Full text data of CA8
CA8
(CALS)
[Confidence: low (only semi-automatic identification from reviews)]
Carbonic anhydrase-related protein; CARP (Carbonic anhydrase VIII; CA-VIII)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Carbonic anhydrase-related protein; CARP (Carbonic anhydrase VIII; CA-VIII)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P35219
ID CAH8_HUMAN Reviewed; 290 AA.
AC P35219; A8K0A5; B3KQZ7; Q32MY2;
DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 123.
DE RecName: Full=Carbonic anhydrase-related protein;
DE Short=CARP;
DE AltName: Full=Carbonic anhydrase VIII;
DE Short=CA-VIII;
GN Name=CA8; Synonyms=CALS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8482548; DOI=10.1016/0378-1119(93)90385-G;
RA Skaggs L.A., Bergenhem N.C.H., Venta P.J., Tashian R.E.;
RT "The deduced amino acid sequence of human carbonic anhydrase-related
RT protein (CARP) is 98% identical to the mouse homologue.";
RL Gene 126:291-292(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Chen Y., Huang C.-H.;
RT "Molecular identification of carbonic anhydrases (CA) and CA-related
RT (CAR) genes.";
RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cerebellum;
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].
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 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 [7]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS).
RX PubMed=19360879; DOI=10.1002/prot.22411;
RA Picaud S.S., Muniz J.R.C., Kramm A., Pilka E.S., Kochan G.,
RA Oppermann U., Yue W.W.;
RT "Crystal structure of human carbonic anhydrase-related protein VIII
RT reveals the basis for catalytic silencing.";
RL Proteins 76:507-511(2009).
RN [8]
RP VARIANT CMARQ3 PRO-100, AND CHARACTERIZATION OF VARIANT CMARQ3
RP PRO-100.
RX PubMed=19461874; DOI=10.1371/journal.pgen.1000487;
RA Turkmen S., Guo G., Garshasbi M., Hoffmann K., Alshalah A.J.,
RA Mischung C., Kuss A., Humphrey N., Mundlos S., Robinson P.N.;
RT "CA8 mutations cause a novel syndrome characterized by ataxia and mild
RT mental retardation with predisposition to quadrupedal gait.";
RL PLoS Genet. 5:E1000487-E1000487(2009).
CC -!- FUNCTION: Does not have a carbonic anhydrase catalytic activity.
CC -!- DISEASE: Cerebellar ataxia, mental retardation, and dysequilibrium
CC syndrome 3 (CMARQ3) [MIM:613227]: A congenital cerebellar ataxia
CC associated with dysarthia, quadrupedal gait and mental
CC retardation. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the alpha-carbonic anhydrase family.
CC -!- CAUTION: Although it belongs to the alpha-carbonic anhydrase
CC family, Arg-116 is present instead of the conserved His which is a
CC zinc-binding residue. It is therefore expected that this protein
CC lacks carbonic anhydrase activity.
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; L04656; AAA35653.2; -; mRNA.
DR EMBL; AY075022; AAL78170.1; -; mRNA.
DR EMBL; AK289470; BAF82159.1; -; mRNA.
DR EMBL; AK314538; BAG37128.1; -; mRNA.
DR EMBL; AK090655; BAG52209.1; -; mRNA.
DR EMBL; CH471068; EAW86826.1; -; Genomic_DNA.
DR EMBL; BC069744; AAH69744.1; -; mRNA.
DR EMBL; BC069794; AAH69794.1; -; mRNA.
DR EMBL; BC108929; AAI08930.1; -; mRNA.
DR PIR; JN0576; JN0576.
DR RefSeq; NP_004047.3; NM_004056.4.
DR UniGene; Hs.654388; -.
DR PDB; 2W2J; X-ray; 1.60 A; A=1-290.
DR PDBsum; 2W2J; -.
DR ProteinModelPortal; P35219; -.
DR SMR; P35219; 23-290.
DR IntAct; P35219; 1.
DR MINT; MINT-1406878; -.
DR STRING; 9606.ENSP00000314407; -.
DR BindingDB; P35219; -.
DR PhosphoSite; P35219; -.
DR DMDM; 461681; -.
DR PaxDb; P35219; -.
DR PeptideAtlas; P35219; -.
DR PRIDE; P35219; -.
DR DNASU; 767; -.
DR Ensembl; ENST00000317995; ENSP00000314407; ENSG00000178538.
DR GeneID; 767; -.
DR KEGG; hsa:767; -.
DR UCSC; uc003xtz.1; human.
DR CTD; 767; -.
DR GeneCards; GC08M061151; -.
DR HGNC; HGNC:1382; CA8.
DR HPA; CAB025545; -.
DR HPA; CAB047309; -.
DR HPA; HPA024748; -.
DR MIM; 114815; gene.
DR MIM; 613227; phenotype.
DR neXtProt; NX_P35219; -.
DR Orphanet; 1766; Dysequilibrium syndrome.
DR PharmGKB; PA25997; -.
DR eggNOG; COG3338; -.
DR HOGENOM; HOG000112637; -.
DR HOVERGEN; HBG002837; -.
DR InParanoid; P35219; -.
DR KO; K01672; -.
DR OMA; DGMLGDN; -.
DR OrthoDB; EOG7WMCK7; -.
DR PhylomeDB; P35219; -.
DR ChiTaRS; CA8; human.
DR EvolutionaryTrace; P35219; -.
DR GeneWiki; CA8; -.
DR GenomeRNAi; 767; -.
DR NextBio; 3102; -.
DR PRO; PR:P35219; -.
DR ArrayExpress; P35219; -.
DR Bgee; P35219; -.
DR CleanEx; HS_CA8; -.
DR Genevestigator; P35219; -.
DR GO; GO:0005737; C:cytoplasm; IEA:Ensembl.
DR GO; GO:0004089; F:carbonate dehydratase activity; TAS:ProtInc.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006730; P:one-carbon metabolic process; IEA:InterPro.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; IEA:Ensembl.
DR Gene3D; 3.10.200.10; -; 1.
DR InterPro; IPR001148; Carbonic_anhydrase_a.
DR InterPro; IPR023561; Carbonic_anhydrase_a-class.
DR InterPro; IPR018338; Carbonic_anhydrase_a-class_CS.
DR InterPro; IPR018434; Carbonic_anhydrase_RP_CA8.
DR PANTHER; PTHR18952; PTHR18952; 1.
DR PANTHER; PTHR18952:SF23; PTHR18952:SF23; 1.
DR Pfam; PF00194; Carb_anhydrase; 1.
DR SMART; SM01057; Carb_anhydrase; 1.
DR SUPFAM; SSF51069; SSF51069; 1.
DR PROSITE; PS00162; ALPHA_CA_1; 1.
DR PROSITE; PS51144; ALPHA_CA_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Disease mutation; Mental retardation;
KW Metal-binding; Reference proteome; Zinc.
FT CHAIN 1 290 Carbonic anhydrase-related protein.
FT /FTId=PRO_0000077433.
FT COMPBIAS 15 36 Glu-rich (acidic).
FT METAL 118 118 Zinc (Potential).
FT METAL 141 141 Zinc (Potential).
FT SITE 116 116 Ancestral zinc ligand.
FT VARIANT 100 100 S -> P (in CMARQ3; affects protein
FT stability owing to accelerated
FT proteasomal degradation).
FT /FTId=VAR_063634.
FT CONFLICT 106 106 Q -> R (in Ref. 3; BAG52209).
FT STRAND 31 34
FT HELIX 37 39
FT HELIX 42 45
FT HELIX 56 58
FT HELIX 63 66
FT STRAND 71 73
FT STRAND 77 84
FT STRAND 89 92
FT STRAND 97 101
FT STRAND 110 119
FT STRAND 128 131
FT STRAND 137 146
FT TURN 147 149
FT HELIX 153 156
FT STRAND 163 174
FT HELIX 177 183
FT HELIX 184 189
FT STRAND 194 199
FT HELIX 203 206
FT STRAND 215 221
FT STRAND 229 238
FT STRAND 240 242
FT HELIX 244 250
FT STRAND 254 256
FT STRAND 286 288
SQ SEQUENCE 290 AA; 32973 MW; C142711660A972DB CRC64;
MADLSFIEDT VAFPEKEEDE EEEEEGVEWG YEEGVEWGLV FPDANGEYQS PINLNSREAR
YDPSLLDVRL SPNYVVCRDC EVTNDGHTIQ VILKSKSVLS GGPLPQGHEF ELYEVRFHWG
RENQRGSEHT VNFKAFPMEL HLIHWNSTLF GSIDEAVGKP HGIAIIALFV QIGKEHVGLK
AVTEILQDIQ YKGKSKTIPC FNPNTLLPDP LLRDYWVYEG SLTIPPCSEG VTWILFRYPL
TISQLQIEEF RRLRTHVKGA ELVEGCDGIL GDNFRPTQPL SDRVIRAAFQ
//
ID CAH8_HUMAN Reviewed; 290 AA.
AC P35219; A8K0A5; B3KQZ7; Q32MY2;
DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 123.
DE RecName: Full=Carbonic anhydrase-related protein;
DE Short=CARP;
DE AltName: Full=Carbonic anhydrase VIII;
DE Short=CA-VIII;
GN Name=CA8; Synonyms=CALS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8482548; DOI=10.1016/0378-1119(93)90385-G;
RA Skaggs L.A., Bergenhem N.C.H., Venta P.J., Tashian R.E.;
RT "The deduced amino acid sequence of human carbonic anhydrase-related
RT protein (CARP) is 98% identical to the mouse homologue.";
RL Gene 126:291-292(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Chen Y., Huang C.-H.;
RT "Molecular identification of carbonic anhydrases (CA) and CA-related
RT (CAR) genes.";
RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cerebellum;
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].
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 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 [7]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS).
RX PubMed=19360879; DOI=10.1002/prot.22411;
RA Picaud S.S., Muniz J.R.C., Kramm A., Pilka E.S., Kochan G.,
RA Oppermann U., Yue W.W.;
RT "Crystal structure of human carbonic anhydrase-related protein VIII
RT reveals the basis for catalytic silencing.";
RL Proteins 76:507-511(2009).
RN [8]
RP VARIANT CMARQ3 PRO-100, AND CHARACTERIZATION OF VARIANT CMARQ3
RP PRO-100.
RX PubMed=19461874; DOI=10.1371/journal.pgen.1000487;
RA Turkmen S., Guo G., Garshasbi M., Hoffmann K., Alshalah A.J.,
RA Mischung C., Kuss A., Humphrey N., Mundlos S., Robinson P.N.;
RT "CA8 mutations cause a novel syndrome characterized by ataxia and mild
RT mental retardation with predisposition to quadrupedal gait.";
RL PLoS Genet. 5:E1000487-E1000487(2009).
CC -!- FUNCTION: Does not have a carbonic anhydrase catalytic activity.
CC -!- DISEASE: Cerebellar ataxia, mental retardation, and dysequilibrium
CC syndrome 3 (CMARQ3) [MIM:613227]: A congenital cerebellar ataxia
CC associated with dysarthia, quadrupedal gait and mental
CC retardation. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the alpha-carbonic anhydrase family.
CC -!- CAUTION: Although it belongs to the alpha-carbonic anhydrase
CC family, Arg-116 is present instead of the conserved His which is a
CC zinc-binding residue. It is therefore expected that this protein
CC lacks carbonic anhydrase activity.
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; L04656; AAA35653.2; -; mRNA.
DR EMBL; AY075022; AAL78170.1; -; mRNA.
DR EMBL; AK289470; BAF82159.1; -; mRNA.
DR EMBL; AK314538; BAG37128.1; -; mRNA.
DR EMBL; AK090655; BAG52209.1; -; mRNA.
DR EMBL; CH471068; EAW86826.1; -; Genomic_DNA.
DR EMBL; BC069744; AAH69744.1; -; mRNA.
DR EMBL; BC069794; AAH69794.1; -; mRNA.
DR EMBL; BC108929; AAI08930.1; -; mRNA.
DR PIR; JN0576; JN0576.
DR RefSeq; NP_004047.3; NM_004056.4.
DR UniGene; Hs.654388; -.
DR PDB; 2W2J; X-ray; 1.60 A; A=1-290.
DR PDBsum; 2W2J; -.
DR ProteinModelPortal; P35219; -.
DR SMR; P35219; 23-290.
DR IntAct; P35219; 1.
DR MINT; MINT-1406878; -.
DR STRING; 9606.ENSP00000314407; -.
DR BindingDB; P35219; -.
DR PhosphoSite; P35219; -.
DR DMDM; 461681; -.
DR PaxDb; P35219; -.
DR PeptideAtlas; P35219; -.
DR PRIDE; P35219; -.
DR DNASU; 767; -.
DR Ensembl; ENST00000317995; ENSP00000314407; ENSG00000178538.
DR GeneID; 767; -.
DR KEGG; hsa:767; -.
DR UCSC; uc003xtz.1; human.
DR CTD; 767; -.
DR GeneCards; GC08M061151; -.
DR HGNC; HGNC:1382; CA8.
DR HPA; CAB025545; -.
DR HPA; CAB047309; -.
DR HPA; HPA024748; -.
DR MIM; 114815; gene.
DR MIM; 613227; phenotype.
DR neXtProt; NX_P35219; -.
DR Orphanet; 1766; Dysequilibrium syndrome.
DR PharmGKB; PA25997; -.
DR eggNOG; COG3338; -.
DR HOGENOM; HOG000112637; -.
DR HOVERGEN; HBG002837; -.
DR InParanoid; P35219; -.
DR KO; K01672; -.
DR OMA; DGMLGDN; -.
DR OrthoDB; EOG7WMCK7; -.
DR PhylomeDB; P35219; -.
DR ChiTaRS; CA8; human.
DR EvolutionaryTrace; P35219; -.
DR GeneWiki; CA8; -.
DR GenomeRNAi; 767; -.
DR NextBio; 3102; -.
DR PRO; PR:P35219; -.
DR ArrayExpress; P35219; -.
DR Bgee; P35219; -.
DR CleanEx; HS_CA8; -.
DR Genevestigator; P35219; -.
DR GO; GO:0005737; C:cytoplasm; IEA:Ensembl.
DR GO; GO:0004089; F:carbonate dehydratase activity; TAS:ProtInc.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006730; P:one-carbon metabolic process; IEA:InterPro.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; IEA:Ensembl.
DR Gene3D; 3.10.200.10; -; 1.
DR InterPro; IPR001148; Carbonic_anhydrase_a.
DR InterPro; IPR023561; Carbonic_anhydrase_a-class.
DR InterPro; IPR018338; Carbonic_anhydrase_a-class_CS.
DR InterPro; IPR018434; Carbonic_anhydrase_RP_CA8.
DR PANTHER; PTHR18952; PTHR18952; 1.
DR PANTHER; PTHR18952:SF23; PTHR18952:SF23; 1.
DR Pfam; PF00194; Carb_anhydrase; 1.
DR SMART; SM01057; Carb_anhydrase; 1.
DR SUPFAM; SSF51069; SSF51069; 1.
DR PROSITE; PS00162; ALPHA_CA_1; 1.
DR PROSITE; PS51144; ALPHA_CA_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Disease mutation; Mental retardation;
KW Metal-binding; Reference proteome; Zinc.
FT CHAIN 1 290 Carbonic anhydrase-related protein.
FT /FTId=PRO_0000077433.
FT COMPBIAS 15 36 Glu-rich (acidic).
FT METAL 118 118 Zinc (Potential).
FT METAL 141 141 Zinc (Potential).
FT SITE 116 116 Ancestral zinc ligand.
FT VARIANT 100 100 S -> P (in CMARQ3; affects protein
FT stability owing to accelerated
FT proteasomal degradation).
FT /FTId=VAR_063634.
FT CONFLICT 106 106 Q -> R (in Ref. 3; BAG52209).
FT STRAND 31 34
FT HELIX 37 39
FT HELIX 42 45
FT HELIX 56 58
FT HELIX 63 66
FT STRAND 71 73
FT STRAND 77 84
FT STRAND 89 92
FT STRAND 97 101
FT STRAND 110 119
FT STRAND 128 131
FT STRAND 137 146
FT TURN 147 149
FT HELIX 153 156
FT STRAND 163 174
FT HELIX 177 183
FT HELIX 184 189
FT STRAND 194 199
FT HELIX 203 206
FT STRAND 215 221
FT STRAND 229 238
FT STRAND 240 242
FT HELIX 244 250
FT STRAND 254 256
FT STRAND 286 288
SQ SEQUENCE 290 AA; 32973 MW; C142711660A972DB CRC64;
MADLSFIEDT VAFPEKEEDE EEEEEGVEWG YEEGVEWGLV FPDANGEYQS PINLNSREAR
YDPSLLDVRL SPNYVVCRDC EVTNDGHTIQ VILKSKSVLS GGPLPQGHEF ELYEVRFHWG
RENQRGSEHT VNFKAFPMEL HLIHWNSTLF GSIDEAVGKP HGIAIIALFV QIGKEHVGLK
AVTEILQDIQ YKGKSKTIPC FNPNTLLPDP LLRDYWVYEG SLTIPPCSEG VTWILFRYPL
TISQLQIEEF RRLRTHVKGA ELVEGCDGIL GDNFRPTQPL SDRVIRAAFQ
//
MIM
114815
*RECORD*
*FIELD* NO
114815
*FIELD* TI
*114815 CARBONIC ANHYDRASE VIII; CA8
;;CA VIII;;
CARBONIC ANHYDRASE-RELATED POLYPEPTIDE; CARP;;
read moreCARBONIC ANHYDRASE-LIKE SEQUENCE; CALS
*FIELD* TX
DESCRIPTION
The CA8 (CARP) gene encodes carbonic anhydrase VIII, which is part of a
family of zinc metalloenzymes. Although CA8 has a central carbonic
anhydrase motif, it lacks carbonic anhydrase activity (EC 4.2.1.1) due
to absence of catalytic zinc coordinating residues (Kato, 1990).
Nonetheless, the gene product was designated carbonic anhydrase VIII by
several workers because it showed a clear sequence identity to other
members of the carbonic anhydrase gene family from many sources.
For background information on the CA family, see CA1 (114800).
CLONING
Kato (1990) discovered a new member of the carbonic anhydrase gene
family in a mouse brain cDNA library and demonstrated that it is
expressed in the Purkinje cells of the cerebellum. The deduced
291-residue gene product was referred to as CA-related protein, or
polypeptide (CARP).
Skaggs et al. (1993) used PCR to amplify the human CARP gene from
several cDNA libraries. They found a cDNA with a sequence that was 89.3%
identical to mouse CARP at the nucleotide level and 97.9% at the amino
acid level.
MAPPING
Bergenhem et al. (1993) found that CARP cosegregated with human
chromosome 8. Using human-mouse hybrid mapping and fluorescence in situ
hybridization, Bergenhem et al. (1995) demonstrated that the CA8 gene is
located on human chromosome 8q11-q12 between the centromere and the
CA1/CA2/CA3 cluster at 8q22-q23.
Kelly et al. (1994) mapped the mouse homolog (Car8) to chromosome 4 in a
region syntenic to human chromosome 8.
GENE FUNCTION
In mouse brain, Hirota et al. (2003) identified Carp as an ITPR1
(147265)-binding protein. Western blot and immunohistochemical studies
showed that Carp colocalized and interacted with ITPR1 predominantly in
the cytoplasm of cerebellar Purkinje cells. Lower levels of Carp
expression were seen in other regions, including cerebrum, olfactory
bulb, lung, liver, and adrenal gland. Deletion mutagenesis studies
showed that residues 45 to 291 of Carp were essential for its
association with the modulatory domain of ITPR1 (residues 1387 to 1647).
Carp functioned as an inhibitor of IP3 binding to ITPR1 by reducing the
affinity of the receptor for IP3.
MOLECULAR GENETICS
By genomewide linkage analysis followed by candidate gene sequencing of
a consanguineous Iraqi family with congenital cerebellar ataxia and mild
mental retardation (CAMRQ3; 613227), Turkmen et al. (2009) identified a
homozygous mutation in the CA8 gene (S100P; 186910.0001) on chromosome
8q12.
By homozygosity mapping followed by exon enrichment and next-generation
sequencing in 136 consanguineous families (over 90% Iranian and less
than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms
of autosomal recessive intellectual disability, Najmabadi et al. (2011)
identified a missense mutation in the CA8 gene (114815.0002) as the
cause of CAMRQ3 in a family (M107) in which first-cousin parents had 2
healthy and 4 affected children.
ANIMAL MODEL
Kelly et al. (1994) reported absence of CA VIII mRNA in the cerebellum
of the 'lurcher' mutant mouse with a neurologic defect.
Sjoblom et al. (1996) constructed a mutant form of mouse Carp by
introducing arg117-to-his and glu115-to-gln mutations and showed that
this mutated protein binds zinc and catalyzes the hydration of carbon
dioxide.
The autosomal recessive 'waddles' (wdl) mouse shows ataxia and
appendicular dystonia with frequent tail elevation and an abnormally
elevated trunk during ambulation. These changes are readily apparent by
2 weeks of age and persists throughout their life span. The appendicular
dystonia produces nearly straight limbs with minimal flexion at the knee
and elbow joints, elevation of the pelvis, and a waddling motion during
ambulation, particularly at higher velocities. Mutant mice also show
increased falling compared to wildtype. These abnormalities occur in the
absence of associated pathologic changes in the central or peripheral
nervous system. Jiao et al. (2005) determined that the wdl phenotype
results from a 19-bp deletion in exon 8 of the Car8 gene on chromosome
4. Mice homozygous for the mutation had almost complete absence of the
Car8 protein in Purkinje cells of the cerebellum, consistent with
nonsense-mediated decay of mutant transcripts. Itpr1 showed normal
expression. The findings indicated that Car8 plays a central role in
motor control.
Hirasawa et al. (2007) determined that the autosomal recessive ataxic
'Rigoletto' (rig) mutant mouse has the same 19-bp deletion in Car8 as
the wdl mouse. Electrophysiologic studies of cerebellar Purkinje cells
from mutant mice showed decreased spontaneous excitatory transmission
compared to wildtype mice. Paired pulse ratios were similar in both
strains, suggesting that synapses are functional with normal release
probability, but that mutants may have a lower number of functional
synapses. Light microscopy showed an abnormal extension of climbing
fibers to distal Purkinje cell dendrites. Ultrastructural studies showed
abnormalities of parallel fibers and dendritic spines, including free
spines that did not form normal synapses and multiple synaptic
varicosities. Hirasawa et al. (2007) concluded that Car8 plays a
critical role in synaptogenesis and/or maintenance of proper synaptic
morphology and function in the cerebellum.
*FIELD* AV
.0001
CEREBELLAR ATAXIA AND MENTAL RETARDATION WITH OR WITHOUT QUADRUPEDAL
LOCOMOTION 3
CA8, SER100PRO
In 4 affected sibs of a consanguineous Iraqi family with congenital
cerebellar ataxia and mild mental retardation (CAMRQ3; 613227), Turkmen
et al. (2009) identified a homozygous 298T-C transition in the CA8 gene,
resulting in a ser100-to-pro (S100P) substitution. The mutation was not
found in 200 matched controls. All affected individuals showed
quadrupedal locomotion. Although there was no apparent difference
between the CA8 S100P mutant and wildtype in binding to ITRP1 (147265),
in vitro functional expression studies showed that the S100P mutation
resulted in decreased protein stability, suggesting a loss of function.
.0002
CEREBELLAR ATAXIA AND MENTAL RETARDATION WITH OR WITHOUT QUADRUPEDAL
LOCOMOTION 3
CA8, ARG237GLN
In a family (M107) in which 4 of 6 children of first-cousin parents had
moderate intellectual disability and ataxia (613227), Najmabadi et al.
(2011) identified a C-to-T transition at genomic coordinate
chr8:61297790 (NCBI36) in the CA8 gene, resulting in an arg237-to-gln
(R237Q). The mutation was found in homozygosity among affected
individuals and segregated with the disease in the family.
*FIELD* RF
1. Bergenhem, N. C. H.; Eddy, R. L.; Shows, T. B.; Tashian, R. E.
: Assignment of the gene for human carbonic anhydrase-related protein
to chromosome 8. (Abstract) Human Genome Meeting, Kobe, Japan, 15-17
November , 1993.
2. Bergenhem, N. C. H.; Sait, S. S. J.; Eddy, R. L.; Shows, T. B.;
Tashian, R. E.: Assignment of the gene for human carbonic anhydrase
VIII (CA8) to chromosome 8q11-q12. Cytogenet. Cell Genet. 71: 299-300,
1995.
3. Hirasawa, M.; Xu, X.; Trask, R.B.; Maddatu, T. P.; Johnson, B.A.;
Naggert, J. K.; Nishina, P. M.; Ikeda, A.: Carbonic anhydrase related
protein 8 mutation results in aberrant synaptic morphology and excitatory
synaptic function in the cerebellum. Molec. Cell. Neurosci. 35:
161-170, 2007.
4. Hirota, J.; Ando, H.; Hamada, K.; Mikoshiba, K.: Carbonic anhydrase-related
protein is a novel binding protein for inositol 1,4,5-trisphosphate
receptor type 1. Biochem. J. 372: 435-441, 2003.
5. Jiao, Y.; Yan, J.; Zhao, Y.; Donahue, L. R.; Beamer, W. G.; Li,
X.; Roe, B. A.; LeDoux, M. S.; Gu, W.: Carbonic anhydrase-related
protein VIII deficiency is associated with a distinctive lifelong
gait disorder in waddles mice. Genetics 171: 1239-1246, 2005.
6. Kato, K.: Sequence of a novel carbonic anhydrase-related polypeptide
and its exclusive presence in Purkinje cells. FEBS Lett. 271: 137-140,
1990.
7. Kelly, C.; Nogradi, A.; Walker, R.; Caddy, K.; Peters, J.; Carter,
N.: Lurching, reeling, waddling and staggering in mice: is carbonic
anhydrase (CA) VIII a candidate gene? Biochem. Soc. Trans. 22: 359S,
1994.
8. Najmabadi, H.; Hu, H.; Garshasbi, M.; Zemojtel, T.; Abedini, S.
S.; Chen, W.; Hosseini, M.; Behjati, F.; Haas, S.; Jamali, P.; Zecha,
A.; Mohseni, M.; and 33 others: Deep sequencing reveals 50 novel
genes for recessive cognitive disorders. Nature 478: 57-63, 2011.
9. Sjoblom, B.; Elleby, B.; Wallgren, K.; Jonsson, B.-H.; Lindskog,
S.: Two point mutations convert a catalytically inactive carbonic
anhydrase-related protein (CARP) to an active enzyme. FEBS Lett. 398:
322-325, 1996.
10. Skaggs, L. A.; Bergenhem, N. C. H.; Venta, P. J.; Tashian, R.
E.: The deduced amino acid sequence of human carbonic anhydrase-related
protein (CARP) is 98% identical to the mouse homologue. Gene 126:
291-292, 1993.
11. Turkmen, S.; Guo, G.; Garshasbi, M.; Hoffmann, K.; Alshalah, A.J.;
Mischung, C.; Kuss, A.; Humphrey, N.; Mundlos, S.; Robinson, P. N.
: CA8 mutations cause a novel syndrome characterized by ataxia and
mild mental retardation with predisposition to quadrupedal gait. PLoS
Genet. 5: e1000487, 2009. Note: Electronic Article.
*FIELD* CN
Ada Hamosh - updated: 1/6/2012
Cassandra L. Kniffin - updated: 2/3/2010
Lori M. Kelman - updated: 6/3/1997
*FIELD* CD
Victor A. McKusick: 6/29/1993
*FIELD* ED
carol: 01/06/2012
terry: 1/6/2012
wwang: 4/29/2010
carol: 2/4/2010
ckniffin: 2/3/2010
carol: 3/1/2000
carol: 11/9/1998
alopez: 6/3/1997
alopez: 3/21/1997
mark: 1/28/1996
terry: 1/23/1996
mark: 5/10/1995
carol: 12/16/1993
carol: 6/29/1993
*RECORD*
*FIELD* NO
114815
*FIELD* TI
*114815 CARBONIC ANHYDRASE VIII; CA8
;;CA VIII;;
CARBONIC ANHYDRASE-RELATED POLYPEPTIDE; CARP;;
read moreCARBONIC ANHYDRASE-LIKE SEQUENCE; CALS
*FIELD* TX
DESCRIPTION
The CA8 (CARP) gene encodes carbonic anhydrase VIII, which is part of a
family of zinc metalloenzymes. Although CA8 has a central carbonic
anhydrase motif, it lacks carbonic anhydrase activity (EC 4.2.1.1) due
to absence of catalytic zinc coordinating residues (Kato, 1990).
Nonetheless, the gene product was designated carbonic anhydrase VIII by
several workers because it showed a clear sequence identity to other
members of the carbonic anhydrase gene family from many sources.
For background information on the CA family, see CA1 (114800).
CLONING
Kato (1990) discovered a new member of the carbonic anhydrase gene
family in a mouse brain cDNA library and demonstrated that it is
expressed in the Purkinje cells of the cerebellum. The deduced
291-residue gene product was referred to as CA-related protein, or
polypeptide (CARP).
Skaggs et al. (1993) used PCR to amplify the human CARP gene from
several cDNA libraries. They found a cDNA with a sequence that was 89.3%
identical to mouse CARP at the nucleotide level and 97.9% at the amino
acid level.
MAPPING
Bergenhem et al. (1993) found that CARP cosegregated with human
chromosome 8. Using human-mouse hybrid mapping and fluorescence in situ
hybridization, Bergenhem et al. (1995) demonstrated that the CA8 gene is
located on human chromosome 8q11-q12 between the centromere and the
CA1/CA2/CA3 cluster at 8q22-q23.
Kelly et al. (1994) mapped the mouse homolog (Car8) to chromosome 4 in a
region syntenic to human chromosome 8.
GENE FUNCTION
In mouse brain, Hirota et al. (2003) identified Carp as an ITPR1
(147265)-binding protein. Western blot and immunohistochemical studies
showed that Carp colocalized and interacted with ITPR1 predominantly in
the cytoplasm of cerebellar Purkinje cells. Lower levels of Carp
expression were seen in other regions, including cerebrum, olfactory
bulb, lung, liver, and adrenal gland. Deletion mutagenesis studies
showed that residues 45 to 291 of Carp were essential for its
association with the modulatory domain of ITPR1 (residues 1387 to 1647).
Carp functioned as an inhibitor of IP3 binding to ITPR1 by reducing the
affinity of the receptor for IP3.
MOLECULAR GENETICS
By genomewide linkage analysis followed by candidate gene sequencing of
a consanguineous Iraqi family with congenital cerebellar ataxia and mild
mental retardation (CAMRQ3; 613227), Turkmen et al. (2009) identified a
homozygous mutation in the CA8 gene (S100P; 186910.0001) on chromosome
8q12.
By homozygosity mapping followed by exon enrichment and next-generation
sequencing in 136 consanguineous families (over 90% Iranian and less
than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms
of autosomal recessive intellectual disability, Najmabadi et al. (2011)
identified a missense mutation in the CA8 gene (114815.0002) as the
cause of CAMRQ3 in a family (M107) in which first-cousin parents had 2
healthy and 4 affected children.
ANIMAL MODEL
Kelly et al. (1994) reported absence of CA VIII mRNA in the cerebellum
of the 'lurcher' mutant mouse with a neurologic defect.
Sjoblom et al. (1996) constructed a mutant form of mouse Carp by
introducing arg117-to-his and glu115-to-gln mutations and showed that
this mutated protein binds zinc and catalyzes the hydration of carbon
dioxide.
The autosomal recessive 'waddles' (wdl) mouse shows ataxia and
appendicular dystonia with frequent tail elevation and an abnormally
elevated trunk during ambulation. These changes are readily apparent by
2 weeks of age and persists throughout their life span. The appendicular
dystonia produces nearly straight limbs with minimal flexion at the knee
and elbow joints, elevation of the pelvis, and a waddling motion during
ambulation, particularly at higher velocities. Mutant mice also show
increased falling compared to wildtype. These abnormalities occur in the
absence of associated pathologic changes in the central or peripheral
nervous system. Jiao et al. (2005) determined that the wdl phenotype
results from a 19-bp deletion in exon 8 of the Car8 gene on chromosome
4. Mice homozygous for the mutation had almost complete absence of the
Car8 protein in Purkinje cells of the cerebellum, consistent with
nonsense-mediated decay of mutant transcripts. Itpr1 showed normal
expression. The findings indicated that Car8 plays a central role in
motor control.
Hirasawa et al. (2007) determined that the autosomal recessive ataxic
'Rigoletto' (rig) mutant mouse has the same 19-bp deletion in Car8 as
the wdl mouse. Electrophysiologic studies of cerebellar Purkinje cells
from mutant mice showed decreased spontaneous excitatory transmission
compared to wildtype mice. Paired pulse ratios were similar in both
strains, suggesting that synapses are functional with normal release
probability, but that mutants may have a lower number of functional
synapses. Light microscopy showed an abnormal extension of climbing
fibers to distal Purkinje cell dendrites. Ultrastructural studies showed
abnormalities of parallel fibers and dendritic spines, including free
spines that did not form normal synapses and multiple synaptic
varicosities. Hirasawa et al. (2007) concluded that Car8 plays a
critical role in synaptogenesis and/or maintenance of proper synaptic
morphology and function in the cerebellum.
*FIELD* AV
.0001
CEREBELLAR ATAXIA AND MENTAL RETARDATION WITH OR WITHOUT QUADRUPEDAL
LOCOMOTION 3
CA8, SER100PRO
In 4 affected sibs of a consanguineous Iraqi family with congenital
cerebellar ataxia and mild mental retardation (CAMRQ3; 613227), Turkmen
et al. (2009) identified a homozygous 298T-C transition in the CA8 gene,
resulting in a ser100-to-pro (S100P) substitution. The mutation was not
found in 200 matched controls. All affected individuals showed
quadrupedal locomotion. Although there was no apparent difference
between the CA8 S100P mutant and wildtype in binding to ITRP1 (147265),
in vitro functional expression studies showed that the S100P mutation
resulted in decreased protein stability, suggesting a loss of function.
.0002
CEREBELLAR ATAXIA AND MENTAL RETARDATION WITH OR WITHOUT QUADRUPEDAL
LOCOMOTION 3
CA8, ARG237GLN
In a family (M107) in which 4 of 6 children of first-cousin parents had
moderate intellectual disability and ataxia (613227), Najmabadi et al.
(2011) identified a C-to-T transition at genomic coordinate
chr8:61297790 (NCBI36) in the CA8 gene, resulting in an arg237-to-gln
(R237Q). The mutation was found in homozygosity among affected
individuals and segregated with the disease in the family.
*FIELD* RF
1. Bergenhem, N. C. H.; Eddy, R. L.; Shows, T. B.; Tashian, R. E.
: Assignment of the gene for human carbonic anhydrase-related protein
to chromosome 8. (Abstract) Human Genome Meeting, Kobe, Japan, 15-17
November , 1993.
2. Bergenhem, N. C. H.; Sait, S. S. J.; Eddy, R. L.; Shows, T. B.;
Tashian, R. E.: Assignment of the gene for human carbonic anhydrase
VIII (CA8) to chromosome 8q11-q12. Cytogenet. Cell Genet. 71: 299-300,
1995.
3. Hirasawa, M.; Xu, X.; Trask, R.B.; Maddatu, T. P.; Johnson, B.A.;
Naggert, J. K.; Nishina, P. M.; Ikeda, A.: Carbonic anhydrase related
protein 8 mutation results in aberrant synaptic morphology and excitatory
synaptic function in the cerebellum. Molec. Cell. Neurosci. 35:
161-170, 2007.
4. Hirota, J.; Ando, H.; Hamada, K.; Mikoshiba, K.: Carbonic anhydrase-related
protein is a novel binding protein for inositol 1,4,5-trisphosphate
receptor type 1. Biochem. J. 372: 435-441, 2003.
5. Jiao, Y.; Yan, J.; Zhao, Y.; Donahue, L. R.; Beamer, W. G.; Li,
X.; Roe, B. A.; LeDoux, M. S.; Gu, W.: Carbonic anhydrase-related
protein VIII deficiency is associated with a distinctive lifelong
gait disorder in waddles mice. Genetics 171: 1239-1246, 2005.
6. Kato, K.: Sequence of a novel carbonic anhydrase-related polypeptide
and its exclusive presence in Purkinje cells. FEBS Lett. 271: 137-140,
1990.
7. Kelly, C.; Nogradi, A.; Walker, R.; Caddy, K.; Peters, J.; Carter,
N.: Lurching, reeling, waddling and staggering in mice: is carbonic
anhydrase (CA) VIII a candidate gene? Biochem. Soc. Trans. 22: 359S,
1994.
8. Najmabadi, H.; Hu, H.; Garshasbi, M.; Zemojtel, T.; Abedini, S.
S.; Chen, W.; Hosseini, M.; Behjati, F.; Haas, S.; Jamali, P.; Zecha,
A.; Mohseni, M.; and 33 others: Deep sequencing reveals 50 novel
genes for recessive cognitive disorders. Nature 478: 57-63, 2011.
9. Sjoblom, B.; Elleby, B.; Wallgren, K.; Jonsson, B.-H.; Lindskog,
S.: Two point mutations convert a catalytically inactive carbonic
anhydrase-related protein (CARP) to an active enzyme. FEBS Lett. 398:
322-325, 1996.
10. Skaggs, L. A.; Bergenhem, N. C. H.; Venta, P. J.; Tashian, R.
E.: The deduced amino acid sequence of human carbonic anhydrase-related
protein (CARP) is 98% identical to the mouse homologue. Gene 126:
291-292, 1993.
11. Turkmen, S.; Guo, G.; Garshasbi, M.; Hoffmann, K.; Alshalah, A.J.;
Mischung, C.; Kuss, A.; Humphrey, N.; Mundlos, S.; Robinson, P. N.
: CA8 mutations cause a novel syndrome characterized by ataxia and
mild mental retardation with predisposition to quadrupedal gait. PLoS
Genet. 5: e1000487, 2009. Note: Electronic Article.
*FIELD* CN
Ada Hamosh - updated: 1/6/2012
Cassandra L. Kniffin - updated: 2/3/2010
Lori M. Kelman - updated: 6/3/1997
*FIELD* CD
Victor A. McKusick: 6/29/1993
*FIELD* ED
carol: 01/06/2012
terry: 1/6/2012
wwang: 4/29/2010
carol: 2/4/2010
ckniffin: 2/3/2010
carol: 3/1/2000
carol: 11/9/1998
alopez: 6/3/1997
alopez: 3/21/1997
mark: 1/28/1996
terry: 1/23/1996
mark: 5/10/1995
carol: 12/16/1993
carol: 6/29/1993
MIM
613227
*RECORD*
*FIELD* NO
613227
*FIELD* TI
#613227 CEREBELLAR ATAXIA, MENTAL RETARDATION, AND DYSEQUILIBRIUM SYNDROME
3; CAMRQ3
read more;;CEREBELLAR ATAXIA AND MENTAL RETARDATION WITH OR WITHOUT QUADRUPEDAL
LOCOMOTION 3
*FIELD* TX
A number sign (#) is used with this entry because this form of
congenital cerebellar ataxia with mental retardation (CAMRQ3) is caused
by homozygous mutation in the CA8 gene (114815) on chromosome 8q12.
DESCRIPTION
Cerebellar ataxia, mental retardation, and dysequilibrium syndrome
(CAMRQ) is a genetically heterogeneous disorder characterized by
congenital cerebellar ataxia and mental retardation (summary by Gulsuner
et al., 2011).
For a discussion of genetic heterogeneity of CAMRQ, see CAMRQ1 (224050).
CLINICAL FEATURES
Turkmen et al. (2009) reported a consanguineous Iraqi family in which 4
of 8 sibs had congenital ataxia, mild mental retardation, and
dysarthria. All walked with a quadrupedal gait, with straight legs and
placing their weight on the palms of their hands. The parents claimed
that the affected persons never learned to crawl on their knees as most
infants do, but ambulated from infancy on with their legs held straight
with a 'bear-like' gait. Attempts to teach the children to walk on 2
legs with crutches or other supports failed. All complained of lack of
balance and frequent falls when trying to walk bipedally. There were no
other neurologic symptoms. Brain imaging was not performed, but the
authors speculated that the ataxia resulted from cerebellar dysfunction
based on an animal model.
- Etiology of Quadrupedal Locomotion
Ozcelik et al. (2008) maintained that quadrupedal locomotion in the
affected individuals results from abnormal function of brain structures
that are critical for gait. Humphrey et al. (2008) concluded that the
tendency toward quadrupedal locomotion in affected individuals is an
adaptive and effective compensation for problems with balance caused by
congenital cerebellar hypoplasia. Thus, the unusual gait could be
attributed to the local cultural environment. Herz et al. (2008) also
concluded that quadrupedal locomotion is more likely an adaptation to
severe truncal ataxia, resulting from a combination of uneven, rough
surfaces in rural areas, imitation of affected sibs, and lack of
supportive therapy. Ozcelik et al. (2008) defended their position.
MOLECULAR GENETICS
By genomewide linkage analysis followed by candidate gene sequencing of
a consanguineous Iraqi family with ataxia and mild mental retardation,
Turkmen et al. (2009) identified a homozygous mutation in the CA8 gene
(S100P; 114815.0001).
By homozygosity mapping followed by exon enrichment and next-generation
sequencing in 136 consanguineous families (over 90% Iranian and less
than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms
of autosomal recessive intellectual disability, Najmabadi et al. (2011)
identified a missense mutation in the CA8 gene (114815.0002) as the
cause of CAMRQ3 in a family (M107) in which first-cousin parents had 2
healthy and 4 affected children.
ANIMAL MODEL
The autosomal recessive 'waddles' (wdl) mouse shows ataxia and
appendicular dystonia with frequent tail elevation and an abnormally
elevated trunk during ambulation. These changes are readily apparent by
2 weeks of age and persist throughout their life span. The appendicular
dystonia produces nearly straight limbs with minimal flexion at the knee
and elbow joints, elevation of the pelvis, and a waddling motion during
ambulation, particularly at higher velocities. Mutant mice also show
increased falling compared to wildtype. These abnormalities occur in the
absence of associated pathologic changes in the central or peripheral
nervous system. Jiao et al. (2005) determined that the wdl phenotype
results from a homozygous 19-bp deletion in exon 8 of the Ca8 gene on
mouse chromosome 4, resulting in a loss of function.
*FIELD* RF
1. Gulsuner, S.; Tekinay, A. B.; Doerschner, K.; Boyaci, H.; Bilguvar,
K.; Unal, H.; Ors, A.; Onat, O. E.; Atalar, E.; Basak, A. N.; Topaloglu,
H.; Kansu, T.; Tan, M.; Tan, U.; Gunel, M.; Ozcelik, T.: Homozygosity
mapping and targeted genomic sequencing reveal the gene responsible
for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous
kindred. Genome Res. 21: 1995-2003, 2011.
2. Herz, J.; Boycott, K. M.; Parboosingh, J. S.: 'Devolution' of
bipedality. (Letter) Proc. Nat. Acad. Sci. 105: E25 only, 2008.
Note: Electronic Article.
3. Humphrey, N.; Mundlos, S.; Turkmen, S.: Genes and quadrupedal
locomotion in humans. (Letter) Proc. Nat. Acad. Sci. 105: E26 only,
2008. Note: Electronic Article.
4. Jiao, Y.; Yan, J.; Zhao, Y.; Donahue, L. R.; Beamer, W. G.; Li,
X.; Roe, B. A.; LeDoux, M. S.; Gu, W.: Carbonic anhydrase-related
protein VIII deficiency is associated with a distinctive lifelong
gait disorder in waddles mice. Genetics 171: 1239-1246, 2005.
5. Najmabadi, H.; Hu, H.; Garshasbi, M.; Zemojtel, T.; Abedini, S.
S.; Chen, W.; Hosseini, M.; Behjati, F.; Haas, S.; Jamali, P.; Zecha,
A.; Mohseni, M.; and 33 others: Deep sequencing reveals 50 novel
genes for recessive cognitive disorders. Nature 478: 57-63, 2011.
6. Ozcelik, T.; Akarsu, N.; Uz, E.; Caglayan, S.; Gulsuner, S.; Onat,
O. E.; Tan, M.: Mutations in the very low-density lipoprotein receptor
VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proc.
Nat. Acad. Sci. 105: 4232-4236, 2008.
7. Ozcelik, T.; Akarsu, N.; Uz, E.; Caglayan, S.; Gulsuner, S.; Onat,
O. E.; Tan, M.; Tan, U.: Reply to Herz et al. and Humphrey et al.:
Genetic heterogeneity of cerebellar hypoplasia with quadrupedal locomotion.
(Letter) Proc. Nat. Acad. Sci. 105: E32-E33, 2008. Note: Electronic
Article.
8. Turkmen, S.; Guo, G.; Garshasbi, M.; Hoffmann, K.; Alshalah, A.J.;
Mischung, C.; Kuss, A.; Humphrey, N.; Mundlos, S.; Robinson, P. N.
: CA8 mutations cause a novel syndrome characterized by ataxia and
mild mental retardation with predisposition to quadrupedal gait. PLoS
Genet. 5: e1000487, 2009. Note: Electronic Article.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Strabismus
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild;
Cerebellar ataxia;
Quadrupedal gait;
Dysarthria;
Slurred speech;
Tremor
MISCELLANEOUS:
One family has been reported;
Congenital onset
MOLECULAR BASIS:
Caused by mutation in the carbonic anhydrase VIII gene (CA8, 114815.0001)
*FIELD* CD
Cassandra L. Kniffin: 1/21/2010
*FIELD* ED
joanna: 10/17/2011
joanna: 2/17/2010
ckniffin: 2/3/2010
*FIELD* CN
Ada Hamosh - updated: 1/6/2012
*FIELD* CD
Cassandra L. Kniffin: 1/20/2010
*FIELD* ED
alopez: 06/11/2013
alopez: 6/10/2013
carol: 1/6/2012
terry: 1/6/2012
terry: 4/28/2011
wwang: 4/29/2010
joanna: 3/10/2010
carol: 2/4/2010
ckniffin: 2/3/2010
*RECORD*
*FIELD* NO
613227
*FIELD* TI
#613227 CEREBELLAR ATAXIA, MENTAL RETARDATION, AND DYSEQUILIBRIUM SYNDROME
3; CAMRQ3
read more;;CEREBELLAR ATAXIA AND MENTAL RETARDATION WITH OR WITHOUT QUADRUPEDAL
LOCOMOTION 3
*FIELD* TX
A number sign (#) is used with this entry because this form of
congenital cerebellar ataxia with mental retardation (CAMRQ3) is caused
by homozygous mutation in the CA8 gene (114815) on chromosome 8q12.
DESCRIPTION
Cerebellar ataxia, mental retardation, and dysequilibrium syndrome
(CAMRQ) is a genetically heterogeneous disorder characterized by
congenital cerebellar ataxia and mental retardation (summary by Gulsuner
et al., 2011).
For a discussion of genetic heterogeneity of CAMRQ, see CAMRQ1 (224050).
CLINICAL FEATURES
Turkmen et al. (2009) reported a consanguineous Iraqi family in which 4
of 8 sibs had congenital ataxia, mild mental retardation, and
dysarthria. All walked with a quadrupedal gait, with straight legs and
placing their weight on the palms of their hands. The parents claimed
that the affected persons never learned to crawl on their knees as most
infants do, but ambulated from infancy on with their legs held straight
with a 'bear-like' gait. Attempts to teach the children to walk on 2
legs with crutches or other supports failed. All complained of lack of
balance and frequent falls when trying to walk bipedally. There were no
other neurologic symptoms. Brain imaging was not performed, but the
authors speculated that the ataxia resulted from cerebellar dysfunction
based on an animal model.
- Etiology of Quadrupedal Locomotion
Ozcelik et al. (2008) maintained that quadrupedal locomotion in the
affected individuals results from abnormal function of brain structures
that are critical for gait. Humphrey et al. (2008) concluded that the
tendency toward quadrupedal locomotion in affected individuals is an
adaptive and effective compensation for problems with balance caused by
congenital cerebellar hypoplasia. Thus, the unusual gait could be
attributed to the local cultural environment. Herz et al. (2008) also
concluded that quadrupedal locomotion is more likely an adaptation to
severe truncal ataxia, resulting from a combination of uneven, rough
surfaces in rural areas, imitation of affected sibs, and lack of
supportive therapy. Ozcelik et al. (2008) defended their position.
MOLECULAR GENETICS
By genomewide linkage analysis followed by candidate gene sequencing of
a consanguineous Iraqi family with ataxia and mild mental retardation,
Turkmen et al. (2009) identified a homozygous mutation in the CA8 gene
(S100P; 114815.0001).
By homozygosity mapping followed by exon enrichment and next-generation
sequencing in 136 consanguineous families (over 90% Iranian and less
than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms
of autosomal recessive intellectual disability, Najmabadi et al. (2011)
identified a missense mutation in the CA8 gene (114815.0002) as the
cause of CAMRQ3 in a family (M107) in which first-cousin parents had 2
healthy and 4 affected children.
ANIMAL MODEL
The autosomal recessive 'waddles' (wdl) mouse shows ataxia and
appendicular dystonia with frequent tail elevation and an abnormally
elevated trunk during ambulation. These changes are readily apparent by
2 weeks of age and persist throughout their life span. The appendicular
dystonia produces nearly straight limbs with minimal flexion at the knee
and elbow joints, elevation of the pelvis, and a waddling motion during
ambulation, particularly at higher velocities. Mutant mice also show
increased falling compared to wildtype. These abnormalities occur in the
absence of associated pathologic changes in the central or peripheral
nervous system. Jiao et al. (2005) determined that the wdl phenotype
results from a homozygous 19-bp deletion in exon 8 of the Ca8 gene on
mouse chromosome 4, resulting in a loss of function.
*FIELD* RF
1. Gulsuner, S.; Tekinay, A. B.; Doerschner, K.; Boyaci, H.; Bilguvar,
K.; Unal, H.; Ors, A.; Onat, O. E.; Atalar, E.; Basak, A. N.; Topaloglu,
H.; Kansu, T.; Tan, M.; Tan, U.; Gunel, M.; Ozcelik, T.: Homozygosity
mapping and targeted genomic sequencing reveal the gene responsible
for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous
kindred. Genome Res. 21: 1995-2003, 2011.
2. Herz, J.; Boycott, K. M.; Parboosingh, J. S.: 'Devolution' of
bipedality. (Letter) Proc. Nat. Acad. Sci. 105: E25 only, 2008.
Note: Electronic Article.
3. Humphrey, N.; Mundlos, S.; Turkmen, S.: Genes and quadrupedal
locomotion in humans. (Letter) Proc. Nat. Acad. Sci. 105: E26 only,
2008. Note: Electronic Article.
4. Jiao, Y.; Yan, J.; Zhao, Y.; Donahue, L. R.; Beamer, W. G.; Li,
X.; Roe, B. A.; LeDoux, M. S.; Gu, W.: Carbonic anhydrase-related
protein VIII deficiency is associated with a distinctive lifelong
gait disorder in waddles mice. Genetics 171: 1239-1246, 2005.
5. Najmabadi, H.; Hu, H.; Garshasbi, M.; Zemojtel, T.; Abedini, S.
S.; Chen, W.; Hosseini, M.; Behjati, F.; Haas, S.; Jamali, P.; Zecha,
A.; Mohseni, M.; and 33 others: Deep sequencing reveals 50 novel
genes for recessive cognitive disorders. Nature 478: 57-63, 2011.
6. Ozcelik, T.; Akarsu, N.; Uz, E.; Caglayan, S.; Gulsuner, S.; Onat,
O. E.; Tan, M.: Mutations in the very low-density lipoprotein receptor
VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proc.
Nat. Acad. Sci. 105: 4232-4236, 2008.
7. Ozcelik, T.; Akarsu, N.; Uz, E.; Caglayan, S.; Gulsuner, S.; Onat,
O. E.; Tan, M.; Tan, U.: Reply to Herz et al. and Humphrey et al.:
Genetic heterogeneity of cerebellar hypoplasia with quadrupedal locomotion.
(Letter) Proc. Nat. Acad. Sci. 105: E32-E33, 2008. Note: Electronic
Article.
8. Turkmen, S.; Guo, G.; Garshasbi, M.; Hoffmann, K.; Alshalah, A.J.;
Mischung, C.; Kuss, A.; Humphrey, N.; Mundlos, S.; Robinson, P. N.
: CA8 mutations cause a novel syndrome characterized by ataxia and
mild mental retardation with predisposition to quadrupedal gait. PLoS
Genet. 5: e1000487, 2009. Note: Electronic Article.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Strabismus
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild;
Cerebellar ataxia;
Quadrupedal gait;
Dysarthria;
Slurred speech;
Tremor
MISCELLANEOUS:
One family has been reported;
Congenital onset
MOLECULAR BASIS:
Caused by mutation in the carbonic anhydrase VIII gene (CA8, 114815.0001)
*FIELD* CD
Cassandra L. Kniffin: 1/21/2010
*FIELD* ED
joanna: 10/17/2011
joanna: 2/17/2010
ckniffin: 2/3/2010
*FIELD* CN
Ada Hamosh - updated: 1/6/2012
*FIELD* CD
Cassandra L. Kniffin: 1/20/2010
*FIELD* ED
alopez: 06/11/2013
alopez: 6/10/2013
carol: 1/6/2012
terry: 1/6/2012
terry: 4/28/2011
wwang: 4/29/2010
joanna: 3/10/2010
carol: 2/4/2010
ckniffin: 2/3/2010