full=Calpain htra-3;
DE AltName: Full=New calpain 3;
DE Short=nCL-3;
GN Name=CAPN5; Synonyms=NCL3;
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=9367857; DOI=10.1006/bbrc.1997.7571;
RA Mugita N., Kimura Y., Ogawa M., Saya H., Nakao M.;
RT "Identification of a novel, tissue-specific calpain htra-3; a human
RT homologue of the Caenorhabditis elegans sex determination gene.";
RL Biochem. Biophys. Res. Commun. 239:845-850(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas;
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 [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-633.
RC TISSUE=Hippocampus;
RX PubMed=9339374; DOI=10.1006/geno.1997.4870;
RA Dear T.N., Matena K., Vingron M., Boehm T.;
RT "A new subfamily of vertebrate calpains lacking a calmodulin-like
RT domain: implications for calpain regulation and evolution.";
RL Genomics 45:175-184(1997).
RN [4]
RP TISSUE SPECIFICITY, VARIANTS VRNI LEU-243 AND PRO-244, AND
RP CHARACTERIZATION OF VARIANTS VRNI LEU-243 AND PRO-244.
RX PubMed=23055945; DOI=10.1371/journal.pgen.1003001;
RA Mahajan V.B., Skeie J.M., Bassuk A.G., Fingert J.H., Braun T.A.,
RA Daggett H.T., Folk J.C., Sheffield V.C., Stone E.M.;
RT "Calpain-5 mutations cause autoimmune uveitis, retinal
RT neovascularization, and photoreceptor degeneration.";
RL PLoS Genet. 8:E1003001-E1003001(2012).
CC -!- CATALYTIC ACTIVITY: Broad endopeptidase specificity.
CC -!- TISSUE SPECIFICITY: Expressed in many tissues. Strong expression
CC in the photoreceptor cells of the retina, with a punctate pattern
CC of labeling over the nuclei and inner segments with less
CC expression along the other segments and outer plexiform layer.
CC -!- DISEASE: Vitreoretinopathy, neovascular inflammatory (VRNI)
CC [MIM:193235]: An autoimmune condition of the eye that sequentially
CC mimics uveitis, retinitis pigmentosa, and proliferative diabetic
CC retinopathy as it progresses to complete blindness. Patients
CC present during the second or third decade of life with posterior
CC uveitis and reduction of the electroretinogram b-wave. They become
CC more symptomatic when cataracts, cystoid macular edema, and disk
CC edema diminish visual acuity during the second stage. Severe
CC vision loss begins during the third stage when proliferative
CC retinal neovascularization and epiretinal membranes appear. There
CC is an ongoing pigmentary retinal degeneration and peripheral
CC visual field loss during all stages. In the fourth stage,
CC proliferative vitreoretinopathy causes tractional retinal
CC detachments at the macula and vitreous base. The fifth or end-
CC stage disease is marked by phthisis. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase C2 family.
CC -!- SIMILARITY: Contains 1 C2 domain.
CC -!- SIMILARITY: Contains 1 calpain catalytic domain.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; U94346; AAC51869.1; -; mRNA.
DR EMBL; BC018123; AAH18123.1; -; mRNA.
DR EMBL; Y10552; CAA71584.1; -; mRNA.
DR PIR; JC5772; JC5772.
DR RefSeq; NP_004046.2; NM_004055.4.
DR UniGene; Hs.248153; -.
DR ProteinModelPortal; O15484; -.
DR SMR; O15484; 8-490.
DR IntAct; O15484; 1.
DR STRING; 9606.ENSP00000278559; -.
DR MEROPS; C02.011; -.
DR PhosphoSite; O15484; -.
DR PaxDb; O15484; -.
DR PRIDE; O15484; -.
DR DNASU; 726; -.
DR Ensembl; ENST00000278559; ENSP00000278559; ENSG00000149260.
DR Ensembl; ENST00000529629; ENSP00000432332; ENSG00000149260.
DR Ensembl; ENST00000571230; ENSP00000461719; ENSG00000262875.
DR Ensembl; ENST00000576267; ENSP00000458516; ENSG00000262875.
DR GeneID; 726; -.
DR KEGG; hsa:726; -.
DR UCSC; uc001oxx.3; human.
DR CTD; 726; -.
DR GeneCards; GC11P076777; -.
DR HGNC; HGNC:1482; CAPN5.
DR HPA; CAB033237; -.
DR MIM; 193235; phenotype.
DR MIM; 602537; gene.
DR neXtProt; NX_O15484; -.
DR PharmGKB; PA26062; -.
DR eggNOG; NOG258770; -.
DR HOGENOM; HOG000232036; -.
DR HOVERGEN; HBG001095; -.
DR InParanoid; O15484; -.
DR KO; K08574; -.
DR PhylomeDB; O15484; -.
DR GeneWiki; CAPN5; -.
DR GenomeRNAi; 726; -.
DR NextBio; 2956; -.
DR PRO; PR:O15484; -.
DR ArrayExpress; O15484; -.
DR Bgee; O15484; -.
DR CleanEx; HS_CAPN5; -.
DR Genevestigator; O15484; -.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005622; C:intracellular; IEA:InterPro.
DR GO; GO:0004198; F:calcium-dependent cysteine-type endopeptidase activity; TAS:ProtInc.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR022684; Calpain_cysteine_protease.
DR InterPro; IPR022682; Calpain_domain_III.
DR InterPro; IPR022683; Calpain_III.
DR InterPro; IPR000169; Pept_cys_AS.
DR InterPro; IPR001300; Peptidase_C2_calpain_cat.
DR Pfam; PF00168; C2; 1.
DR Pfam; PF01067; Calpain_III; 1.
DR Pfam; PF00648; Peptidase_C2; 1.
DR PRINTS; PR00704; CALPAIN.
DR SMART; SM00239; C2; 1.
DR SMART; SM00720; calpain_III; 1.
DR SMART; SM00230; CysPc; 1.
DR SUPFAM; SSF49562; SSF49562; 1.
DR SUPFAM; SSF49758; SSF49758; 1.
DR PROSITE; PS50004; C2; FALSE_NEG.
DR PROSITE; PS50203; CALPAIN_CAT; 1.
DR PROSITE; PS00640; THIOL_PROTEASE_ASN; FALSE_NEG.
DR PROSITE; PS00139; THIOL_PROTEASE_CYS; 1.
DR PROSITE; PS00639; THIOL_PROTEASE_HIS; FALSE_NEG.
PE 1: Evidence at protein level;
KW Complete proteome; Disease mutation; Hydrolase; Protease;
KW Reference proteome; Thiol protease.
FT CHAIN 1 640 Calpain-5.
FT /FTId=PRO_0000207713.
FT DOMAIN 26 343 Calpain catalytic.
FT DOMAIN 518 619 C2.
FT REGION 344 496 Domain III.
FT ACT_SITE 81 81 By similarity.
FT ACT_SITE 252 252 By similarity.
FT ACT_SITE 284 284 By similarity.
FT VARIANT 243 243 R -> L (in VRNI; largely mislocalized to
FT the cytoplasm whereas the wild-type
FT protein is localized near the cell
FT surface).
FT /FTId=VAR_069277.
FT VARIANT 244 244 L -> P (in VRNI; largely mislocalized to
FT the cytoplasm whereas the wild-type
FT protein is localized near the cell
FT surface).
FT /FTId=VAR_069278.
FT CONFLICT 18 18 R -> Q (in Ref. 1; AAC51869).
FT CONFLICT 51 51 W -> R (in Ref. 3; CAA71584).
FT CONFLICT 112 115 EKPN -> RKAQ (in Ref. 1; AAC51869).
FT CONFLICT 128 131 FGEW -> LGM (in Ref. 1; AAC51869).
FT CONFLICT 138 138 D -> E (in Ref. 1; AAC51869).
FT CONFLICT 502 502 E -> K (in Ref. 1; AAC51869).
SQ SEQUENCE 640 AA; 73169 MW; 7A3A9A1A920410BC CRC64;
MFSCVKPYED QNYSALRRDC RRRKVLFEDP LFPATDDSLY YKGTPGPAVR WKRPKGICED
PRLFVDGISS HDLHQGQVGN CWFVAACSSL ASRESLWQKV IPDWKEQEWD PEKPNAYAGI
FHFHFWRFGE WVDVVIDDRL PTVNNQLIYC HSNSRNEFWC ALVEKAYAKL AGCYQALDGG
NTADALVDFT GGVSEPIDLT EGDFANDETK RNQLFERMLK VHSRGGLISA SIKAVTAADM
EARLACGLVK GHAYAVTDVR KVRLGHGLLA FFKSEKLDMI RLRNPWGERE WNGPWSDTSE
EWQKVSKSER EKMGVTVQDD GEFWMTFEDV CRYFTDIIKC RVINTSHLSI HKTWEEARLH
GAWTLHEDPR QNRGGGCINH KDTFFQNPQY IFEVKKPEDE VLICIQQRPK RSTRREGKGE
NLAIGFDIYK VEENRQYRMH SLQHKAASSI YINSRSVFLR TDQPEGRYVI IPTTFEPGHT
GEFLLRVFTD VPSNCRELRL DEPPHTCWSS LCGYPQLVTQ VHVLGAAGLK DSPTGANSYV
IIKCEGDKVR SAVQKGTSTP EYNVKGIFYR KKLSQPITVQ VWNHRVLKDE FLGQVHLKAD
PDNLQALHTL HLRDRNSRQP SNLPGTVAVH ILSSTSLMAV
//
MIM
193235
*RECORD*
*FIELD* NO
193235
*FIELD* TI
#193235 VITREORETINOPATHY, NEOVASCULAR INFLAMMATORY; VRNI
;;PROLIFERATIVE VITREORETINOPATHY; PVR;;
read moreVITREORETINOPATHY, NEOVASCULAR INFLAMMATORY, AUTOSOMAL DOMINANT; ADNIV
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
neovascular inflammatory vitreoretinopathy (VRNI) is caused by
heterozygous mutation in the CAPN5 gene (602537) on chromosome 11q14.
DESCRIPTION
Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is
a blinding disorder that shares some clinical features with retinitis
pigmentosa (see 268000), uveitis, and proliferative diabetic retinopathy
(see 603933). Features include prominent ocular inflammation; vascular
dropout, large spots of hyperpigmentation, and neovascularization of the
peripheral and posterior retina; vitreous hemorrhage; and retinal
detachment (summary by Sheffield et al., 1992).
CLINICAL FEATURES
Bennett et al. (1990) studied a large 6-generation family of northern
European ancestry segregating autosomal dominant inflammatory eye
disease. There were 28 affected individuals, the condition was present
in every generation, and there was at least 1 documented male-to-male
transmission. The youngest age at which symptoms developed was 16 years;
most affected individuals remained asymptomatic until their third or
fourth decade. The first signs of disease included vitreous cells,
minimal far-peripheral arteriolar closure and pigmentation, and
selective reduction in the b-wave of the electroretinogram (ERG). In
middle age, more prominent anterior and posterior inflammation,
progressive vascular closure with neovascularization of the far
peripheral retina or optic disc, vitreous hemorrhage, tractional retinal
detachment, fluorescein leakage in the posterior pole and midperiphery,
and cystoid macular edema develop. By 60 years of age, cataracts, marked
progressive neovascularization, and tractional retinal detachment were
observed, and anterior segment neovascularization developed. Cystoid
macular edema, vitreous hemorrhage, tractional retinal detachment, and
neovascular glaucoma caused profound visual loss in some patients. The
ERG was extinguished late in the disease.
Mahajan et al. (2012) studied 2 families segregating autosomal dominant
neovascular inflammatory vitreoretinopathy (ADNIV) and noted that the
phenotype was very similar to that described by the pedigree described
by Bennett et al. (1990). Affected members exhibited noninfectious
uveitis, early loss of the b-wave on electroretinography, pigmentary
retinal degeneration, cystoid macular edema, retinal and iris
neovascularization, vitreous hemorrhage, epiretinal membrane formation,
proliferative vitreoretinopathy, retinal detachment, cataract,
neovascular glaucoma, and ultimately phthisis and complete blindness.
Both pedigrees were consistent with autosomal dominant inheritance with
complete penetrance.
MAPPING
Sheffield et al. (1992) established close linkage of VRNI to markers
that map to 11q13. In a single large pedigree, linkage analysis with the
closest marker, D11S527, demonstrated a maximum lod of 6.29 with no
recombinants. Stone et al. (1992) reported that they had found 34
affected members in this pedigree, that no recombinants were found
between the disease phenotype and D11S527, and that multipoint analysis
yielded a maximum lod score of 11.9 centered on this marker. Another
inherited retinal dystrophy, Best macular dystrophy (VMD; 153700), also
maps to 11q13. However, Sheffield et al. (1992) stated that the 2
diseases appear to be at least 10 cM apart.
Mahajan et al. (2012) genotyped 2 unrelated families segregating
autosomal dominant neovascular inflammatory vitreoretinopathy and
confirmed linkage to the 11q13 locus. Haplotype analysis was suggestive
of an ancestral relationship between 1 of the families (ADNIV-2) and the
original ADNIV (ADNIV-1) family described by Bennett et al. (1990).
Recombination events in 1 of the families (ADNIV-3) narrowed the
critical interval to 6.5 Mb between D11S4139 and D11S1789; high
resolution SNP genotyping of ADNIV-1 and ADNIV-3 further reduced the
interval to 6 Mb between SNP dbSNP rs879380 and D11S1789.
PATHOGENESIS
Proliferative vitreoretinopathy is characterized by the development of
epi- and subretinal fibrocellular membranes containing modified retinal
pigment epithelial (RPE) cells among others. Priglinger et al. (2003)
found that tissue transglutaminase (190196) was present and functionally
active in proliferative vitreoretinopathy membranes. The amount and
activity of tissue transglutaminase appeared to be related to the
differentiation state of the RPE cells and their stimulation by TGFB2
(190220), a growth factor known to be increased in the vitreous of
proliferative vitreoretinopathy.
MOLECULAR GENETICS
Mahajan et al. (2012) performed whole-exome sequencing in the family
with autosomal dominant neovascular inflammatory vitreoretinopathy
originally reported by Bennett et al. (1990) (ADNIV-1) and identified a
heterozygous missense mutation in the CAPN5 gene (R243L; 602537.0001)
that segregated fully with disease. Sequencing of CAPN5 in 2 additional
ADNIV families revealed that affected members of family ADNIV-2 carried
the same heterozygous R243L mutation, whereas affected individuals from
family ADNIV-3 were heterozygous for an adjacent missense mutation,
L244P (602537.0002). The mutations segregated with disease in each
family and were not found in 272 ethnically matched controls or in the
dbSNP or 1000 Genome databases.
ANIMAL MODEL
Saika et al. (2007) determined the effects of Smad7 (602932) gene
transfer in the prevention of fibrogenic responses by the retinal
pigment epithelium, a major cause of proliferative vitreoretinopathy
after retinal detachment in mice. In a retinal detachment-induced
proliferative vitreoretinopathy in a mouse model, Smad7 gene transfer
inhibited TGFB2/Smad signaling in ARPE19 cells and expression of
collagen type I and TGFB1 but had no effect on their basal levels. In
vivo Smad7 overexpression resulted in suppression of Smad2/3 signals and
of the fibrogenic response to epithelial-mesenchymal transition by the
retinal pigment epithelium. Saika et al. (2007) concluded that Smad7
gene transfer suppressed fibrogenic responses to TGFB2 by retinal
pigment epithelial cells in vitro and in vivo.
*FIELD* RF
1. Bennett, S. R.; Folk, J. C.; Kimura, A. E.; Russell, S. R.; Stone,
E. M.; Raphtis, E. M.: Autosomal dominant neovascular inflammatory
vitreoretinopathy. Ophthalmology 97: 1125-1135, 1990.
2. Mahajan, V. B.; Skeie, J. M.; Bassuk, A. G.; Fingert, J. H.; Braun,
T. A.; Daggett, H. T.; Folk, J. C.; Sheffield, V. C.; Stone, E. M.
: Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization,
and photoreceptor degeneration. PLoS Genet. 8: e1003001, 2012. Note:
Electronic Article.
3. Priglinger, S. G.; May, C. A.; Neubauer, A. S.; Alge, C. S.; Schoenfeld,
C.-L.; Kampik, A.; Welge-Lussen, U.: Tissue transglutaminase as a
modifying enzyme of the extracellular matrix in PVR membranes. Invest.
Ophthal. Vis. Sci. 44: 355-364, 2003.
4. Saika, S.; Yamanaka, O.; Nishikawa-Ishida, I.; Kitano, A.; Flanders,
K. C.; Okada, Y.; Ohnishi, Y.; Nakajima, Y.; Ikeda, K.: Effect of
Smad7 gene overexpression on transforming growth factor beta-induced
retinal pigment fibrosis in a proliferative vitreoretinopathy mouse
model. Arch. Ophthal. 125: 647-654, 2007.
5. Sheffield, V. C.; Kimura, A. E.; Folk, J. C.; Bennett, S. R.; Streb,
L. M.; Nichols, B. E.; Stone, E. M.: The gene for autosomal dominant
neovascular inflammatory vitreoretinopathy maps to 11q13. (Abstract) Am.
J. Hum. Genet. 51 (suppl.): A35 only, 1992.
6. Stone, E. M.; Kimura, A. E.; Folk, J. C.; Bennett, S. R.; Nichols,
B. E.; Streb, L. M.; Sheffield, V. C.: Genetic linkage of autosomal
dominant neovascular inflammatory vitreoretinopathy to chromosome
11q13. Hum. Molec. Genet. 1: 685-689, 1992.
*FIELD* CS
Eyes:
Neovascular inflammatory vitreoretinopathy;
Blindness;
Prominent ocular inflammation;
Retinal vascular dropout;
Large hyperpigmented retinal spots;
Neovascularization of peripheral and posterior retina;
Vitreous hemorrhage;
Retinal detachment
Lab:
Distinct b-wave abnormality on electrooculography
Inheritance:
Autosomal dominant (11q13)
*FIELD* CN
Marla J. F. O'Neill - updated: 02/20/2013
Marla J. F. O'Neill - updated: 11/19/2012
Jane Kelly - updated: 9/25/2007
Jane Kelly - updated: 3/18/2003
*FIELD* CD
Victor A. McKusick: 10/29/1992
*FIELD* ED
carol: 02/20/2013
alopez: 11/20/2012
terry: 11/19/2012
carol: 11/29/2007
carol: 9/25/2007
wwang: 10/12/2006
mgross: 3/18/2004
cwells: 3/18/2003
mimadm: 6/7/1995
warfield: 4/14/1994
carol: 4/4/1994
carol: 2/2/1993
carol: 1/13/1993
carol: 10/29/1992
*RECORD*
*FIELD* NO
193235
*FIELD* TI
#193235 VITREORETINOPATHY, NEOVASCULAR INFLAMMATORY; VRNI
;;PROLIFERATIVE VITREORETINOPATHY; PVR;;
read moreVITREORETINOPATHY, NEOVASCULAR INFLAMMATORY, AUTOSOMAL DOMINANT; ADNIV
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
neovascular inflammatory vitreoretinopathy (VRNI) is caused by
heterozygous mutation in the CAPN5 gene (602537) on chromosome 11q14.
DESCRIPTION
Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is
a blinding disorder that shares some clinical features with retinitis
pigmentosa (see 268000), uveitis, and proliferative diabetic retinopathy
(see 603933). Features include prominent ocular inflammation; vascular
dropout, large spots of hyperpigmentation, and neovascularization of the
peripheral and posterior retina; vitreous hemorrhage; and retinal
detachment (summary by Sheffield et al., 1992).
CLINICAL FEATURES
Bennett et al. (1990) studied a large 6-generation family of northern
European ancestry segregating autosomal dominant inflammatory eye
disease. There were 28 affected individuals, the condition was present
in every generation, and there was at least 1 documented male-to-male
transmission. The youngest age at which symptoms developed was 16 years;
most affected individuals remained asymptomatic until their third or
fourth decade. The first signs of disease included vitreous cells,
minimal far-peripheral arteriolar closure and pigmentation, and
selective reduction in the b-wave of the electroretinogram (ERG). In
middle age, more prominent anterior and posterior inflammation,
progressive vascular closure with neovascularization of the far
peripheral retina or optic disc, vitreous hemorrhage, tractional retinal
detachment, fluorescein leakage in the posterior pole and midperiphery,
and cystoid macular edema develop. By 60 years of age, cataracts, marked
progressive neovascularization, and tractional retinal detachment were
observed, and anterior segment neovascularization developed. Cystoid
macular edema, vitreous hemorrhage, tractional retinal detachment, and
neovascular glaucoma caused profound visual loss in some patients. The
ERG was extinguished late in the disease.
Mahajan et al. (2012) studied 2 families segregating autosomal dominant
neovascular inflammatory vitreoretinopathy (ADNIV) and noted that the
phenotype was very similar to that described by the pedigree described
by Bennett et al. (1990). Affected members exhibited noninfectious
uveitis, early loss of the b-wave on electroretinography, pigmentary
retinal degeneration, cystoid macular edema, retinal and iris
neovascularization, vitreous hemorrhage, epiretinal membrane formation,
proliferative vitreoretinopathy, retinal detachment, cataract,
neovascular glaucoma, and ultimately phthisis and complete blindness.
Both pedigrees were consistent with autosomal dominant inheritance with
complete penetrance.
MAPPING
Sheffield et al. (1992) established close linkage of VRNI to markers
that map to 11q13. In a single large pedigree, linkage analysis with the
closest marker, D11S527, demonstrated a maximum lod of 6.29 with no
recombinants. Stone et al. (1992) reported that they had found 34
affected members in this pedigree, that no recombinants were found
between the disease phenotype and D11S527, and that multipoint analysis
yielded a maximum lod score of 11.9 centered on this marker. Another
inherited retinal dystrophy, Best macular dystrophy (VMD; 153700), also
maps to 11q13. However, Sheffield et al. (1992) stated that the 2
diseases appear to be at least 10 cM apart.
Mahajan et al. (2012) genotyped 2 unrelated families segregating
autosomal dominant neovascular inflammatory vitreoretinopathy and
confirmed linkage to the 11q13 locus. Haplotype analysis was suggestive
of an ancestral relationship between 1 of the families (ADNIV-2) and the
original ADNIV (ADNIV-1) family described by Bennett et al. (1990).
Recombination events in 1 of the families (ADNIV-3) narrowed the
critical interval to 6.5 Mb between D11S4139 and D11S1789; high
resolution SNP genotyping of ADNIV-1 and ADNIV-3 further reduced the
interval to 6 Mb between SNP dbSNP rs879380 and D11S1789.
PATHOGENESIS
Proliferative vitreoretinopathy is characterized by the development of
epi- and subretinal fibrocellular membranes containing modified retinal
pigment epithelial (RPE) cells among others. Priglinger et al. (2003)
found that tissue transglutaminase (190196) was present and functionally
active in proliferative vitreoretinopathy membranes. The amount and
activity of tissue transglutaminase appeared to be related to the
differentiation state of the RPE cells and their stimulation by TGFB2
(190220), a growth factor known to be increased in the vitreous of
proliferative vitreoretinopathy.
MOLECULAR GENETICS
Mahajan et al. (2012) performed whole-exome sequencing in the family
with autosomal dominant neovascular inflammatory vitreoretinopathy
originally reported by Bennett et al. (1990) (ADNIV-1) and identified a
heterozygous missense mutation in the CAPN5 gene (R243L; 602537.0001)
that segregated fully with disease. Sequencing of CAPN5 in 2 additional
ADNIV families revealed that affected members of family ADNIV-2 carried
the same heterozygous R243L mutation, whereas affected individuals from
family ADNIV-3 were heterozygous for an adjacent missense mutation,
L244P (602537.0002). The mutations segregated with disease in each
family and were not found in 272 ethnically matched controls or in the
dbSNP or 1000 Genome databases.
ANIMAL MODEL
Saika et al. (2007) determined the effects of Smad7 (602932) gene
transfer in the prevention of fibrogenic responses by the retinal
pigment epithelium, a major cause of proliferative vitreoretinopathy
after retinal detachment in mice. In a retinal detachment-induced
proliferative vitreoretinopathy in a mouse model, Smad7 gene transfer
inhibited TGFB2/Smad signaling in ARPE19 cells and expression of
collagen type I and TGFB1 but had no effect on their basal levels. In
vivo Smad7 overexpression resulted in suppression of Smad2/3 signals and
of the fibrogenic response to epithelial-mesenchymal transition by the
retinal pigment epithelium. Saika et al. (2007) concluded that Smad7
gene transfer suppressed fibrogenic responses to TGFB2 by retinal
pigment epithelial cells in vitro and in vivo.
*FIELD* RF
1. Bennett, S. R.; Folk, J. C.; Kimura, A. E.; Russell, S. R.; Stone,
E. M.; Raphtis, E. M.: Autosomal dominant neovascular inflammatory
vitreoretinopathy. Ophthalmology 97: 1125-1135, 1990.
2. Mahajan, V. B.; Skeie, J. M.; Bassuk, A. G.; Fingert, J. H.; Braun,
T. A.; Daggett, H. T.; Folk, J. C.; Sheffield, V. C.; Stone, E. M.
: Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization,
and photoreceptor degeneration. PLoS Genet. 8: e1003001, 2012. Note:
Electronic Article.
3. Priglinger, S. G.; May, C. A.; Neubauer, A. S.; Alge, C. S.; Schoenfeld,
C.-L.; Kampik, A.; Welge-Lussen, U.: Tissue transglutaminase as a
modifying enzyme of the extracellular matrix in PVR membranes. Invest.
Ophthal. Vis. Sci. 44: 355-364, 2003.
4. Saika, S.; Yamanaka, O.; Nishikawa-Ishida, I.; Kitano, A.; Flanders,
K. C.; Okada, Y.; Ohnishi, Y.; Nakajima, Y.; Ikeda, K.: Effect of
Smad7 gene overexpression on transforming growth factor beta-induced
retinal pigment fibrosis in a proliferative vitreoretinopathy mouse
model. Arch. Ophthal. 125: 647-654, 2007.
5. Sheffield, V. C.; Kimura, A. E.; Folk, J. C.; Bennett, S. R.; Streb,
L. M.; Nichols, B. E.; Stone, E. M.: The gene for autosomal dominant
neovascular inflammatory vitreoretinopathy maps to 11q13. (Abstract) Am.
J. Hum. Genet. 51 (suppl.): A35 only, 1992.
6. Stone, E. M.; Kimura, A. E.; Folk, J. C.; Bennett, S. R.; Nichols,
B. E.; Streb, L. M.; Sheffield, V. C.: Genetic linkage of autosomal
dominant neovascular inflammatory vitreoretinopathy to chromosome
11q13. Hum. Molec. Genet. 1: 685-689, 1992.
*FIELD* CS
Eyes:
Neovascular inflammatory vitreoretinopathy;
Blindness;
Prominent ocular inflammation;
Retinal vascular dropout;
Large hyperpigmented retinal spots;
Neovascularization of peripheral and posterior retina;
Vitreous hemorrhage;
Retinal detachment
Lab:
Distinct b-wave abnormality on electrooculography
Inheritance:
Autosomal dominant (11q13)
*FIELD* CN
Marla J. F. O'Neill - updated: 02/20/2013
Marla J. F. O'Neill - updated: 11/19/2012
Jane Kelly - updated: 9/25/2007
Jane Kelly - updated: 3/18/2003
*FIELD* CD
Victor A. McKusick: 10/29/1992
*FIELD* ED
carol: 02/20/2013
alopez: 11/20/2012
terry: 11/19/2012
carol: 11/29/2007
carol: 9/25/2007
wwang: 10/12/2006
mgross: 3/18/2004
cwells: 3/18/2003
mimadm: 6/7/1995
warfield: 4/14/1994
carol: 4/4/1994
carol: 2/2/1993
carol: 1/13/1993
carol: 10/29/1992
MIM
602537
*RECORD*
*FIELD* NO
602537
*FIELD* TI
*602537 CALPAIN 5; CAPN5
;;HTRA3
*FIELD* TX
DESCRIPTION
Calpains are calcium-dependent cysteine proteases involved in signal
read moretransduction in a variety of cellular processes. A functional calpain
protein consists of an invariant small subunit (114170) and 1 of a
family of large subunits.
CLONING
Dear et al. (1997) used degenerate PCR on mouse genomic DNA to isolate
fragments of 2 novel calpain large subunits, CAPN5 and CAPN6 (300146).
The authors assembled the human cDNA sequence of CAPN5 from a clone in
an EST database and RACE PCR fragments from human hippocampus. RACE PCR
also revealed an alternative 3-prime end to the human CAPN5 cDNA. The
longest human CAPN5 cDNA encodes a 640-amino acid polypeptide that
contains the 3 amino acids that are part of the conserved active site
for cysteine proteases. Dear et al. (1997) noted that CAPN5 and CAPN6
differ from previously identified vertebrate calpains in that they lack
a calmodulin-like domain IV. Using RNA dot blot and Northern blot
analyses, Dear et al. (1997) found that the CAPN5 gene was expressed as
a major transcript of 5.0 kb and a minor one of 3.5 kb at a low level in
all human tissues and at a higher level in brain, liver, and kidney.
By PCR-based screening of EST sequences, Mugita et al. (1997) isolated a
CAPN5 cDNA. The cDNA encodes a 639-amino acid polypeptide that shares
significant homology with C. elegans tra-3, a sex determination gene,
and was therefore termed HTRA3 (human tra-3). The authors stated that
the HTRA3 protein differs at its 3-prime end from the sequence
identified by Dear et al. (1997). Northern blot analysis revealed that
the HTRA3 gene was expressed as a major 4.4- and a minor 2.7-kb
transcript predominantly in colon, small intestine, and testis. Mugita
et al. (1997) suggested that the 2.7-kb transcript may represent a
related or alternatively spliced sequence.
Using RNA sequencing, Mahajan et al. (2012) observed CAPN5 transcript
levels in human retinal tissue between the first quartile and the median
level for all transcripts observed in the retina. No significant splice
variants were detected. Antibody labeling showed strong calpain-5
expression in the photoreceptor cells, with a punctate pattern of
labeling over the nuclei and inner segments with less expression along
the other segments and outer plexiform layer.
MAPPING
By PCR analysis of a radiation hybrid panel, Mugita et al. (1997) mapped
the CAPN5 gene to 11q14.
MOLECULAR GENETICS
In 3 families with neovascular inflammatory vitreoretinopathy (VRNI;
193235), Mahajan et al. (2012) identified heterozygosity for 2 missense
mutations in the CAPN5 gene (602537.0001 and 602537.0002) that
segregated with disease in each family and were not found in controls.
ANIMAL MODEL
By gene targeting, Franz et al. (2004) integrated a lacZ expression
cassette into the Capn5 gene, allowing the expression of Capn5 mRNA to
be examined in heterozygous mice. Expression was observed in embryonic
and newborn thymi, in various epithelial tissues, and in tissues of the
central nervous system. In the thymus, Capn5 was expressed mainly in
immature Cd25 (147730)-positive embryonic thymocytes. Despite the
widespread expression, most homozygous Capn5-null mice were viable and
fertile and appeared healthy. Histopathologic analysis revealed no
differences between Capn5-null and wildtype mice. There were no defects
in the major T- or B-cell populations in the thymus, spleen, bone
marrow, or peritoneum, nor did apoptosis appear abnormal in Capn5-null T
cells. There was no evidence for the development of autoimmune disease
in Capn5-null animals. However, a small proportion of homozygous null
offspring from heterozygous matings were runted and frequently did not
survive to adulthood.
*FIELD* AV
.0001
VITREORETINOPATHY, NEOVASCULAR INFLAMMATORY
CAPN5, ARG243LEU
In all affected members of a large 7-generation pedigree segregating
autosomal dominant neovascular inflammatory vitreoretinopathy (VRNI;
193235), originally reported by Bennett et al. (1990), Mahajan et al.
(2012) identified heterozygosity for a 728G-T transversion in exon 6 of
the CAPN5 gene, resulting in an arg243-to-leu (R243L) substitution at a
highly conserved residue in the alpha-helical domain. Heterozygosity for
the R243L mutation was also found in affected members of a second VRNI
family that was suspected of having an ancestral relationship with the
first pedigree. The mutation was not found in unaffected members of
either family or in 272 ethnically similar controls, or in the dbSNP or
1000 Genomes databases, or in more than 10,700 CAPN5 alleles sequenced
in the NHLBI Exome Sequencing Project. Transfection studies in HEK293T
cells demonstrated that R243L mutant protein was found largely within
the cytoplasm, whereas wildtype was localized near the cell surface.
.0002
VITREORETINOPATHY, NEOVASCULAR INFLAMMATORY
CAPN5, LEU244PRO
In all affected members of a large 4-generation family segregating
autosomal dominant neovascular inflammatory vitreoretinopathy (VRNI;
193235), Mahajan et al. (2012) identified heterozygosity for a 731T-C
transition in exon 6 of the CAPN5 gene, resulting in a leu244-to-pro
(L244P) substitution at a highly conserved residue in the alpha-helical
domain. The mutation was not found in unaffected members of the family
or in 272 ethnically similar controls, or in the dbSNP or 1000 Genomes
databases, or in more than 10,700 CAPN5 alleles sequenced in the NHLBI
Exome Sequencing Project. Transfection studies in HEK293T cells
demonstrated that L244P mutant protein was found largely within the
cytoplasm, whereas wildtype was localized near the cell surface.
*FIELD* RF
1. Bennett, S. R.; Folk, J. C.; Kimura, A. E.; Russell, S. R.; Stone,
E. M.; Raphtis, E. M.: Autosomal dominant neovascular inflammatory
vitreoretinopathy. Ophthalmology 97: 1125-1135, 1990.
2. Dear, N.; Matena, K.; Vingron, M.; Boehm, T.: A new subfamily
of vertebrate calpains lacking a calmodulin-like domain: implications
for calpain regulation and evolution. Genomics 45: 175-184, 1997.
3. Franz, T.; Winckler, L.; Boehm, T.; Dear, T. N.: Capn5 is expressed
in a subset of T cells and is dispensable for development. Molec.
Cell. Biol. 24: 1649-1654, 2004.
4. Mahajan, V. B.; Skeie, J. M.; Bassuk, A. G.; Fingert, J. H.; Braun,
T. A.; Daggett, H. T.; Folk, J. C.; Sheffield, V. C.; Stone, E. M.
: Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization,
and photoreceptor degeneration. PLoS Genet. 8: e1003001, 2012. Note:
Electronic Article.
5. Mugita, N.; Kumura, Y.; Ogawa, M.; Saya, H.; Nakao, M.: Identification
of a novel, tissue-specific calpain htra-3; a human homologue of the
Caenorhabditis elegans sex determination gene. Biochem. Biophys.
Res. Commun. 239: 845-850, 1997.
*FIELD* CN
Marla J. F. O'Neill - updated: 11/19/2012
Patricia A. Hartz - updated: 2/17/2004
Jennifer P. Macke - updated: 8/6/1999
*FIELD* CD
Jennifer P. Macke: 4/21/1998
*FIELD* ED
carol: 10/22/2013
alopez: 11/20/2012
terry: 11/19/2012
carol: 10/27/2004
cwells: 2/23/2004
terry: 2/17/2004
mgross: 8/6/1999
carol: 9/25/1998
dholmes: 6/16/1998
*RECORD*
*FIELD* NO
602537
*FIELD* TI
*602537 CALPAIN 5; CAPN5
;;HTRA3
*FIELD* TX
DESCRIPTION
Calpains are calcium-dependent cysteine proteases involved in signal
read moretransduction in a variety of cellular processes. A functional calpain
protein consists of an invariant small subunit (114170) and 1 of a
family of large subunits.
CLONING
Dear et al. (1997) used degenerate PCR on mouse genomic DNA to isolate
fragments of 2 novel calpain large subunits, CAPN5 and CAPN6 (300146).
The authors assembled the human cDNA sequence of CAPN5 from a clone in
an EST database and RACE PCR fragments from human hippocampus. RACE PCR
also revealed an alternative 3-prime end to the human CAPN5 cDNA. The
longest human CAPN5 cDNA encodes a 640-amino acid polypeptide that
contains the 3 amino acids that are part of the conserved active site
for cysteine proteases. Dear et al. (1997) noted that CAPN5 and CAPN6
differ from previously identified vertebrate calpains in that they lack
a calmodulin-like domain IV. Using RNA dot blot and Northern blot
analyses, Dear et al. (1997) found that the CAPN5 gene was expressed as
a major transcript of 5.0 kb and a minor one of 3.5 kb at a low level in
all human tissues and at a higher level in brain, liver, and kidney.
By PCR-based screening of EST sequences, Mugita et al. (1997) isolated a
CAPN5 cDNA. The cDNA encodes a 639-amino acid polypeptide that shares
significant homology with C. elegans tra-3, a sex determination gene,
and was therefore termed HTRA3 (human tra-3). The authors stated that
the HTRA3 protein differs at its 3-prime end from the sequence
identified by Dear et al. (1997). Northern blot analysis revealed that
the HTRA3 gene was expressed as a major 4.4- and a minor 2.7-kb
transcript predominantly in colon, small intestine, and testis. Mugita
et al. (1997) suggested that the 2.7-kb transcript may represent a
related or alternatively spliced sequence.
Using RNA sequencing, Mahajan et al. (2012) observed CAPN5 transcript
levels in human retinal tissue between the first quartile and the median
level for all transcripts observed in the retina. No significant splice
variants were detected. Antibody labeling showed strong calpain-5
expression in the photoreceptor cells, with a punctate pattern of
labeling over the nuclei and inner segments with less expression along
the other segments and outer plexiform layer.
MAPPING
By PCR analysis of a radiation hybrid panel, Mugita et al. (1997) mapped
the CAPN5 gene to 11q14.
MOLECULAR GENETICS
In 3 families with neovascular inflammatory vitreoretinopathy (VRNI;
193235), Mahajan et al. (2012) identified heterozygosity for 2 missense
mutations in the CAPN5 gene (602537.0001 and 602537.0002) that
segregated with disease in each family and were not found in controls.
ANIMAL MODEL
By gene targeting, Franz et al. (2004) integrated a lacZ expression
cassette into the Capn5 gene, allowing the expression of Capn5 mRNA to
be examined in heterozygous mice. Expression was observed in embryonic
and newborn thymi, in various epithelial tissues, and in tissues of the
central nervous system. In the thymus, Capn5 was expressed mainly in
immature Cd25 (147730)-positive embryonic thymocytes. Despite the
widespread expression, most homozygous Capn5-null mice were viable and
fertile and appeared healthy. Histopathologic analysis revealed no
differences between Capn5-null and wildtype mice. There were no defects
in the major T- or B-cell populations in the thymus, spleen, bone
marrow, or peritoneum, nor did apoptosis appear abnormal in Capn5-null T
cells. There was no evidence for the development of autoimmune disease
in Capn5-null animals. However, a small proportion of homozygous null
offspring from heterozygous matings were runted and frequently did not
survive to adulthood.
*FIELD* AV
.0001
VITREORETINOPATHY, NEOVASCULAR INFLAMMATORY
CAPN5, ARG243LEU
In all affected members of a large 7-generation pedigree segregating
autosomal dominant neovascular inflammatory vitreoretinopathy (VRNI;
193235), originally reported by Bennett et al. (1990), Mahajan et al.
(2012) identified heterozygosity for a 728G-T transversion in exon 6 of
the CAPN5 gene, resulting in an arg243-to-leu (R243L) substitution at a
highly conserved residue in the alpha-helical domain. Heterozygosity for
the R243L mutation was also found in affected members of a second VRNI
family that was suspected of having an ancestral relationship with the
first pedigree. The mutation was not found in unaffected members of
either family or in 272 ethnically similar controls, or in the dbSNP or
1000 Genomes databases, or in more than 10,700 CAPN5 alleles sequenced
in the NHLBI Exome Sequencing Project. Transfection studies in HEK293T
cells demonstrated that R243L mutant protein was found largely within
the cytoplasm, whereas wildtype was localized near the cell surface.
.0002
VITREORETINOPATHY, NEOVASCULAR INFLAMMATORY
CAPN5, LEU244PRO
In all affected members of a large 4-generation family segregating
autosomal dominant neovascular inflammatory vitreoretinopathy (VRNI;
193235), Mahajan et al. (2012) identified heterozygosity for a 731T-C
transition in exon 6 of the CAPN5 gene, resulting in a leu244-to-pro
(L244P) substitution at a highly conserved residue in the alpha-helical
domain. The mutation was not found in unaffected members of the family
or in 272 ethnically similar controls, or in the dbSNP or 1000 Genomes
databases, or in more than 10,700 CAPN5 alleles sequenced in the NHLBI
Exome Sequencing Project. Transfection studies in HEK293T cells
demonstrated that L244P mutant protein was found largely within the
cytoplasm, whereas wildtype was localized near the cell surface.
*FIELD* RF
1. Bennett, S. R.; Folk, J. C.; Kimura, A. E.; Russell, S. R.; Stone,
E. M.; Raphtis, E. M.: Autosomal dominant neovascular inflammatory
vitreoretinopathy. Ophthalmology 97: 1125-1135, 1990.
2. Dear, N.; Matena, K.; Vingron, M.; Boehm, T.: A new subfamily
of vertebrate calpains lacking a calmodulin-like domain: implications
for calpain regulation and evolution. Genomics 45: 175-184, 1997.
3. Franz, T.; Winckler, L.; Boehm, T.; Dear, T. N.: Capn5 is expressed
in a subset of T cells and is dispensable for development. Molec.
Cell. Biol. 24: 1649-1654, 2004.
4. Mahajan, V. B.; Skeie, J. M.; Bassuk, A. G.; Fingert, J. H.; Braun,
T. A.; Daggett, H. T.; Folk, J. C.; Sheffield, V. C.; Stone, E. M.
: Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization,
and photoreceptor degeneration. PLoS Genet. 8: e1003001, 2012. Note:
Electronic Article.
5. Mugita, N.; Kumura, Y.; Ogawa, M.; Saya, H.; Nakao, M.: Identification
of a novel, tissue-specific calpain htra-3; a human homologue of the
Caenorhabditis elegans sex determination gene. Biochem. Biophys.
Res. Commun. 239: 845-850, 1997.
*FIELD* CN
Marla J. F. O'Neill - updated: 11/19/2012
Patricia A. Hartz - updated: 2/17/2004
Jennifer P. Macke - updated: 8/6/1999
*FIELD* CD
Jennifer P. Macke: 4/21/1998
*FIELD* ED
carol: 10/22/2013
alopez: 11/20/2012
terry: 11/19/2012
carol: 10/27/2004
cwells: 2/23/2004
terry: 2/17/2004
mgross: 8/6/1999
carol: 9/25/1998
dholmes: 6/16/1998