Full text data of GNB4
GNB4
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Guanine nucleotide-binding protein subunit beta-4 (Transducin beta chain 4)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Guanine nucleotide-binding protein subunit beta-4 (Transducin beta chain 4)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q9HAV0
ID GBB4_HUMAN Reviewed; 340 AA.
AC Q9HAV0; B3KMH5; D3DNR8;
DT 13-AUG-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 122.
DE RecName: Full=Guanine nucleotide-binding protein subunit beta-4;
DE AltName: Full=Transducin beta chain 4;
GN Name=GNB4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=11842130; DOI=10.1152/physiolgenomics.00085.2001;
RA Ruiz-Velasco V., Ikeda S.R., Puhl H.L. III;
RT "Cloning, tissue distribution, and functional expression of the human
RT G protein beta 4-subunit.";
RL Physiol. Genomics 8:41-50(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cervix;
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 [5]
RP PROTEIN SEQUENCE OF 2-15 AND 58-78, CLEAVAGE OF INITIATOR METHIONINE,
RP ACETYLATION AT SER-2, AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RA Bienvenut W.V., Quadroni M.;
RL Submitted (JUL-2005) to UniProtKB.
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 TISSUE SPECIFICITY, VARIANTS CMTDIF ASP-53 AND GLU-89, AND
RP CHARACTERIZATIOIN OF VARIANTS CMTDIF ASP-53 AND GLU-89.
RX PubMed=23434117; DOI=10.1016/j.ajhg.2013.01.014;
RA Soong B.W., Huang Y.H., Tsai P.C., Huang C.C., Pan H.C., Lu Y.C.,
RA Chien H.J., Liu T.T., Chang M.H., Lin K.P., Tu P.H., Kao L.S.,
RA Lee Y.C.;
RT "Exome sequencing identifies GNB4 mutations as a cause of dominant
RT intermediate Charcot-Marie-Tooth disease.";
RL Am. J. Hum. Genet. 92:422-430(2013).
CC -!- FUNCTION: Guanine nucleotide-binding proteins (G proteins) are
CC involved as a modulator or transducer in various transmembrane
CC signaling systems. The beta and gamma chains are required for the
CC GTPase activity, for replacement of GDP by GTP, and for G protein-
CC effector interaction.
CC -!- SUBUNIT: G proteins are composed of 3 units, alpha, beta and
CC gamma.
CC -!- TISSUE SPECIFICITY: Strongly expressed in lung and placenta,
CC whereas it is weakly expressed in brain and heart. Abundantly
CC expressed in the axons and Schwann cells of peripheral nerves.
CC -!- DISEASE: Charcot-Marie-Tooth disease, dominant, intermediate type,
CC F (CMTDIF) [MIM:615185]: A form of Charcot-Marie-Tooth disease, a
CC disorder of the peripheral nervous system, characterized by
CC progressive weakness and atrophy, initially of the peroneal
CC muscles and later of the distal muscles of the arms. CMTDIF is
CC characterized by onset around adolescence of slowly progressive
CC distal muscle atrophy and weakness affecting the upper and lower
CC limbs and resulting in steppage gait. There is distal sensory
CC impairment with decreased reflexes. Nerve conduction velocities
CC are variable, ranging from the demyelinating to the axonal range.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the WD repeat G protein beta family.
CC -!- SIMILARITY: Contains 7 WD repeats.
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; AF300648; AAG18442.1; -; mRNA.
DR EMBL; AK001890; BAG50987.1; -; mRNA.
DR EMBL; CH471052; EAW78403.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78404.1; -; Genomic_DNA.
DR EMBL; BC000873; AAH00873.1; -; mRNA.
DR RefSeq; NP_067642.1; NM_021629.3.
DR RefSeq; XP_005247749.1; XM_005247692.1.
DR UniGene; Hs.173030; -.
DR ProteinModelPortal; Q9HAV0; -.
DR SMR; Q9HAV0; 1-340.
DR IntAct; Q9HAV0; 11.
DR MINT; MINT-1135986; -.
DR STRING; 9606.ENSP00000232564; -.
DR PhosphoSite; Q9HAV0; -.
DR DMDM; 22256759; -.
DR OGP; Q9HAV0; -.
DR PeptideAtlas; Q9HAV0; -.
DR PRIDE; Q9HAV0; -.
DR DNASU; 59345; -.
DR Ensembl; ENST00000232564; ENSP00000232564; ENSG00000114450.
DR Ensembl; ENST00000468623; ENSP00000419693; ENSG00000114450.
DR GeneID; 59345; -.
DR KEGG; hsa:59345; -.
DR UCSC; uc003fjv.4; human.
DR CTD; 59345; -.
DR GeneCards; GC03M179113; -.
DR HGNC; HGNC:20731; GNB4.
DR HPA; CAB018383; -.
DR HPA; CAB018737; -.
DR HPA; HPA040736; -.
DR MIM; 610863; gene.
DR MIM; 615185; phenotype.
DR neXtProt; NX_Q9HAV0; -.
DR Orphanet; 352670; Autosomal dominant intermediate Charcot-Marie-Tooth disease type F.
DR PharmGKB; PA134864200; -.
DR HOGENOM; HOG000176356; -.
DR HOVERGEN; HBG000188; -.
DR InParanoid; Q9HAV0; -.
DR KO; K04538; -.
DR OMA; ATSFTGH; -.
DR OrthoDB; EOG7GN2N5; -.
DR PhylomeDB; Q9HAV0; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_13685; Neuronal System.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_604; Hemostasis.
DR SignaLink; Q9HAV0; -.
DR GeneWiki; GNB4; -.
DR GenomeRNAi; 59345; -.
DR NextBio; 65246; -.
DR PRO; PR:Q9HAV0; -.
DR ArrayExpress; Q9HAV0; -.
DR Bgee; Q9HAV0; -.
DR CleanEx; HS_GNB4; -.
DR Genevestigator; Q9HAV0; -.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0004871; F:signal transducer activity; IEA:UniProtKB-KW.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0071377; P:cellular response to glucagon stimulus; TAS:Reactome.
DR GO; GO:0006112; P:energy reserve metabolic process; TAS:Reactome.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 2.130.10.10; -; 1.
DR InterPro; IPR020472; G-protein_beta_WD-40_rep.
DR InterPro; IPR001632; Gprotein_B.
DR InterPro; IPR016346; Guanine_nucleotide-bd_bsu.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom.
DR InterPro; IPR001680; WD40_repeat.
DR InterPro; IPR019775; WD40_repeat_CS.
DR InterPro; IPR017986; WD40_repeat_dom.
DR Pfam; PF00400; WD40; 7.
DR PIRSF; PIRSF002394; GN-bd_beta; 1.
DR PRINTS; PR00319; GPROTEINB.
DR PRINTS; PR00320; GPROTEINBRPT.
DR SMART; SM00320; WD40; 7.
DR SUPFAM; SSF50978; SSF50978; 1.
DR PROSITE; PS00678; WD_REPEATS_1; 3.
DR PROSITE; PS50082; WD_REPEATS_2; 6.
DR PROSITE; PS50294; WD_REPEATS_REGION; 1.
PE 1: Evidence at protein level;
KW Acetylation; Charcot-Marie-Tooth disease; Complete proteome;
KW Direct protein sequencing; Disease mutation; Neurodegeneration;
KW Neuropathy; Reference proteome; Repeat; Transducer; WD repeat.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 340 Guanine nucleotide-binding protein
FT subunit beta-4.
FT /FTId=PRO_0000127702.
FT REPEAT 53 92 WD 1.
FT REPEAT 95 134 WD 2.
FT REPEAT 141 179 WD 3.
FT REPEAT 182 221 WD 4.
FT REPEAT 224 263 WD 5.
FT REPEAT 268 307 WD 6.
FT REPEAT 310 339 WD 7.
FT MOD_RES 2 2 N-acetylserine.
FT VARIANT 53 53 G -> D (in CMTDIF; the mutant protein has
FT impaired bradykinin-induced G-protein-
FT coupled receptor intracellular signaling
FT compared to the wild-type protein).
FT /FTId=VAR_069908.
FT VARIANT 89 89 K -> E (in CMTDIF; the mutant protein has
FT impaired bradykinin-induced G-protein-
FT coupled receptor intracellular signaling
FT compared to the wild-type protein).
FT /FTId=VAR_069909.
SQ SEQUENCE 340 AA; 37567 MW; EDF085155A1EDC89 CRC64;
MSELEQLRQE AEQLRNQIQD ARKACNDATL VQITSNMDSV GRIQMRTRRT LRGHLAKIYA
MHWGYDSRLL VSASQDGKLI IWDSYTTNKM HAIPLRSSWV MTCAYAPSGN YVACGGLDNI
CSIYNLKTRE GNVRVSRELP GHTGYLSCCR FLDDSQIVTS SGDTTCALWD IETAQQTTTF
TGHSGDVMSL SLSPDMRTFV SGACDASSKL WDIRDGMCRQ SFTGHVSDIN AVSFFPNGYA
FATGSDDATC RLFDLRADQE LLLYSHDNII CGITSVAFSK SGRLLLAGYD DFNCNVWDTL
KGDRAGVLAG HDNRVSCLGV TDDGMAVATG SWDSFLRIWN
//
ID GBB4_HUMAN Reviewed; 340 AA.
AC Q9HAV0; B3KMH5; D3DNR8;
DT 13-AUG-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 122.
DE RecName: Full=Guanine nucleotide-binding protein subunit beta-4;
DE AltName: Full=Transducin beta chain 4;
GN Name=GNB4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=11842130; DOI=10.1152/physiolgenomics.00085.2001;
RA Ruiz-Velasco V., Ikeda S.R., Puhl H.L. III;
RT "Cloning, tissue distribution, and functional expression of the human
RT G protein beta 4-subunit.";
RL Physiol. Genomics 8:41-50(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cervix;
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 [5]
RP PROTEIN SEQUENCE OF 2-15 AND 58-78, CLEAVAGE OF INITIATOR METHIONINE,
RP ACETYLATION AT SER-2, AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RA Bienvenut W.V., Quadroni M.;
RL Submitted (JUL-2005) to UniProtKB.
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 TISSUE SPECIFICITY, VARIANTS CMTDIF ASP-53 AND GLU-89, AND
RP CHARACTERIZATIOIN OF VARIANTS CMTDIF ASP-53 AND GLU-89.
RX PubMed=23434117; DOI=10.1016/j.ajhg.2013.01.014;
RA Soong B.W., Huang Y.H., Tsai P.C., Huang C.C., Pan H.C., Lu Y.C.,
RA Chien H.J., Liu T.T., Chang M.H., Lin K.P., Tu P.H., Kao L.S.,
RA Lee Y.C.;
RT "Exome sequencing identifies GNB4 mutations as a cause of dominant
RT intermediate Charcot-Marie-Tooth disease.";
RL Am. J. Hum. Genet. 92:422-430(2013).
CC -!- FUNCTION: Guanine nucleotide-binding proteins (G proteins) are
CC involved as a modulator or transducer in various transmembrane
CC signaling systems. The beta and gamma chains are required for the
CC GTPase activity, for replacement of GDP by GTP, and for G protein-
CC effector interaction.
CC -!- SUBUNIT: G proteins are composed of 3 units, alpha, beta and
CC gamma.
CC -!- TISSUE SPECIFICITY: Strongly expressed in lung and placenta,
CC whereas it is weakly expressed in brain and heart. Abundantly
CC expressed in the axons and Schwann cells of peripheral nerves.
CC -!- DISEASE: Charcot-Marie-Tooth disease, dominant, intermediate type,
CC F (CMTDIF) [MIM:615185]: A form of Charcot-Marie-Tooth disease, a
CC disorder of the peripheral nervous system, characterized by
CC progressive weakness and atrophy, initially of the peroneal
CC muscles and later of the distal muscles of the arms. CMTDIF is
CC characterized by onset around adolescence of slowly progressive
CC distal muscle atrophy and weakness affecting the upper and lower
CC limbs and resulting in steppage gait. There is distal sensory
CC impairment with decreased reflexes. Nerve conduction velocities
CC are variable, ranging from the demyelinating to the axonal range.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the WD repeat G protein beta family.
CC -!- SIMILARITY: Contains 7 WD repeats.
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; AF300648; AAG18442.1; -; mRNA.
DR EMBL; AK001890; BAG50987.1; -; mRNA.
DR EMBL; CH471052; EAW78403.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78404.1; -; Genomic_DNA.
DR EMBL; BC000873; AAH00873.1; -; mRNA.
DR RefSeq; NP_067642.1; NM_021629.3.
DR RefSeq; XP_005247749.1; XM_005247692.1.
DR UniGene; Hs.173030; -.
DR ProteinModelPortal; Q9HAV0; -.
DR SMR; Q9HAV0; 1-340.
DR IntAct; Q9HAV0; 11.
DR MINT; MINT-1135986; -.
DR STRING; 9606.ENSP00000232564; -.
DR PhosphoSite; Q9HAV0; -.
DR DMDM; 22256759; -.
DR OGP; Q9HAV0; -.
DR PeptideAtlas; Q9HAV0; -.
DR PRIDE; Q9HAV0; -.
DR DNASU; 59345; -.
DR Ensembl; ENST00000232564; ENSP00000232564; ENSG00000114450.
DR Ensembl; ENST00000468623; ENSP00000419693; ENSG00000114450.
DR GeneID; 59345; -.
DR KEGG; hsa:59345; -.
DR UCSC; uc003fjv.4; human.
DR CTD; 59345; -.
DR GeneCards; GC03M179113; -.
DR HGNC; HGNC:20731; GNB4.
DR HPA; CAB018383; -.
DR HPA; CAB018737; -.
DR HPA; HPA040736; -.
DR MIM; 610863; gene.
DR MIM; 615185; phenotype.
DR neXtProt; NX_Q9HAV0; -.
DR Orphanet; 352670; Autosomal dominant intermediate Charcot-Marie-Tooth disease type F.
DR PharmGKB; PA134864200; -.
DR HOGENOM; HOG000176356; -.
DR HOVERGEN; HBG000188; -.
DR InParanoid; Q9HAV0; -.
DR KO; K04538; -.
DR OMA; ATSFTGH; -.
DR OrthoDB; EOG7GN2N5; -.
DR PhylomeDB; Q9HAV0; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_13685; Neuronal System.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_604; Hemostasis.
DR SignaLink; Q9HAV0; -.
DR GeneWiki; GNB4; -.
DR GenomeRNAi; 59345; -.
DR NextBio; 65246; -.
DR PRO; PR:Q9HAV0; -.
DR ArrayExpress; Q9HAV0; -.
DR Bgee; Q9HAV0; -.
DR CleanEx; HS_GNB4; -.
DR Genevestigator; Q9HAV0; -.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0004871; F:signal transducer activity; IEA:UniProtKB-KW.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0071377; P:cellular response to glucagon stimulus; TAS:Reactome.
DR GO; GO:0006112; P:energy reserve metabolic process; TAS:Reactome.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 2.130.10.10; -; 1.
DR InterPro; IPR020472; G-protein_beta_WD-40_rep.
DR InterPro; IPR001632; Gprotein_B.
DR InterPro; IPR016346; Guanine_nucleotide-bd_bsu.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom.
DR InterPro; IPR001680; WD40_repeat.
DR InterPro; IPR019775; WD40_repeat_CS.
DR InterPro; IPR017986; WD40_repeat_dom.
DR Pfam; PF00400; WD40; 7.
DR PIRSF; PIRSF002394; GN-bd_beta; 1.
DR PRINTS; PR00319; GPROTEINB.
DR PRINTS; PR00320; GPROTEINBRPT.
DR SMART; SM00320; WD40; 7.
DR SUPFAM; SSF50978; SSF50978; 1.
DR PROSITE; PS00678; WD_REPEATS_1; 3.
DR PROSITE; PS50082; WD_REPEATS_2; 6.
DR PROSITE; PS50294; WD_REPEATS_REGION; 1.
PE 1: Evidence at protein level;
KW Acetylation; Charcot-Marie-Tooth disease; Complete proteome;
KW Direct protein sequencing; Disease mutation; Neurodegeneration;
KW Neuropathy; Reference proteome; Repeat; Transducer; WD repeat.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 340 Guanine nucleotide-binding protein
FT subunit beta-4.
FT /FTId=PRO_0000127702.
FT REPEAT 53 92 WD 1.
FT REPEAT 95 134 WD 2.
FT REPEAT 141 179 WD 3.
FT REPEAT 182 221 WD 4.
FT REPEAT 224 263 WD 5.
FT REPEAT 268 307 WD 6.
FT REPEAT 310 339 WD 7.
FT MOD_RES 2 2 N-acetylserine.
FT VARIANT 53 53 G -> D (in CMTDIF; the mutant protein has
FT impaired bradykinin-induced G-protein-
FT coupled receptor intracellular signaling
FT compared to the wild-type protein).
FT /FTId=VAR_069908.
FT VARIANT 89 89 K -> E (in CMTDIF; the mutant protein has
FT impaired bradykinin-induced G-protein-
FT coupled receptor intracellular signaling
FT compared to the wild-type protein).
FT /FTId=VAR_069909.
SQ SEQUENCE 340 AA; 37567 MW; EDF085155A1EDC89 CRC64;
MSELEQLRQE AEQLRNQIQD ARKACNDATL VQITSNMDSV GRIQMRTRRT LRGHLAKIYA
MHWGYDSRLL VSASQDGKLI IWDSYTTNKM HAIPLRSSWV MTCAYAPSGN YVACGGLDNI
CSIYNLKTRE GNVRVSRELP GHTGYLSCCR FLDDSQIVTS SGDTTCALWD IETAQQTTTF
TGHSGDVMSL SLSPDMRTFV SGACDASSKL WDIRDGMCRQ SFTGHVSDIN AVSFFPNGYA
FATGSDDATC RLFDLRADQE LLLYSHDNII CGITSVAFSK SGRLLLAGYD DFNCNVWDTL
KGDRAGVLAG HDNRVSCLGV TDDGMAVATG SWDSFLRIWN
//
MIM
610863
*RECORD*
*FIELD* NO
610863
*FIELD* TI
*610863 GUANINE NUCLEOTIDE-BINDING PROTEIN, BETA-4; GNB4
;;G PROTEIN, BETA-4 SUBUNIT; G BETA-4
read more*FIELD* TX
DESCRIPTION
Heterotrimeric G proteins, made up of an alpha subunit (see GNAS,
139320), a beta subunit, like GNB4, and a gamma subunit (see GNG2,
606981), relay signals from cell surface receptors to internal
effectors. The alpha subunit is a GTPase that interacts in the GDP-bound
state with beta-gamma dimers (Rosskopf et al., 2003).
CLONING
By searching an EST database for G-protein beta-like sequences, followed
by 5-prime RACE of a human brain cDNA library, Ruiz-Velasco et al.
(2002) cloned GNB4. Like other beta subunits, the deduced GNB4 protein
contains 340 amino acids with 7 WD repeat motifs forming a
beta-propeller structure. GNB4 shares 91% identity with GNB1 (139380)
and 96% identity with mouse Gnb4. PCR analysis detected high GNB4
expression in human lung, pancreas, and placenta, moderate expression in
kidney and liver, and weak expression in brain and heart.
By searching an EST database for sequences similar to mouse Gnb4,
followed by PCR of human B lymphoblast and brain RNA, Rosskopf et al.
(2003) cloned GNB4. PCR analysis of human, rat, and mouse tissues and
cultured cells showed wide GNB4 expression.
Soong et al. (2013) found that GNB4 colocalized with neurofilament heavy
chain and S100 in peripheral human nerves, indicating that it is
expressed in both axons and Schwann cells.
GENE FUNCTION
By heterologous overexpression in rat sympathetic neurons, Ruiz-Velasco
et al. (2002) found that human G-beta-4 coexpressed with G-gamma-2
(GNG2; 606981) or G-gamma-4 (GNG4; 604388) caused tonic modulation of
N-type voltage-gated calcium currents and G protein-gated inwardly
rectifying potassium currents. Coexpression of G-beta-4, G-gamma-2 and
G-alpha-oA (GNAO1; 139311) resulted in heterotrimer formation.
Using coprecipitation analysis, Rosskopf et al. (2003) showed that GNB4
formed dimers with all 11 gamma subunits analyzed. The strength of the
interaction was variable and was strongest between GNB1 and GNG4,
followed by GNG13 (607298) and GNG1 (GNGT1; 189970), and was weakest
with GNG8C (GNGT2; 139391). Overexpression of most GNB4-GNG dimers
resulted in significant, although sometimes modest, activation of
phospholipase beta-2 (PLCB2; 604114), with highest activation by the
GNB4-GNG4 dimer.
Vertebrate retinas have distinct light-on (ON) and light-off (OFF)
channels that originate at the level of the retinal bipolar cells. For
the conversion from OFF to ON, ON bipolar cells use the GNAO1-coupled
glutamate receptor-6 (GRIK2; 138244) such that binding of glutamate
suppresses a cation current rather than activating it. Using
immunohistochemical analysis and single-cell PCR, Huang et al. (2003)
showed that the gamma subunit Gng13 (607298) was coexpressed with the
beta subunits Gnb3 (139130) and Gnb4, but no other beta subunit, in
dissociated mouse ON bipolar cells. Huang et al. (2003) hypothesized
that these G protein subunits selectively participate in signal
transduction in ON bipolar cells.
Soong et al. (2013) found that Gnb4 expression in rats decreased in
nerve tissue distal to sciatic nerve transection and increased in nerve
tissue after conditioning, suggesting that the protein plays a role in
peripheral nerve regeneration.
GENE STRUCTURE
Rosskopf et al. (2003) determined that the GNB4 gene contains 10 exons.
The first exon is noncoding.
MAPPING
By genomic sequence analysis, Rosskopf et al. (2003) mapped the GNB4
gene to chromosome 3.
MOLECULAR GENETICS
In affected members of a Han Chinese family with dominant intermediate
Charcot-Marie-Tooth disease F (CMTDIF; 615185) (Lee et al., 2010), Soong
et al. (2013) identified a heterozygous mutation in the GNB4 gene (G53D;
610863.0001). The mutation was identified by exome sequencing. An
unrelated Han Chinese girl with demyelinating CMT carried a different
heterozygous mutation that occurred de novo (K89E; 610863.0002). The
frequency of GNB4 mutations in the CMT cohort was 0.8% (2 of 251
families). The phenotype was characterized by onset around adolescence
of slowly progressive distal muscle weakness and atrophy affecting the
upper and lower limbs, as well as distal sensory impairment and
areflexia. In the family, male mutation carriers were more severely
affected than female mutation carriers. Immunofluorescence studies of
patient sural nerves showed GNB4 staining of onion bulb formations in a
rosette pattern. However, immunohistochemical studies showed weaker GNB4
expression in patient sural nerve biopsies compared to controls.
Expression of both mutations in COS-7 cells showed that the mutant
proteins had impaired bradykinin-induced G protein-coupled receptor
intracellular signaling compared to the wildtype protein. The mutant
proteins were stable in transfected cells, and Soong et al. (2013)
postulated a dominant-negative effect. The findings indicated that
GNB4-related G protein-coupled receptor signaling is important for
proper functioning of peripheral nerves.
*FIELD* AV
.0001
CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE F
GNB4, GLY53ASP
In affected members of a large 4-generation Han Chinese family with
dominant intermediate Charcot-Marie-Tooth disease F (CMTDIF; 615185),
Soong et al. (2013) identified a heterozygous 158G-A transition in the
GNB4 gene, resulting in a gly53-to-asp (G53D) substitution at a highly
conserved residue. The mutation, which was identified by exome
sequencing, segregated with the disorder in the family and was not found
in several large control databases, including 1,920 ethnic control
chromosomes. The phenotype was characterized by onset around adolescence
of slowly progressive distal muscle weakness and atrophy affecting the
upper and lower limbs, as well as distal sensory impairment. Male
mutation carriers were more severely affected than female mutation
carriers. Expression of the mutation in COS-7 cells showed that the
mutant protein had impaired bradykinin-induced G-protein-coupled
receptor intracellular signaling compared to the wildtype protein. The
mutant protein was stable in transfected cells, and Soong et al. (2013)
postulated a dominant-negative effect.
.0002
CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE F
GNB4, LYS89GLU
In a 9-year-old Han Chinese girl with CMTDIF (615185), Soong et al.
(2013) identified a de novo heterozygous 265A-G transition in exon 5 of
the GNB4 gene, resulting in a lys89-to-glu (K89E) substitution at a
highly conserved residue. The mutation was not found in several large
control databases, including 1,920 ethnic control chromosomes.
Expression of the mutation in COS-7 cells showed that the mutant protein
had impaired bradykinin-induced G-protein-coupled receptor intracellular
signaling compared to the wildtype protein. The mutant protein was
stable in transfected cells, and Soong et al. (2013) postulated a
dominant-negative effect.
*FIELD* RF
1. Huang, L.; Max, M.; Margolskee, R. F.; Su, H.; Masland, R. H.;
Euler, T.: G protein subunit G-gamma-13 is coexpressed with G-alpha-o,
G-beta-3, and G-beta-4 in retinal ON bipolar cells. J. Comp. Neurol. 455:
1-10, 2003.
2. Lee, Y.-C.; Lee, T.-C.; Lin, K.-P, Lin, M.-W.; Chang, M.-H; Soong,
B.-W.: Clinical characterization and genetic analysis of a possible
novel type of dominant Charcot-Marie-Tooth disease. Neuromusc. Disord. 20:
534-539, 2010.
3. Rosskopf, D.; Nikula, C.; Manthey, I.; Joisten, M.; Frey, U.; Kohnen,
S.; Siffert, W.: The human G protein beta-4 subunit: gene structure,
expression, G-gamma and effector interaction. FEBS Lett. 544: 27-32,
2003.
4. Ruiz-Velasco, V.; Ikeda, S. R.; Puhl, H. L.: Cloning, tissue distribution,
and functional expression of the human G protein beta-4-subunit. Physiol.
Genomics 8: 41-50, 2002.
5. Soong, B.-W.; Huang, Y.-H.; Tsai, P.-C.; Huang, C.-C.; Pan, H.-C.;
Lu, Y.-C.; Chien, H.-J.; Liu, T.-T.; Chang, M.-H.; Lin, K.-P.; Tu,
P.-H.; Kao, L.-S.; Lee, Y.-C. Exome sequencing identifies GNB4
mutations as a cause of dominant intermediate Charcot-Marie-Tooth
disease. Am. J. Hum. Genet. 92: 422-430, 2013.
*FIELD* CN
Cassandra L. Kniffin - updated: 4/18/2013
*FIELD* CD
Patricia A. Hartz: 3/20/2007
*FIELD* ED
carol: 04/22/2013
carol: 4/19/2013
ckniffin: 4/18/2013
terry: 1/4/2011
wwang: 3/20/2007
*RECORD*
*FIELD* NO
610863
*FIELD* TI
*610863 GUANINE NUCLEOTIDE-BINDING PROTEIN, BETA-4; GNB4
;;G PROTEIN, BETA-4 SUBUNIT; G BETA-4
read more*FIELD* TX
DESCRIPTION
Heterotrimeric G proteins, made up of an alpha subunit (see GNAS,
139320), a beta subunit, like GNB4, and a gamma subunit (see GNG2,
606981), relay signals from cell surface receptors to internal
effectors. The alpha subunit is a GTPase that interacts in the GDP-bound
state with beta-gamma dimers (Rosskopf et al., 2003).
CLONING
By searching an EST database for G-protein beta-like sequences, followed
by 5-prime RACE of a human brain cDNA library, Ruiz-Velasco et al.
(2002) cloned GNB4. Like other beta subunits, the deduced GNB4 protein
contains 340 amino acids with 7 WD repeat motifs forming a
beta-propeller structure. GNB4 shares 91% identity with GNB1 (139380)
and 96% identity with mouse Gnb4. PCR analysis detected high GNB4
expression in human lung, pancreas, and placenta, moderate expression in
kidney and liver, and weak expression in brain and heart.
By searching an EST database for sequences similar to mouse Gnb4,
followed by PCR of human B lymphoblast and brain RNA, Rosskopf et al.
(2003) cloned GNB4. PCR analysis of human, rat, and mouse tissues and
cultured cells showed wide GNB4 expression.
Soong et al. (2013) found that GNB4 colocalized with neurofilament heavy
chain and S100 in peripheral human nerves, indicating that it is
expressed in both axons and Schwann cells.
GENE FUNCTION
By heterologous overexpression in rat sympathetic neurons, Ruiz-Velasco
et al. (2002) found that human G-beta-4 coexpressed with G-gamma-2
(GNG2; 606981) or G-gamma-4 (GNG4; 604388) caused tonic modulation of
N-type voltage-gated calcium currents and G protein-gated inwardly
rectifying potassium currents. Coexpression of G-beta-4, G-gamma-2 and
G-alpha-oA (GNAO1; 139311) resulted in heterotrimer formation.
Using coprecipitation analysis, Rosskopf et al. (2003) showed that GNB4
formed dimers with all 11 gamma subunits analyzed. The strength of the
interaction was variable and was strongest between GNB1 and GNG4,
followed by GNG13 (607298) and GNG1 (GNGT1; 189970), and was weakest
with GNG8C (GNGT2; 139391). Overexpression of most GNB4-GNG dimers
resulted in significant, although sometimes modest, activation of
phospholipase beta-2 (PLCB2; 604114), with highest activation by the
GNB4-GNG4 dimer.
Vertebrate retinas have distinct light-on (ON) and light-off (OFF)
channels that originate at the level of the retinal bipolar cells. For
the conversion from OFF to ON, ON bipolar cells use the GNAO1-coupled
glutamate receptor-6 (GRIK2; 138244) such that binding of glutamate
suppresses a cation current rather than activating it. Using
immunohistochemical analysis and single-cell PCR, Huang et al. (2003)
showed that the gamma subunit Gng13 (607298) was coexpressed with the
beta subunits Gnb3 (139130) and Gnb4, but no other beta subunit, in
dissociated mouse ON bipolar cells. Huang et al. (2003) hypothesized
that these G protein subunits selectively participate in signal
transduction in ON bipolar cells.
Soong et al. (2013) found that Gnb4 expression in rats decreased in
nerve tissue distal to sciatic nerve transection and increased in nerve
tissue after conditioning, suggesting that the protein plays a role in
peripheral nerve regeneration.
GENE STRUCTURE
Rosskopf et al. (2003) determined that the GNB4 gene contains 10 exons.
The first exon is noncoding.
MAPPING
By genomic sequence analysis, Rosskopf et al. (2003) mapped the GNB4
gene to chromosome 3.
MOLECULAR GENETICS
In affected members of a Han Chinese family with dominant intermediate
Charcot-Marie-Tooth disease F (CMTDIF; 615185) (Lee et al., 2010), Soong
et al. (2013) identified a heterozygous mutation in the GNB4 gene (G53D;
610863.0001). The mutation was identified by exome sequencing. An
unrelated Han Chinese girl with demyelinating CMT carried a different
heterozygous mutation that occurred de novo (K89E; 610863.0002). The
frequency of GNB4 mutations in the CMT cohort was 0.8% (2 of 251
families). The phenotype was characterized by onset around adolescence
of slowly progressive distal muscle weakness and atrophy affecting the
upper and lower limbs, as well as distal sensory impairment and
areflexia. In the family, male mutation carriers were more severely
affected than female mutation carriers. Immunofluorescence studies of
patient sural nerves showed GNB4 staining of onion bulb formations in a
rosette pattern. However, immunohistochemical studies showed weaker GNB4
expression in patient sural nerve biopsies compared to controls.
Expression of both mutations in COS-7 cells showed that the mutant
proteins had impaired bradykinin-induced G protein-coupled receptor
intracellular signaling compared to the wildtype protein. The mutant
proteins were stable in transfected cells, and Soong et al. (2013)
postulated a dominant-negative effect. The findings indicated that
GNB4-related G protein-coupled receptor signaling is important for
proper functioning of peripheral nerves.
*FIELD* AV
.0001
CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE F
GNB4, GLY53ASP
In affected members of a large 4-generation Han Chinese family with
dominant intermediate Charcot-Marie-Tooth disease F (CMTDIF; 615185),
Soong et al. (2013) identified a heterozygous 158G-A transition in the
GNB4 gene, resulting in a gly53-to-asp (G53D) substitution at a highly
conserved residue. The mutation, which was identified by exome
sequencing, segregated with the disorder in the family and was not found
in several large control databases, including 1,920 ethnic control
chromosomes. The phenotype was characterized by onset around adolescence
of slowly progressive distal muscle weakness and atrophy affecting the
upper and lower limbs, as well as distal sensory impairment. Male
mutation carriers were more severely affected than female mutation
carriers. Expression of the mutation in COS-7 cells showed that the
mutant protein had impaired bradykinin-induced G-protein-coupled
receptor intracellular signaling compared to the wildtype protein. The
mutant protein was stable in transfected cells, and Soong et al. (2013)
postulated a dominant-negative effect.
.0002
CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE F
GNB4, LYS89GLU
In a 9-year-old Han Chinese girl with CMTDIF (615185), Soong et al.
(2013) identified a de novo heterozygous 265A-G transition in exon 5 of
the GNB4 gene, resulting in a lys89-to-glu (K89E) substitution at a
highly conserved residue. The mutation was not found in several large
control databases, including 1,920 ethnic control chromosomes.
Expression of the mutation in COS-7 cells showed that the mutant protein
had impaired bradykinin-induced G-protein-coupled receptor intracellular
signaling compared to the wildtype protein. The mutant protein was
stable in transfected cells, and Soong et al. (2013) postulated a
dominant-negative effect.
*FIELD* RF
1. Huang, L.; Max, M.; Margolskee, R. F.; Su, H.; Masland, R. H.;
Euler, T.: G protein subunit G-gamma-13 is coexpressed with G-alpha-o,
G-beta-3, and G-beta-4 in retinal ON bipolar cells. J. Comp. Neurol. 455:
1-10, 2003.
2. Lee, Y.-C.; Lee, T.-C.; Lin, K.-P, Lin, M.-W.; Chang, M.-H; Soong,
B.-W.: Clinical characterization and genetic analysis of a possible
novel type of dominant Charcot-Marie-Tooth disease. Neuromusc. Disord. 20:
534-539, 2010.
3. Rosskopf, D.; Nikula, C.; Manthey, I.; Joisten, M.; Frey, U.; Kohnen,
S.; Siffert, W.: The human G protein beta-4 subunit: gene structure,
expression, G-gamma and effector interaction. FEBS Lett. 544: 27-32,
2003.
4. Ruiz-Velasco, V.; Ikeda, S. R.; Puhl, H. L.: Cloning, tissue distribution,
and functional expression of the human G protein beta-4-subunit. Physiol.
Genomics 8: 41-50, 2002.
5. Soong, B.-W.; Huang, Y.-H.; Tsai, P.-C.; Huang, C.-C.; Pan, H.-C.;
Lu, Y.-C.; Chien, H.-J.; Liu, T.-T.; Chang, M.-H.; Lin, K.-P.; Tu,
P.-H.; Kao, L.-S.; Lee, Y.-C. Exome sequencing identifies GNB4
mutations as a cause of dominant intermediate Charcot-Marie-Tooth
disease. Am. J. Hum. Genet. 92: 422-430, 2013.
*FIELD* CN
Cassandra L. Kniffin - updated: 4/18/2013
*FIELD* CD
Patricia A. Hartz: 3/20/2007
*FIELD* ED
carol: 04/22/2013
carol: 4/19/2013
ckniffin: 4/18/2013
terry: 1/4/2011
wwang: 3/20/2007
MIM
615185
*RECORD*
*FIELD* NO
615185
*FIELD* TI
#615185 CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE F; CMTDIF
*FIELD* TX
A number sign (#) is used with this entry because dominant intermediate
read moreCharcot-Marie-Tooth disease F (CMTDIF) is caused by heterozygous
mutation in the GNB4 gene (610863) on chromosome 3q28.
DESCRIPTION
CMTDIF is an autosomal dominant neurologic disorder characterized by
onset around adolescence of slowly progressive distal muscle atrophy and
weakness affecting the upper and lower limbs and resulting in steppage
gait. There is distal sensory impairment with decreased reflexes. Nerve
conduction velocities are variable, ranging from the demyelinating to
the axonal range (summary by Soong et al., 2013).
For a discussion of genetic heterogeneity of CMTDI, see 606482.
CLINICAL FEATURES
Lee et al. (2010) reported a 3-generation Han Chinese family in which 7
patients had Charcot-Marie-Tooth disease. The proband was a 49-year-old
man who had been wheelchair-bound for 3 years. He had normal motor
development as a child, but reported slowly progressive weakness and
atrophy of the legs since adolescence. Physical examination showed
marked atrophy and weakness of the muscles in the legs, feet, and
intrinsic hand muscles, with generalized areflexia, pes cavus, and
hammer toes. He had diminished sensation of all modalities in the distal
parts of the 4 extremities. All 3 of his children were affected. His 2
sons showed a similar disorder with onset around adolescence. His
17-year-old daughter denied neurologic symptoms, but examination
revealed mild atrophy and weakness of intrinsic foot muscles,
generalized areflexia, mild pes cavus, and hammer toes. The proband's
sister had a less severe phenotype, and her daughter also denied any
neurologic signs, but examination showed mild features. The proband's
deceased father was reportedly affected. Nerve conduction velocities
(NCV) of the 6 patients studied varied widely, ranging from 16.5 to 45.7
m/s. The male patients had definitive demyelinating sensorimotor
polyneuropathy with axonal loss, whereas the female patients had a
milder phenotype with mild or intermediate slowing of motor nerve
conduction velocities. Sural nerve biopsy of the proband showed severe
loss of myelinated fibers and many onion bulb formations with clusters
of regenerating fibers.
Soong et al. (2013) reported a 9-year-old Han Chinese girl who presented
with slowly progressive weakness of the distal lower limbs since age 5
years. She had high-arched feet, hammer toes, atrophy, and weakness of
the intrinsic muscles of the feet, impaired dorsiflexion of the feet,
and generalized areflexia. Examination showed mildly diminished
sensation for all modalities in regions distal to the ankles despite a
lack of sensory complaints. Nerve conduction studies showed a
demyelinating sensorimotor polyneuropathy with axonal loss with
decreased median NCV of 20 m/s.
INHERITANCE
The transmission pattern in the family with CMTDIF reported by Lee et
al. (2010) was consistent with autosomal dominant inheritance.
MAPPING
By linkage analysis of a Chinese family with dominant intermediate CMT,
Lee et al. (2010) found suggestive linkage to chromosome 3q28-q29
(maximum lod score of 1.6).
MOLECULAR GENETICS
In affected members of a Chinese family with dominant intermediate CMT
(Lee et al., 2010), Soong et al. (2013) identified a heterozygous
mutation in the GNB4 gene (G53D; 610863.0001). The mutation was
identified by exome sequencing. An unrelated Chinese girl with
demyelinating CMT carried a different heterozygous mutation that
occurred de novo (K89E; 610863.0002). The frequency of GNB4 mutations in
the CMT cohort was 0.8% (2 of 251 families). Immunofluorescence studies
of patient sural nerves showed GNB4 staining of onion bulb formations in
a rosette pattern. However, immunohistochemical studies showed weaker
GNB4 expression in patient sural nerve biopsies compared to controls.
Expression of both mutations in COS-7 cells showed that the mutant
proteins had impaired bradykinin-induced G protein-coupled receptor
intracellular signaling compared to the wildtype protein. The mutant
proteins were stable in transfected cells, and Soong et al. (2013)
postulated a dominant-negative effect. The findings indicated that
GNB4-related G protein-coupled receptor signaling is important for
proper function of peripheral nerves.
*FIELD* RF
1. Lee, Y.-C.; Lee, T.-C.; Lin, K.-P, Lin, M.-W.; Chang, M.-H; Soong,
B.-W.: Clinical characterization and genetic analysis of a possible
novel type of dominant Charcot-Marie-Tooth disease. Neuromusc. Disord. 20:
534-539, 2010.
2. Soong, B.-W.; Huang, Y.-H.; Tsai, P.-C.; Huang, C.-C.; Pan, H.-C.;
Lu, Y.-C.; Chien, H.-J.; Liu, T.-T.; Chang, M.-H.; Lin, K.-P.; Tu,
P.-H.; Kao, L.-S.; Lee, Y.-C. Exome sequencing identifies GNB4
mutations as a cause of dominant intermediate Charcot-Marie-Tooth
disease. Am. J. Hum. Genet. 92: 422-430, 2013.
*FIELD* CS
INHERITANCE:
Autosomal dominant
SKELETAL:
[Feet];
Pes cavus;
Hammertoes
NEUROLOGIC:
[Peripheral nervous system];
Distal muscle weakness due to peripheral neuropathy of upper and lower
limbs;
Distal muscle atrophy due to peripheral neuropathy of upper and lower
limbs;
Steppage gait;
Hyporeflexia;
Distal sensory impairment;
Sural nerve biopsy shows loss of myelinated fibers;
Onion bulb formation;
Axonal regeneration;
Variable nerve conduction velocities (range 16.5 to 45.7 m/s)
MISCELLANEOUS:
Onset around adolescence in males;
Later onset in females;
Slowly progressive;
Males are more severely affected than females;
One Chinese family and 1 unrelated patient have been reported (last
curated April 2013)
MOLECULAR BASIS:
Caused by mutation in the guanine nucleotide-binding protein, beta-4
gene (GNB4, 610863.0001)
*FIELD* CD
Cassandra L. Kniffin: 4/18/2013
*FIELD* ED
joanna: 06/04/2013
joanna: 5/7/2013
ckniffin: 4/23/2013
*FIELD* CD
Cassandra L. Kniffin: 4/18/2013
*FIELD* ED
carol: 04/22/2013
carol: 4/19/2013
ckniffin: 4/18/2013
*RECORD*
*FIELD* NO
615185
*FIELD* TI
#615185 CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE F; CMTDIF
*FIELD* TX
A number sign (#) is used with this entry because dominant intermediate
read moreCharcot-Marie-Tooth disease F (CMTDIF) is caused by heterozygous
mutation in the GNB4 gene (610863) on chromosome 3q28.
DESCRIPTION
CMTDIF is an autosomal dominant neurologic disorder characterized by
onset around adolescence of slowly progressive distal muscle atrophy and
weakness affecting the upper and lower limbs and resulting in steppage
gait. There is distal sensory impairment with decreased reflexes. Nerve
conduction velocities are variable, ranging from the demyelinating to
the axonal range (summary by Soong et al., 2013).
For a discussion of genetic heterogeneity of CMTDI, see 606482.
CLINICAL FEATURES
Lee et al. (2010) reported a 3-generation Han Chinese family in which 7
patients had Charcot-Marie-Tooth disease. The proband was a 49-year-old
man who had been wheelchair-bound for 3 years. He had normal motor
development as a child, but reported slowly progressive weakness and
atrophy of the legs since adolescence. Physical examination showed
marked atrophy and weakness of the muscles in the legs, feet, and
intrinsic hand muscles, with generalized areflexia, pes cavus, and
hammer toes. He had diminished sensation of all modalities in the distal
parts of the 4 extremities. All 3 of his children were affected. His 2
sons showed a similar disorder with onset around adolescence. His
17-year-old daughter denied neurologic symptoms, but examination
revealed mild atrophy and weakness of intrinsic foot muscles,
generalized areflexia, mild pes cavus, and hammer toes. The proband's
sister had a less severe phenotype, and her daughter also denied any
neurologic signs, but examination showed mild features. The proband's
deceased father was reportedly affected. Nerve conduction velocities
(NCV) of the 6 patients studied varied widely, ranging from 16.5 to 45.7
m/s. The male patients had definitive demyelinating sensorimotor
polyneuropathy with axonal loss, whereas the female patients had a
milder phenotype with mild or intermediate slowing of motor nerve
conduction velocities. Sural nerve biopsy of the proband showed severe
loss of myelinated fibers and many onion bulb formations with clusters
of regenerating fibers.
Soong et al. (2013) reported a 9-year-old Han Chinese girl who presented
with slowly progressive weakness of the distal lower limbs since age 5
years. She had high-arched feet, hammer toes, atrophy, and weakness of
the intrinsic muscles of the feet, impaired dorsiflexion of the feet,
and generalized areflexia. Examination showed mildly diminished
sensation for all modalities in regions distal to the ankles despite a
lack of sensory complaints. Nerve conduction studies showed a
demyelinating sensorimotor polyneuropathy with axonal loss with
decreased median NCV of 20 m/s.
INHERITANCE
The transmission pattern in the family with CMTDIF reported by Lee et
al. (2010) was consistent with autosomal dominant inheritance.
MAPPING
By linkage analysis of a Chinese family with dominant intermediate CMT,
Lee et al. (2010) found suggestive linkage to chromosome 3q28-q29
(maximum lod score of 1.6).
MOLECULAR GENETICS
In affected members of a Chinese family with dominant intermediate CMT
(Lee et al., 2010), Soong et al. (2013) identified a heterozygous
mutation in the GNB4 gene (G53D; 610863.0001). The mutation was
identified by exome sequencing. An unrelated Chinese girl with
demyelinating CMT carried a different heterozygous mutation that
occurred de novo (K89E; 610863.0002). The frequency of GNB4 mutations in
the CMT cohort was 0.8% (2 of 251 families). Immunofluorescence studies
of patient sural nerves showed GNB4 staining of onion bulb formations in
a rosette pattern. However, immunohistochemical studies showed weaker
GNB4 expression in patient sural nerve biopsies compared to controls.
Expression of both mutations in COS-7 cells showed that the mutant
proteins had impaired bradykinin-induced G protein-coupled receptor
intracellular signaling compared to the wildtype protein. The mutant
proteins were stable in transfected cells, and Soong et al. (2013)
postulated a dominant-negative effect. The findings indicated that
GNB4-related G protein-coupled receptor signaling is important for
proper function of peripheral nerves.
*FIELD* RF
1. Lee, Y.-C.; Lee, T.-C.; Lin, K.-P, Lin, M.-W.; Chang, M.-H; Soong,
B.-W.: Clinical characterization and genetic analysis of a possible
novel type of dominant Charcot-Marie-Tooth disease. Neuromusc. Disord. 20:
534-539, 2010.
2. Soong, B.-W.; Huang, Y.-H.; Tsai, P.-C.; Huang, C.-C.; Pan, H.-C.;
Lu, Y.-C.; Chien, H.-J.; Liu, T.-T.; Chang, M.-H.; Lin, K.-P.; Tu,
P.-H.; Kao, L.-S.; Lee, Y.-C. Exome sequencing identifies GNB4
mutations as a cause of dominant intermediate Charcot-Marie-Tooth
disease. Am. J. Hum. Genet. 92: 422-430, 2013.
*FIELD* CS
INHERITANCE:
Autosomal dominant
SKELETAL:
[Feet];
Pes cavus;
Hammertoes
NEUROLOGIC:
[Peripheral nervous system];
Distal muscle weakness due to peripheral neuropathy of upper and lower
limbs;
Distal muscle atrophy due to peripheral neuropathy of upper and lower
limbs;
Steppage gait;
Hyporeflexia;
Distal sensory impairment;
Sural nerve biopsy shows loss of myelinated fibers;
Onion bulb formation;
Axonal regeneration;
Variable nerve conduction velocities (range 16.5 to 45.7 m/s)
MISCELLANEOUS:
Onset around adolescence in males;
Later onset in females;
Slowly progressive;
Males are more severely affected than females;
One Chinese family and 1 unrelated patient have been reported (last
curated April 2013)
MOLECULAR BASIS:
Caused by mutation in the guanine nucleotide-binding protein, beta-4
gene (GNB4, 610863.0001)
*FIELD* CD
Cassandra L. Kniffin: 4/18/2013
*FIELD* ED
joanna: 06/04/2013
joanna: 5/7/2013
ckniffin: 4/23/2013
*FIELD* CD
Cassandra L. Kniffin: 4/18/2013
*FIELD* ED
carol: 04/22/2013
carol: 4/19/2013
ckniffin: 4/18/2013