RBCC Red Blood Cell Collection

NGF (NGFB) [Confidence: low (only semi-automatic identification from reviews)]
Beta-nerve growth factor; Beta-NGF; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P01138
ID NGF_HUMAN Reviewed; 241 AA.
AC P01138; A1A4E5; Q6FHA0; Q96P60; Q9P2Q8; Q9UKL8;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-MAR-2006, sequence version 3.
DT 22-JAN-2014, entry version 156.
DE RecName: Full=Beta-nerve growth factor;
DE Short=Beta-NGF;
DE Flags: Precursor;
GN Name=NGF; Synonyms=NGFB;
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 [GENOMIC DNA], AND VARIANT VAL-35.
RX PubMed=6688123; DOI=10.1038/303821a0;
RA Ullrich A., Gray A., Berman C., Dull T.J.;
RT "Human beta-nerve growth factor gene sequence highly homologous to
RT that of mouse.";
RL Nature 303:821-825(1983).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT VAL-35.
RX PubMed=6327169;
RA Ullrich A., Gray A., Berman C., Coussens L., Dull T.J.;
RT "Sequence homology of human and mouse beta-NGF subunit genes.";
RL Cold Spring Harb. Symp. Quant. Biol. 48:435-442(1983).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT VAL-35.
RC TISSUE=Brain;
RX PubMed=2374737; DOI=10.1093/nar/18.13.4020;
RA Borsani G., Pizzuti A., Rugarli E.I., Falini A., Silani V., Sidoli A.,
RA Scarlato G., Barelle F.E.;
RT "cDNA sequence of human beta-NGF.";
RL Nucleic Acids Res. 18:4020-4020(1990).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=10322959;
RA Tong Y., Wang H., Chen W.;
RT "Cloning and sequencing of the gene for premature beta nerve growth
RT factor.";
RL Zhongguo Ying Yong Sheng Li Xue Za Zhi 13:316-318(1997).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT VAL-35.
RX PubMed=15014171; DOI=10.1093/molbev/msh100;
RA Kitano T., Liu Y.-H., Ueda S., Saitou N.;
RT "Human-specific amino acid changes found in 103 protein-coding
RT genes.";
RL Mol. Biol. Evol. 21:936-944(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Zhang Y., Zhang B., Zhou Y., Peng X., Yuan J., Qiang B.;
RL Submitted (AUG-2001) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S.,
RA Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W.,
RA Korn B., Zuo D., Hu Y., LaBaer J.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT VAL-35.
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 [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT VAL-35.
RC TISSUE=Eye;
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 [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 178-219.
RC TISSUE=Leukocyte;
RX PubMed=2025430; DOI=10.1016/0896-6273(91)90180-8;
RA Hallboeoek F., Ibanez C.F., Persson H.;
RT "Evolutionary studies of the nerve growth factor family reveal a novel
RT member abundantly expressed in Xenopus ovary.";
RL Neuron 6:845-858(1991).
RN [13]
RP IDENTIFICATION OF NTRK1 AS THE HIGH AFFINITY NGF RECEPTOR.
RX PubMed=1849459; DOI=10.1016/0092-8674(91)90419-Y;
RA Klein R., Jing S., Nanduri V., O'Rourke E., Barbacid M.;
RT "The trk proto-oncogene encodes a receptor for nerve growth factor.";
RL Cell 65:189-197(1991).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 122-241, AND DISULFIDE BONDS.
RX PubMed=10490030; DOI=10.1038/43705;
RA Wiesmann C., Ultsch M.H., Bass S.H., de Vos A.M.;
RT "Crystal structure of nerve growth factor in complex with the ligand-
RT binding domain of the TrkA receptor.";
RL Nature 401:184-188(1999).
RN [15]
RP VARIANT VAL-35.
RX PubMed=10391209; DOI=10.1038/10290;
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RT "Characterization of single-nucleotide polymorphisms in coding regions
RT of human genes.";
RL Nat. Genet. 22:231-238(1999).
RN [16]
RP ERRATUM.
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RL Nat. Genet. 23:373-373(1999).
RN [17]
RP VARIANT HSAN5 TRP-221.
RX PubMed=14976160; DOI=10.1093/hmg/ddh096;
RA Einarsdottir E., Carlsson A., Minde J., Toolanen G., Svensson O.,
RA Solders G., Holmgren G., Holmberg D., Holmberg M.;
RT "A mutation in the nerve growth factor beta gene (NGFB) causes loss of
RT pain perception.";
RL Hum. Mol. Genet. 13:799-805(2004).
RN [18]
RP CHARACTERIZATION OF VARIANT HSAN5 TRP-221.
RX PubMed=20978020; DOI=10.1136/jmg.2010.081455;
RA Carvalho O.P., Thornton G.K., Hertecant J., Houlden H., Nicholas A.K.,
RA Cox J.J., Rielly M., Al-Gazali L., Woods C.G.;
RT "A novel NGF mutation clarifies the molecular mechanism and extends
RT the phenotypic spectrum of the HSAN5 neuropathy.";
RL J. Med. Genet. 48:131-135(2011).
RN [19]
RP VARIANT HSAN5 GLY-GLU-162 INS, AND VARIANT ASN-187.
RX PubMed=22302274; DOI=10.1007/s00415-011-6397-y;
RA Davidson G.L., Murphy S.M., Polke J.M., Laura M., Salih M.A.,
RA Muntoni F., Blake J., Brandner S., Davies N., Horvath R., Price S.,
RA Donaghy M., Roberts M., Foulds N., Ramdharry G., Soler D., Lunn M.P.,
RA Manji H., Davis M.B., Houlden H., Reilly M.M.;
RT "Frequency of mutations in the genes associated with hereditary
RT sensory and autonomic neuropathy in a UK cohort.";
RL J. Neurol. 259:1673-1685(2012).
CC -!- FUNCTION: Nerve growth factor is important for the development and
CC maintenance of the sympathetic and sensory nervous systems.
CC Extracellular ligand for the NTRK1 and NGFR receptors, activates
CC cellular signaling cascades through those receptor tyrosine kinase
CC to regulate neuronal proliferation, differentiation and survival.
CC -!- SUBUNIT: Homodimer.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- DISEASE: Hereditary sensory and autonomic neuropathy 5 (HSAN5)
CC [MIM:608654]: A form of hereditary sensory and autonomic
CC neuropathy, a genetically and clinically heterogeneous group of
CC disorders characterized by degeneration of dorsal root and
CC autonomic ganglion cells, and by sensory and/or autonomic
CC abnormalities. HSAN5 patients manifest loss of pain perception and
CC impaired temperature sensitivity, ulcers, and in some cases self-
CC mutilation. The autonomic involvement is variable. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the NGF-beta family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH32517.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Nerve growth factor entry;
CC URL="http://en.wikipedia.org/wiki/Nerve_growth_factor";
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; V01511; CAA24755.1; -; Genomic_DNA.
DR EMBL; M21062; AAA59931.1; -; Genomic_DNA.
DR EMBL; AF150960; AAD55975.1; -; Genomic_DNA.
DR EMBL; AB037517; BAA90437.1; -; Genomic_DNA.
DR EMBL; AF411526; AAL05874.1; -; mRNA.
DR EMBL; CR541855; CAG46653.1; -; mRNA.
DR EMBL; BT019733; AAV38538.1; -; mRNA.
DR EMBL; AL049825; CAB75625.1; -; Genomic_DNA.
DR EMBL; CH471122; EAW56629.1; -; Genomic_DNA.
DR EMBL; BC032517; AAH32517.2; ALT_INIT; mRNA.
DR EMBL; BC126148; AAI26149.1; -; mRNA.
DR EMBL; BC126150; AAI26151.1; -; mRNA.
DR EMBL; X52599; CAA36832.1; -; mRNA.
DR PIR; A01399; NGHUBM.
DR RefSeq; NP_002497.2; NM_002506.2.
DR UniGene; Hs.2561; -.
DR PDB; 1SG1; X-ray; 2.40 A; A/B=122-241.
DR PDB; 1WWW; X-ray; 2.20 A; V/W=122-241.
DR PDB; 2IFG; X-ray; 3.40 A; E/F=122-241.
DR PDBsum; 1SG1; -.
DR PDBsum; 1WWW; -.
DR PDBsum; 2IFG; -.
DR ProteinModelPortal; P01138; -.
DR SMR; P01138; 131-237.
DR DIP; DIP-5712N; -.
DR IntAct; P01138; 2.
DR MINT; MINT-122414; -.
DR STRING; 9606.ENSP00000358525; -.
DR ChEMBL; CHEMBL1649058; -.
DR DrugBank; DB01407; Clenbuterol.
DR PhosphoSite; P01138; -.
DR DMDM; 90110037; -.
DR PaxDb; P01138; -.
DR PRIDE; P01138; -.
DR DNASU; 4803; -.
DR Ensembl; ENST00000369512; ENSP00000358525; ENSG00000134259.
DR GeneID; 4803; -.
DR KEGG; hsa:4803; -.
DR UCSC; uc001efu.1; human.
DR CTD; 4803; -.
DR GeneCards; GC01M115828; -.
DR HGNC; HGNC:7808; NGF.
DR MIM; 162030; gene.
DR MIM; 608654; phenotype.
DR neXtProt; NX_P01138; -.
DR Orphanet; 64752; Hereditary sensory and autonomic neuropathy type 5.
DR PharmGKB; PA162397475; -.
DR eggNOG; NOG44820; -.
DR HOGENOM; HOG000231516; -.
DR HOVERGEN; HBG006494; -.
DR InParanoid; P01138; -.
DR KO; K02582; -.
DR OMA; IFHRGEF; -.
DR OrthoDB; EOG7RBZ8Z; -.
DR PhylomeDB; P01138; -.
DR Reactome; REACT_111102; Signal Transduction.
DR SignaLink; P01138; -.
DR EvolutionaryTrace; P01138; -.
DR GeneWiki; Nerve_growth_factor; -.
DR GenomeRNAi; 4803; -.
DR NextBio; 18514; -.
DR PMAP-CutDB; P01138; -.
DR PRO; PR:P01138; -.
DR Bgee; P01138; -.
DR CleanEx; HS_NGF; -.
DR Genevestigator; P01138; -.
DR GO; GO:0005768; C:endosome; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome.
DR GO; GO:0005057; F:receptor signaling protein activity; IEA:Ensembl.
DR GO; GO:0000186; P:activation of MAPKK activity; TAS:Reactome.
DR GO; GO:0007202; P:activation of phospholipase C activity; TAS:Reactome.
DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IDA:BHF-UCL.
DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl.
DR GO; GO:0007613; P:memory; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:Reactome.
DR GO; GO:0045786; P:negative regulation of cell cycle; TAS:Reactome.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0032455; P:nerve growth factor processing; TAS:Reactome.
DR GO; GO:0048812; P:neuron projection morphogenesis; IDA:MGI.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007422; P:peripheral nervous system development; IEA:Ensembl.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome.
DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:Reactome.
DR GO; GO:0045773; P:positive regulation of axon extension; IEA:Ensembl.
DR GO; GO:0050772; P:positive regulation of axonogenesis; TAS:Reactome.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB.
DR GO; GO:0045666; P:positive regulation of neuron differentiation; IEA:Ensembl.
DR GO; GO:0051388; P:positive regulation of neurotrophin TRK receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0031954; P:positive regulation of protein autophosphorylation; IEA:Ensembl.
DR GO; GO:0051091; P:positive regulation of sequence-specific DNA binding transcription factor activity; IEA:Ensembl.
DR GO; GO:2000648; P:positive regulation of stem cell proliferation; IEA:Ensembl.
DR GO; GO:0007265; P:Ras protein signal transduction; TAS:Reactome.
DR GO; GO:0043281; P:regulation of cysteine-type endopeptidase activity involved in apoptotic process; TAS:Reactome.
DR GO; GO:0046928; P:regulation of neurotransmitter secretion; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0051602; P:response to electrical stimulus; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid stimulus; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0009612; P:response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0035094; P:response to nicotine; IEA:Ensembl.
DR GO; GO:0010193; P:response to ozone; IEA:Ensembl.
DR GO; GO:0043434; P:response to peptide hormone stimulus; IEA:Ensembl.
DR GO; GO:0009314; P:response to radiation; IEA:Ensembl.
DR GO; GO:0019233; P:sensory perception of pain; IEA:Ensembl.
DR InterPro; IPR020408; Nerve_growth_factor-like.
DR InterPro; IPR002072; Nerve_growth_factor-rel.
DR InterPro; IPR020425; Nerve_growth_factor_bsu.
DR InterPro; IPR020437; Nerve_growth_factor_bsu_mml.
DR InterPro; IPR019846; Nerve_growth_factor_CS.
DR PANTHER; PTHR11589; PTHR11589; 1.
DR Pfam; PF00243; NGF; 1.
DR PIRSF; PIRSF001789; NGF; 1.
DR PRINTS; PR01925; MAMLNGFBETA.
DR PRINTS; PR00268; NGF.
DR PRINTS; PR01913; NGFBETA.
DR ProDom; PD002052; Nerve_growth_factor-rel; 1.
DR SMART; SM00140; NGF; 1.
DR PROSITE; PS00248; NGF_1; 1.
DR PROSITE; PS50270; NGF_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cleavage on pair of basic residues; Complete proteome;
KW Disease mutation; Disulfide bond; Glycoprotein; Growth factor;
KW Neuropathy; Polymorphism; Reference proteome; Secreted; Signal.
FT SIGNAL 1 18 Potential.
FT PROPEP 19 121
FT /FTId=PRO_0000019599.
FT CHAIN 122 241 Beta-nerve growth factor.
FT /FTId=PRO_0000019600.
FT CARBOHYD 69 69 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 114 114 N-linked (GlcNAc...) (Potential).
FT DISULFID 136 201
FT DISULFID 179 229
FT DISULFID 189 231
FT VARIANT 35 35 A -> V (in dbSNP:rs6330).
FT /FTId=VAR_013783.
FT VARIANT 72 72 V -> M (in dbSNP:rs11466110).
FT /FTId=VAR_025553.
FT VARIANT 80 80 R -> Q (in dbSNP:rs11466111).
FT /FTId=VAR_025554.
FT VARIANT 162 162 E -> EGE (in HSAN5; uncertain
FT pathological significance).
FT /FTId=VAR_068478.
FT VARIANT 187 187 S -> N (found in a patient with
FT congenital insensitivity to pain;
FT uncertain pathological significance).
FT /FTId=VAR_068479.
FT VARIANT 221 221 R -> W (in HSAN5; the mutant protein is
FT unable to activate the NTRK1 receptor;
FT may act as a hypomorphic allele;
FT dbSNP:rs11466112).
FT /FTId=VAR_030659.
FT CONFLICT 164 164 N -> S (in Ref. 6; AAL05874).
FT CONFLICT 230 230 V -> M (in Ref. 6; AAL05874).
FT HELIX 127 130
FT STRAND 133 136
FT STRAND 138 143
FT STRAND 148 151
FT STRAND 156 159
FT STRAND 161 171
FT STRAND 174 179
FT STRAND 190 192
FT TURN 194 196
FT STRAND 197 213
FT STRAND 215 235
SQ SEQUENCE 241 AA; 26959 MW; 619DFC65EB3BD671 CRC64;
MSMLFYTLIT AFLIGIQAEP HSESNVPAGH TIPQAHWTKL QHSLDTALRR ARSAPAAAIA
ARVAGQTRNI TVDPRLFKKR RLRSPRVLFS TQPPREAADT QDLDFEVGGA APFNRTHRSK
RSSSHPIFHR GEFSVCDSVS VWVGDKTTAT DIKGKEVMVL GEVNINNSVF KQYFFETKCR
DPNPVDSGCR GIDSKHWNSY CTTTHTFVKA LTMDGKQAAW RFIRIDTACV CVLSRKAVRR
A
//

MIM 162030
*RECORD*
*FIELD* NO
162030
*FIELD* TI
*162030 NERVE GROWTH FACTOR, BETA SUBUNIT; NGFB
;;NERVE GROWTH FACTOR; NGF
*FIELD* TX
read moreFor background information on neurotrophins and their receptors, see
NGFR (162010).

CLONING

Nerve growth factor is a polypeptide involved in the regulation of
growth and differentiation of sympathetic and certain sensory neurons.
(See review by Levi-Montalcini, 1987.) Ullrich et al. (1983) showed that
the nucleotide sequence of human and mouse beta-NGF are very similar.
NGF consists of 3 types of subunits, alpha, beta and gamma, which
specifically interact to form a 7S, 130,000-molecular weight complex.
This complex contains 2 identical 118-amino acid beta-chains, which are
solely responsible for nerve growth stimulating activity of NGF. Human
DNA fragments coding for NGF were identified by Zabel et al. (1984)
using a mouse submaxillary cDNA probe.

GENE FUNCTION

The arrest of dorsal root axonal regeneration at the transitional zone
between the peripheral and central nervous system has been repeatedly
described. Ramer et al. (2000) demonstrated that with trophic support to
damaged sensory axons, this regenerative barrier is surmountable. In
adult rats with injured dorsal roots, treatment with NGF, neurotrophin-3
(NT3; 162660), or glial cell line-derived neurotrophic factor (GDNF;
600837), but not brain-derived neurotrophic factor (BDNF; 113505),
resulted in selective regrowth of damaged axons across the dorsal root
entry zone and into the spinal cord. Dorsal horn neurons were found to
be synaptically driven by peripheral nerve stimulation in rats treated
with NGF, NT3, and GDNF, demonstrating functional reconnection. In
behavioral studies, rats treated with NGF and GDNF recovered sensitivity
to noxious heat and pressure. Ramer et al. (2000) concluded that
neurotrophic factor treatment may serve as a viable treatment in
promoting recovery from root avulsion injuries.

Sanico et al. (2000) used RT-PCR, Western blot analysis, and ELISA to
evaluate NGF expression and release in subjects with or without allergic
rhinitis. They found that subjects with allergic rhinitis had
significantly decreased NGF mRNA in superficial nasal scrapings and
significantly higher baseline concentrations of NGF protein in nasal
lavage fluids compared with control subjects. Nasal provocation with
allergen significantly increased NGF protein in nasal lavage fluids of
subjects with allergic rhinitis but not of control subjects. Sanico et
al. (2000) concluded that their data provide evidence of a steady state
of dysregulation in mucosal NGF expression and release in allergic
rhinitis and support a role of this neurotrophin in the pathophysiology
of allergic inflammatory disease of the human airways.

Chuang et al. (2001) demonstrated that bradykinin- or NGF-mediated
potentiation of thermal sensitivity in vivo requires expression of VR1
(602076), a heat-activated ion channel on sensory neurons. Diminution of
plasma membrane phosphatidylinositol-4,5,bisphosphate levels through
antibody sequestration or PLC-mediated hydrolysis mimics the
potentiating effects of bradykinin or NGF at the cellular level.
Moreover, recruitment of PLC-gamma (172420) to TRK-alpha (TRKA) (NTRK1;
191315) is essential for NGF-mediated potentiation of channel activity,
and biochemical studies suggested that VR1 associates with this complex.
Chuang et al. (2001) concluded that their studies delineate a
biochemical mechanism through which bradykinin and NGF produce
hypersensitivity and might explain how the activation of PLC signaling
systems regulates other members of the TRP channel family.

Although proneurotrophins have been considered inactive precursors, Lee
et al. (2001) demonstrated that the proforms of NGF and the proforms of
BDNF are secreted and cleaved extracellularly by the serine protease
plasmin (173350) and by selective matrix metalloproteinases (MMP7,
178990; MMP3, 185250). ProNGF is a high-affinity ligand for p75(NTR)
(NGFR; 162010), and induced p75(NTR)-dependent apoptosis in cultured
neurons with minimal activation of TRK-alpha-mediated differentiation or
survival. The biologic action of neurotrophins is thus regulated by
proteolytic cleavage, with proforms preferentially activating p75(NTR)
to mediate apoptosis and mature forms activating TRK receptors to
promote survival.

MacInnis and Campenot (2002) demonstrated that application of nerve
growth factor covalently cross-linked to beads increased the
phosphorylation of TRKA and AKT (164730), but not of mitogen-activated
protein kinase (MAPK1; 176948), in cultured rat sympathetic neurons. NGF
beads or iodine-125-labeled NGF beads supplied to distal axons resulted
in the survival of over 80% of the neurons for 30 hours, with little or
no retrograde transport of iodine-125-labeled NGF. Application of free
iodine-125-labeled NGF produced 20-fold more retrograde transport, but
only 29% of the neurons survived. Thus, MacInnis and Campenot (2002)
concluded that a neuronal survival signal can reach the cell bodies
unaccompanied by the NGF that initiated it.

Nykjaer et al. (2004) demonstrated that proNGF creates a signaling
complex by simultaneously binding to p75(NTR) and sortilin (602458).
Sortilin acts as a coreceptor and molecular switch governing the
p75(NTR)-mediated proapoptotic signal induced by proNGF. Together with
p75(NTR), sortilin facilitates the formation of a composite
high-affinity binding site for proNGF. Thus, sortilin serves as a
coreceptor and molecular switch, enabling neurons expressing TRK and
p75(NTR) to respond to a proneurotrophin and to initiate proapoptotic
rather than prosurvival actions. In the absence of sortilin, regulated
activity of extracellular proteases may cleave proNGF to mature NGF,
promoting TRK-mediated survival signals. Nykjaer et al. (2004) concluded
that NGF-induced neuronal survival and death is far more complicated
than previously appreciated, as it depends on an intricate balance
between proNGF and mature NGF, as well as on the spatial and temporal
expression of 3 distinct receptors: TRKA, p75(NTR), and sortilin.

Harrington et al. (2004) reported that after brain injury in rats and
mice, the unprocessed precursor of NGF (proNGF) was induced and secreted
in an active form capable of triggering apoptosis in culture. They
further demonstrated that proNGF binds the neurotrophin receptor p75 in
vivo and that disruption of this binding results in complete rescue of
injured adult corticospinal neurons. These data suggested that proNGF
binding to p75 is responsible for the death of adult corticospinal
neurons after brain injury.

In a study of regulators of nerve growth factor, Ieda et al. (2004)
found that endothelin-1 (EDN1; 131240) specifically upregulated NGFB
expression in primary cultured cardiomyocytes. EDN1-induced NGF
augmentation was mediated by EDNRA (131243), Gi-beta-gamma (see 139310),
PKC (see 176960), the Src family (see 190090), EGFR (131550), MAPK3
(601795), MAPK14 (600289), AP1 (165160), and CEBPD (116898). Either
conditioned medium or coculture with EDN1-stimulated cardiomyocytes
caused NGF-mediated PC12 cell differentiation. Edn1-deficient mice
exhibited reduced NGF expression and norepinephrine concentration in the
heart, reduced cardiac sympathetic innervation, excess apoptosis of
sympathetic stellate ganglia, and loss of neurons at the late embryonic
stage. Cardiac-specific overexpression of NGF in Edn1-deficient mice
overcame the reduced sympathetic expression and loss of stellate ganglia
neurons. Ieda et al. (2004) concluded that EDN1 plays a critical role in
sympathetic innervation of the heart.

Kuruvilla et al. (2004) found that the related neurotrophins NGF and NT3
(162660), acting through a common receptor, TRKA (191315), were required
for sequential stages of sympathetic axon growth and, thus, innervation
of target fields. Yet, while NGF supported TRKA internalization and
retrograde signaling from distal axons to cell bodies to promote
neuronal survival, NT3 could not. Final target-derived NGF promoted
expression of the p75 neurotrophin receptor, in turn causing a reduction
in the sensitivity of axons to intermediate target-derived NT3.
Kuruvilla et al. (2004) proposed that a hierarchical neurotrophin
signaling cascade coordinates sequential stages of sympathetic axon
growth, innervation of targets, and survival in a manner dependent on
the differential control of TRKA internalization, trafficking, and
retrograde axonal signaling.

Neurotrophins (NTFs) act as survival and differentiation factors in the
nervous system and have been detected in the developing rodent testis.
To determine whether neurotrophins could influence development and
maturation of the human fetal testis, Robinson et al. (2003) examined
the cell-specific expression and distribution of several members of the
neurotrophin family and their receptors during the second trimester,
with particular emphasis on NT4 and TRKB. They detected expression of
mRNA for NGF, NT3 and NT4 (162662), BDNF (113505), the high-affinity
receptors TRKA, TRKB (600456), and TRKC (191316), and the low-affinity
p75 receptor (NGFR; 162010) in the human testis between 14 and 19 weeks'
gestation. NT4 mRNA and protein were predominantly localized to the
peritubular cells. These cells were also the site of expression of p75.
By contrast, NGF and NT3 were mainly expressed in Sertoli and
interstitial cells. Robinson et al. (2003) concluded that these data
demonstrate the expression of neurotrophins and their receptors in the
human fetal testis during the second trimester and indicate possible
roles in the regulation of proliferation and survival of germ cells and
peritubular cells.

MAPPING

In somatic cell hybrid studies, Zabel et al. (1984) found that the human
HindIII DNA fragments for NGF, as demonstrated in Southern blots,
cosegregated with chromosome 1. Using a cell line with a 1;2
translocation, they narrowed the assignment to 1pter-p21. This is the
same area as that implicated cytogenetically in neuroblastoma
(1pter-p32) and the segment containing a neuroblastoma-related RAS
oncogene.

Using fragments of a cloned human gene for the beta subunit of nerve
growth factor as hybridization probes in somatic cell hybrid studies,
Francke et al. (1983) mapped the NGFB locus to 1p22. Oncogene NRAS
(164790) maps to the same band. Both nerve growth factor and epidermal
growth factor (131530) are on mouse chromosome 3; in man they are on
different chromosomes (Zabel et al., 1985). Both factors are present in
unusually high levels in male mouse submaxillary glands and both show
similarities in temporal activation during development and androgen
regulation. There is no known structural homology between them, however.
Arguing from comparative mapping data, Zabel et al. (1985) suggested
that the NGFB locus is localized in the p22.1 to distal p21 region of
chromosome 1. The distal part of human 1p shows conserved homology with
mouse chromosome 4. The region of homology includes the genes ENO1
(172430), PGD (172200), GDH (138090), AK2 (103020), and PGM1 (171900).
The conserved segment extends to PGM1 (homologous to mouse Pgm2), which
is localized to human 1p22.1. From about 1p22.1 toward the centromere,
there is a region of homology to mouse chromosome 3. This region
contains AMY1 and AMY2 in mouse and man and NGF in the mouse. AMY is
mapped to human 1p21. Using a method for improved resolution of in situ
hybridization, Middleton-Price et al. (1987) concluded that NGFB is
located within band 1p13. This explains the apparently anomalous linkage
data between NGFB and PGM1, both of which had previously been assigned
to 1p22.1 but showed no positive linkage. Garson et al. (1987) confirmed
the assignment of NGFB to 1p13. The confusion has, however, not been
completely dispelled. According to Dracopoli (1988), NGFB is telomeric
to TSHB (188540). The 2 loci are in the same 100-kb PFGE fragment, show
virtually no recombination (lod = 43 at theta = 0.0), and are
antithetically regulated by thyroid hormone (Dracopoli et al., 1988),
yet TSHB has been mapped to 1p22. Dracopoli and Meisler (1990) concluded
from linkage analysis and pulsed field gel electrophoresis that TSHB,
NGFB, and NRAS form a tightly linked gene cluster located in the same
chromosomal band. Their location proximal to the AMY2B gene in 1p21 and
close linkage to the alpha-satellite centromeric repeat D1Z5 provided
strong evidence that the correct assignment for these 3 loci is 1p13 and
not 1p22. By fluorescence in situ hybridization, Mitchell et al. (1995)
mapped NGFB to 1p13.1.

Carrier et al. (1996) constructed a 3-Mb YAC contig, including the NGFB
gene. They found that the gene order of this region of the short arm of
chromosome 1 was cen--CD2(186990)--CD58(153420)--ATP1A1
(182310)--NGF--TSHB--NRAS--tel.

BIOCHEMICAL FEATURES

- Crystal Structure

He and Garcia (2004) determined the 2.4-angstrom crystal structure of
the prototypic neurotrophin, NGF, complexed with the extracellular
domain of p75. The complex is composed of an NGF homodimer
asymmetrically bound to a single p75. The p75 protein binds along the
homodimeric interface of NGF, which disables NGF's symmetry-related
second p75 binding site through an allosteric conformational change. He
and Garcia (2004) concluded that neurotrophin signaling through p75 may
occur by disassembly of p75 dimers and assembly of asymmetric 2:1
neurotrophin/p75 complexes, which could potentially engage a Trk
receptor to form a trimolecular signaling complex.

MOLECULAR GENETICS

Einarsdottir et al. (2004) described a large family from northern Sweden
in which affected members exhibited loss of deep pain and temperature
perception. Because severe reduction of unmyelinated nerve fibers and
moderate loss of thin myelinated nerve fibers were also observed in
these patients, they best fit into the category of hereditary sensory
and autonomic neuropathy, type V (HSAN5; 608654). In contrast to HSAN4
(256800), mental abilities and most other neurologic responses remained
intact. Using a model of recessive inheritance, the authors identified
an 8.3-Mb region on chromosome 1p13.2-p11.2 shared by the affected
individuals. Analysis of candidate disease genes revealed a mutation in
the coding region of the NGFB gene that cosegregated with the disease
phenotype (162030.0001). This NGF mutation seems to separate the effects
of NGF involved in development of central nervous system functions (such
as mental abilities) from those involved in peripheral pain pathways.

Carvalho et al. (2011) identified a homozygous loss of function mutation
in the NGFB gene (162030.0002) in a consanguineous Emirati Bedouin
family with HSAN5 and mild mental retardation. The findings expanded the
phenotype of HSAN5 to be closer to that of HSAN4, indicating that there
is a phenotypic spectrum due to changes in the NGF/TRKA signaling
pathway.

HISTORY

Abnormality of NGF had been suspected, with some supporting evidence, in
familial dysautonomia (223900) and in 2 forms of neurofibromatosis
(101000, 162200). The use of the 'candidate gene' approach to mapping
disease and determining its cause is illustrated by the work of
Breakefield et al. (1984). Using a cloned genomic probe for human
beta-NGF, they identified RFLPs in the beta-NGF gene, and in 4
informative families with 2 children with familial dysautonomia found
'no consistent co-inheritance of specific alleles with the disease.'
Thus, they appear to have excluded a defect in or near the structural
gene for beta-NGF as the cause of familial dysautonomia. Using 2 RFLPs
related to the beta-NGF gene, Darby et al. (1985) could exclude this
gene as the site of the mutation in 4 families with neurofibromatosis of
the classic type (162200).

*FIELD* AV
.0001
NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE V
NGFB, ARG211TRP

In a large consanguineous family from northern Sweden with loss of deep
pain and temperature perception (HSAN5; 608654), Einarsdottir et al.
(2004) demonstrated that 3 severely affected family members were
homozygous for a 661C-T transition in the NGFB gene. The mutation was
predicted to result in a substitution of tryptophan for arginine-211
(R211W), corresponding to position 100 in the mature protein, in a
highly conserved region of the protein.

By in vitro functional expression studies in rat pheochromocytoma cells
Carvalho et al. (2011) showed that the mutant protein was unable to
activate the TRKA receptor (NTRK1; 191315). However, a small amount of
residual mutant protein was secreted, suggesting that it may act as a
hypomorphic allele.

.0002
NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE V
NGFB, 680C-A AND 2-BP DEL, 681GG

In 6 sibs from a consanguineous Emirati Bedouin family with HSAN5
(608654), Carvalho et al. (2011) identified a homozygous 680C-A
transversion and a 2-bp deletion (681delGG) in exon 1 of the NGFB gene
(referred to as CAdGG), resulting in a frameshift and replacement of the
terminal 15 amino acids with a novel 43-amino acid terminal sequence.
The mutation creates additional cysteine residues in the novel C
terminus, potentially able to compete in disulfide bond formation. In
vitro functional expression studies in rat pheochromocytoma cells showed
that the mutant protein was unable to activate the TRKA receptor (NTRK1;
191315), consistent with a loss of function. The mutant protein was not
secreted, suggesting impaired processing. In addition to inability to
feel pain, all patients had mild mental retardation, thus expanding the
phenotypic spectrum of HSAN5.

*FIELD* SA
Darby et al. (1985); Munke et al. (1984)
*FIELD* RF
1. Breakefield, X. O.; Orloff, G.; Castiglione, C.; Coussens, L.;
Axelrod, F. B.; Ullrich, A.: Structural gene for beta-nerve growth
factor not defective in familial dysautonomia. Proc. Nat. Acad. Sci. 81:
4213-4216, 1984.

2. Carrier, A.; Rosier, M.-F.; Guillemot, F.; Goguel, A.-F.; Pulcini,
F.; Bernheim, A.; Auffray, C.; Devignes, M.-D.: Integrated physical,
genetic, and genic map covering 3 Mb around the human NGF gene (NGFB)
at 1p13. Genomics 31: 80-89, 1996.

3. Carvalho, O. P.; Thornton, G. K.; Hertecant, J.; Houlden, H.; Nicholas,
A. K.; Cox, J. J.; Rielly, M.; Al-Gazali, L.; Woods, C. G.: A novel
NGF mutation clarifies the molecular mechanism and extends the phenotypic
spectrum of the HSAN5 neuropathy. J. Med. Genet. 48: 131-135, 2011.

4. Chuang, H.; Prescott, E. D.; Kong, H.; Shields, S.; Jordt, S.-E.;
Basbaum, A. I.; Chao, M. V.; Julius, D.: Bradykinin and nerve growth
factor release the capsaicin receptor from PtdIns(4,5)P2-mediated
inhibition. Nature 411: 957-962, 2001.

5. Darby, J. K.; Feder, J.; Selby, M.; Riccardi, V.; Ferrell, R.;
Siao, D.; Goslin, K.; Rutter, W.; Shooter, E. M.; Cavalli-Sforza,
L. L.: A discordant sibship analysis between beta-NGF and neurofibromatosis. Am.
J. Hum. Genet. 37: 52-59, 1985.

6. Darby, J. K.; Kidd, J. R.; Pakstis, A. J.; Sparkes, R. S.; Cann,
H. M.; Ferrell, R. E.; Gerhard, D. G.; Riccardi, V.; Egeland, J. A.;
Shooter, E. M.; Cavalli-Sforza, L. L.; Kidd, K. K.: Linkage relationships
of the gene for the beta subunit of nerve growth factor (NGFB) with
other chromosome 1 marker loci. Cytogenet. Cell Genet. 39: 158-160,
1985.

7. Dracopoli, N. C.: Personal Communication. Cambridge, Mass.
4/29/1988.

8. Dracopoli, N. C.; Meisler, M. H.: Mapping the human amylase gene
cluster on the proximal short arm of chromosome 1 using a highly informative
(CA)n repeat. Genomics 7: 97-102, 1990.

9. Dracopoli, N. C.; Rose, E.; Whitfield, G. K.; Guidon, P. T.; Bale,
S. J.; Chance, P. A.; Kourides, I. A.; Housman, D. E.: Two thyroid
hormone regulated genes, the beta-subunits of nerve growth factor
(NGFB) and thyroid stimulating hormone (TSHB), are located less than
310 kb apart in both human and mouse genomes. Genomics 3: 161-167,
1988.

10. Einarsdottir, E.; Carlsson, A.; Minde, J.; Toolanen, G.; Svensson,
O.; Solders, G.; Holmgren, G.; Holmberg, D.; Holmberg, M.: A mutation
in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum.
Molec. Genet. 13: 799-805, 2004.

11. Francke, U.; de Martinville, B.; Coussens, L.; Ullrich, A.: The
human gene for the beta subunit of nerve growth factor is located
on the proximal short arm of chromosome 1. Science 222: 1248-1251,
1983.

12. Garson, J. A.; van den Berghe, J. A.; Kemshead, J. T.: Novel
non-isotopic in situ hybridization technique detects small (1 kb)
unique sequences in routinely G-banded human chromosomes: fine mapping
of N-myc and beta-NGF genes. Nucleic Acids Res. 15: 4761-4770, 1987.

13. Harrington, A. W.; Leiner, B.; Blechschmitt, C.; Arevalo, J. C.;
Lee, R.; Morl, K.; Meyer, M.; Hempstead, B. L.; Yoon, S. O.; Giehl,
K. M.: Secreted proNGF is a pathophysiological death-inducing ligand
after adult CNS injury. Proc. Nat. Acad. Sci. 101: 6226-6230, 2004.

14. He, X.-L.; Garcia, K. C.: Structure of nerve growth factor complexed
with the shared neurotrophin receptor p75. Science 304: 870-875,
2004.

15. Ieda, M.; Fukuda, K.; Hisaka, Y.; Kimura, K.; Kawaguchi, H.; Fujita,
J.; Shimoda, K.; Takeshita, E.; Okano, H.; Kurihara, Y.; Kurihara,
H.; Ishida, J.; Fukamizu, A.; Federoff, H. J.; Ogawa, S.: Endothelin-1
regulates cardiac sympathetic innervation in the rodent heart by controlling
nerve growth factor expression. J. Clin. Invest. 113: 876-884, 2004.

16. Kuruvilla, R.; Zweifel, L. S.; Glebova, N. O.; Lonze, B. E.; Valdez,
G.; Ye, H.; Ginty, D. D.: A neurotrophin signaling cascade coordinates
sympathetic neuron development through differential control of TrkA
trafficking and retrograde signaling. Cell 118: 243-255, 2004.

17. Lee, R.; Kermani, P.; Teng, K. K.; Hempstead, B. L.: Regulation
of cell survival by secreted proneurotrophins. Science 294: 1945-1948,
2001.

18. Levi-Montalcini, R.: The nerve growth factor thirty-five years
later. Science 237: 1154-1162, 1987.

19. MacInnis, B. L.; Campenot, R. B.: Retrograde support of neuronal
survival without retrograde transport of nerve growth factor. Science 295:
1536-1539, 2002.

20. Middleton-Price, H.; van den Berghe, J.; Harding, A.; Scott, J.;
Malcolm, S.: Analysis of markers on chromosome 1. (Abstract) Cytogenet.
Cell Genet. 46: 662, 1987.

21. Mitchell, E. L. D.; Jones, D.; White, G. R. M.; Varley, J. M.;
Santibanez Koref, M. F.: Determination of the gene order of the three
loci CD2, NGFB, and NRAS at human chromosome band 1p13 and refinement
of their localisation at the subband level by fluorescence in situ
hybridization. Cytogenet. Cell Genet. 70: 183-185, 1995. Note: Erratum:
Cytogenet. Cell Genet. 71: 306 only, 1995.

22. Munke, M.; Lindgren, V.; de Martinville, B.; Francke, U.: Comparative
analysis of mouse-human hybrids with rearranged chromosomes 1 by in
situ hybridization and Southern blotting: high-resolution mapping
of NRAS, NGFB, and AMY on human chromosome 1. Somat. Cell Molec.
Genet. 10: 589-599, 1984.

23. Nykjaer, A.; Lee, R.; Teng, K. K.; Jansen, P.; Madsen, P.; Nielsen,
M. S.; Jacobsen, C.; Kliemannel, M.; Schwarz, E.; Willnow, T. E.;
Hempstead, B. L.; Petersen, C. M.: Sortilin is essential for proNGF-induced
neuronal cell death. Nature 427: 843-848, 2004.

24. Ramer, M. S.; Priestley, J. V.; McMahon, S. B.: Functional regeneration
of sensory axons into the adult spinal cord. Nature 403: 312-316,
2000.

25. Robinson, L. L. L.; Townsend, J.; Anderson, R. A.: The human
fetal testis is a site of expression of neurotrophins and their receptors:
regulation of the germ cell and peritubular cell population. J. Clin.
Endocr. Metab. 88: 3943-3951, 2003.

26. Sanico, A. M.; Stanisz, A. M.; Gleeson, T. D.; Bora, S.; Proud,
D.; Bienenstock, J.; Koliatsos, V. E.; Togias, A.: Nerve growth factor
expression and release in allergic inflammatory disease of the upper
airways. Am. J. Resp. Crit. Care Med. 161: 1631-1635, 2000.

27. Ullrich, A.; Gray, A.; Berman, C.; Dull, T. J.: Human beta-nerve
growth factor gene sequence highly homologous to that of mouse. Nature 303:
821-825, 1983.

28. Zabel, B. U.; Eddy, R. L.; Lalley, P. A.; Scott, J.; Bell, G.
I.; Shows, T. B.: Chromosomal locations of the human and mouse genes
for precursors of epidermal growth factor and the beta subunit of
nerve growth factor. Proc. Nat. Acad. Sci. 82: 469-473, 1985.

29. Zabel, B. U.; Eddy, R. L.; Scott, J.; Shows, T. B.: The human
nerve growth factor gene (NGF) is located on the short arm of chromosome
1. (Abstract) Cytogenet. Cell Genet. 37: 614, 1984.

*FIELD* CN
Cassandra L. Kniffin - updated: 2/23/2011
John A. Phillips, III - updated: 9/24/2004
Stylianos E. Antonarakis - updated: 8/18/2004
George E. Tiller - updated: 8/17/2004
Ada Hamosh - updated: 7/29/2004
Marla J. F. O'Neill - updated: 5/20/2004
Victor A. McKusick - updated: 5/12/2004
Ada Hamosh - updated: 3/8/2004
Ada Hamosh - updated: 3/29/2002
Ada Hamosh - updated: 12/18/2001
Ada Hamosh - updated: 6/20/2001
Paul J. Converse - updated: 5/15/2001
Ada Hamosh - updated: 10/31/2000
Ada Hamosh - updated: 1/20/2000
Alan F. Scott - updated: 4/8/1996

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
terry: 11/29/2012
wwang: 2/24/2011
ckniffin: 2/23/2011
carol: 11/23/2009
terry: 5/17/2005
alopez: 9/24/2004
mgross: 8/18/2004
alopez: 8/17/2004
tkritzer: 7/29/2004
terry: 7/29/2004
carol: 5/25/2004
terry: 5/20/2004
tkritzer: 5/18/2004
terry: 5/12/2004
tkritzer: 3/10/2004
terry: 3/8/2004
cwells: 4/3/2002
cwells: 4/2/2002
terry: 3/29/2002
alopez: 1/3/2002
terry: 12/18/2001
alopez: 6/21/2001
terry: 6/20/2001
mgross: 5/15/2001
mgross: 11/2/2000
terry: 10/31/2000
alopez: 1/20/2000
mark: 1/3/1997
terry: 4/17/1996
mark: 4/8/1996
terry: 4/8/1996
mark: 4/8/1996
mark: 10/20/1995
carol: 12/20/1993
supermim: 3/16/1992
carol: 3/2/1992
carol: 2/27/1992
carol: 10/1/1991

MIM 608654
*RECORD*
*FIELD* NO
608654
*FIELD* TI
#608654 NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE V; HSAN5
;;HSAN V;;
INSENSITIVITY TO PAIN, CONGENITAL
read more*FIELD* TX
A number sign (#) is used with this entry because hereditary sensory
neuropathy type V (HSAN5) is caused by homozygous mutation in the NGFB
gene (162030) on chromosome 1p13.

For a discussion of genetic heterogeneity of hereditary sensory and
autonomic neuropathy, see HSAN1 (162400).

CLINICAL FEATURES

Low et al. (1978) reported a 6-year-old child with congenital sensory
neuropathy characterized by a selective loss of pain and thermal
sensation affecting the extremities. Nerve conduction studies were
normal. Small myelinated fibers were selectively reduced in the sural
nerve, and unmyelinated fibers were normal.

Dyck et al. (1983) reported a girl with congenital insensitivity to
pain. She responded to tactile stimuli, had preserved tendon reflexes,
and had normal motor and sensory nerve conductions. She had
self-mutilation of the lips, tongue, and fingers, and mild autonomic
involvement, including skin blotching, decreased sweating, and episodic
increased body temperature. Nerve conduction velocities were normal, but
no somatosensory evoked responses could be recorded over the spine from
tibial nerve stimulation. Nerve biopsy showed a selective, virtually
complete absence of small myelinated afferent fibers, and a less
apparent reduction in the number of unmyelinated fibers. Dyck et al.
(1983) referred to the case of Low et al. (1978), and termed the
disorder in both cases HSAN type V. Dyck et al. (1983) noted that many
similar earlier cases reported as 'congenital indifference to pain' or
'congenital anesthesia' (see 243000), which are characterized by an
absence of nerve pathology, were reported before the application of
methods to assess the physiologic function of nerve fibers; therefore,
some of these cases may have been HSAN4 (256800) or HSAN5.

In an inbred Kashmiri family, Donaghy et al. (1987) described 3 members
with a congenital sensory and autonomic neuropathy and corneal
opacification. Pain and temperature sensation was lost in the limbs with
a resulting mutilating acropathy. Sudomotor function was also impaired,
with areas of anhidrosis. Motor function, tendon reflexes, large fiber
sensory modalities, and sensory nerve action potentials were normal.
Sural nerve biopsy showed a selectively reduced small myelinated nerve
fiber population. Unmyelinated axons showed normal density with some
evidence of degeneration. Corneal histology showed neurotrophic
keratitis. The 3 affected individuals occurred in 2 sibships related to
each other as first cousins once removed and were children of
first-cousin parents.

Itoh et al. (1999) reported a pair of female monozygotic twin infants
who had generalized loss of pain sensation without impairment of other
sensory modalities or diaphoretic function. Sural nerve biopsy showed
that the number of small myelinated fibers was reduced and that of
unmyelinated fibers was normal or mildly reduced. The authors suggested
a diagnosis of HSAN5.

Karkashan et al. (2002) reported 2 sibs from Saudi Arabia with
congenital insensitivity to pain. Three additional members of related
families who could be traced back to the same grandfather were also
affected. All patients had normal intelligence, normal sweating, and
normal appreciation of other sensory modalities. All had painless
injuries resulting in cuts, bruises, and fractures.

Einarsdottir et al. (2004) described a large multigenerational
consanguineous family from northern Sweden suffering from loss of pain
perception but with most other neurologic functions intact. The patients
suffered from a severe loss of deep pain perception that prevented them
from feeling pain from bone fractures and joints; heat perception was
also impaired. Decreased deep pain perception led to destroyed joints
(Charcot joints) in childhood. Most other neurologic functions including
sweating and mental abilities were intact. A number of additional family
members suffered from a less severe phenotype presenting as joint
problems mostly in the feet and knees and resulting in Charcot joints
later in life. Neurophysiologic and neuropathologic findings showed that
the patients in this family suffered from a peripheral neuropathy with a
severe reduction of unmyelinated nerve fibers and a moderate loss of
thin myelinated nerve fibers. Einarsdottir et al. (2004) classified the
neuropathy in this family as HSAN5, which is characterized by loss of
pain perception, impaired temperature sensitivity, ulcers, and in some
cases self-mutilation, and in which the autonomic involvement is
variable (Hilz, 2002).

Carvalho et al. (2011) reported a consanguineous Emirati Bedouin family
in which 5 sibs ranging in age from 2 to 12 years had HSAN5 and mild
mental retardation. The first medical problem was biting of lips,
tongue, and digits without apparent discomfort or pain. None could
discriminate heat and cold or detect hot spicy food, and all had
anhidrosis. Mild mental retardation was evident by the age of 4 years.
With age, all developed a prematurely aged appearance, with malar
hypoplasia, sunken eyes, and loss of teeth. All had suffered multiple,
painless, injuries of varying severity and showed poor wound healing,
which the authors suggested may reflect a mild immunodeficiency. There
was a normal response to insect bites, which may serve as a proxy for an
intradermal histamine flare test.

MAPPING

In 3 severely affected members of a large consanguineous family from
northern Sweden with HSAN5, Einarsdottir et al. (2004) screened for
shared homozygosis regions. They identified an 8.3-Mb region on
chromosome 1p13.2-p11.2 shared by the affected members.

MOLECULAR GENETICS

Einarsdottir et al. (2004) demonstrated that all 3 severely affected
family members of the Swedish family with HSAN5 studied by them were
homozygous for a 661C-T transition in the gene encoding nerve growth
factor-beta (NGFB; 162030). The mutation was predicted to result in a
substitution of tryptophan for arginine-211 (162030.0001) in a highly
conserved region of the protein.

Carvalho et al. (2011) identified a homozygous loss of function mutation
in the NGFB gene (162030.0002) in a consanguineous Emirati Bedouin
family with HSAN5 and mild mental retardation. The findings expanded the
phenotype of HSAN5 to be closer to that of HSAN4, indicating that there
is a phenotypic spectrum due to changes in the NGF/TRKA signaling
pathway.

*FIELD* RF
1. Carvalho, O. P.; Thornton, G. K.; Hertecant, J.; Houlden, H.; Nicholas,
A. K.; Cox, J. J.; Rielly, M.; Al-Gazali, L.; Woods, C. G.: A novel
NGF mutation clarifies the molecular mechanism and extends the phenotypic
spectrum of the HSAN5 neuropathy. J. Med. Genet. 48: 131-135, 2011.

2. Donaghy, M.; Hakin, R. N.; Bamford, J. M.; Garner, A.; Kirkby,
G. R.; Noble, B. A.; Tazir-Melboucy, M.; King, R. H. M.; Thomas, P.
K.: Hereditary sensory neuropathy with neurotrophic keratitis: description
of an autosomal recessive disorder with a selective reduction of small
myelinated nerve fibres and a discussion of the classification of
the hereditary sensory neuropathies. Brain 110: 563-583, 1987.

3. Dyck, P. J.; Mellinger, J. F.; Reagan, T. J.; Horowitz, S. J.;
McDonald, J. W.; Litchy, W. J.; Daube, J. R.; Fealey, R. D.; Go, V.
L.; Kao, P. C.; Brimijoin, W. S.; Lambert, E. H.: Not 'indifference
to pain' but varieties of hereditary sensory and autonomic neuropathy. Brain 106:
373-390, 1983.

4. Einarsdottir, E.; Carlsson, A.; Minde, J.; Toolanen, G.; Svensson,
O.; Solders, G.; Holmgren, G.; Holmberg, D.; Holmberg, M.: A mutation
in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum.
Molec. Genet. 13: 799-805, 2004.

5. Hilz, M. J.: Assessment and evaluation of hereditary sensory and
autonomic neuropathies with autonomic and neurophysiological examinations. Clin.
Auton. Res. 12 (suppl. 1): I33-I43, 2002.

6. Itoh, Y.; Shishikura, K.; Suzuki, H.; Hirano, K.; Funatsuka, M.;
Hirano, Y.; Imaizumi, T.; Awaya, Y.; Osawa, M.: Monozygotic twins
with suspected hereditary sensory and autonomic neuropathy (HSAN)
type V. No To Hattatsu 31: 63-69, 1999. Note: Article in Japanese.

7. Karkashan, E. M.; Joharji, H. S.; Al-Harbi, N. N.: Congenital
insensitivity to pain in four related Saudi families. Pediat. Derm. 19:
333-335, 2002.

8. Low, P. A.; Burke, W. J.; McLeod, J. G.: Congenital sensory neuropathy
with selective loss of small myelinated fibers. Ann. Neurol. 3:
179-182, 1978.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Mouth];
Accidental injury and ulceration of the lips and tongue due to decreased
sensation

SKELETAL:
Painless fractures due to injury;
[Hands];
Acral ulceration and osteomyelitis leading to autoamputation of the
digits;
[Feet];
Acral ulceration and osteomyelitis leading to autoamputation of the
digits

SKIN, NAILS, HAIR:
[Skin];
Acral ulcers;
Anhidrosis, patchy, in some patients

NEUROLOGIC:
[Central nervous system];
Mental retardation, mild (1 family);
[Peripheral nervous system];
Pain insensitivity, distal;
Temperature insensitivity, distal, in some patients;
Normal large myelinated fiber sensory modalities;
Normal reflexes;
Sural nerve biopsy shows selective decrease in small myelinated fibers;
Mild reduction in unmyelinated fibers

METABOLIC FEATURES:
Increased body temperature, episodic, in some patients

MISCELLANEOUS:
Onset in infancy;
Accidental injury to the self (mouth, digits) has been referred by
some as 'self-mutilation'

MOLECULAR BASIS:
Caused by mutation in the nerve growth factor-beta gene (NGFB, 162030.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 2/23/2011

*FIELD* CD
Cassandra L. Kniffin: 5/17/2004

*FIELD* ED
joanna: 08/12/2013
joanna: 2/9/2012
ckniffin: 2/23/2011
joanna: 9/13/2004
ckniffin: 9/13/2004
alopez: 8/17/2004
ckniffin: 5/18/2004

*FIELD* CN
Cassandra L. Kniffin - updated: 2/23/2011
Cassandra L. Kniffin - updated: 1/21/2005
George E. Tiller - updated: 8/17/2004

*FIELD* CD
Cassandra L. Kniffin: 5/13/2004

*FIELD* ED
terry: 03/26/2012
wwang: 2/24/2011
ckniffin: 2/23/2011
carol: 9/8/2008
ckniffin: 1/21/2005
alopez: 8/17/2004
carol: 5/21/2004
ckniffin: 5/18/2004