NDNF_HUMAN
ID NDNF_HUMAN Reviewed; 568 AA.
AC Q8TB73; A8K0Q0; Q6UWE5; Q9H5P7;
DT 11-SEP-2007, integrated into UniProtKB/Swiss-Prot.
DT 19-SEP-2006, sequence version 2.
DT 03-AUG-2022, entry version 145.
DE RecName: Full=Protein NDNF;
DE AltName: Full=Neuron-derived neurotrophic factor;
DE Flags: Precursor;
GN Name=NDNF; Synonyms=C4orf31; ORFNames=UNQ2748/PRO6487;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Amygdala, and Lung;
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., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., 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., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA 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., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Ovary;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=20969804; DOI=10.1186/1471-2202-11-137;
RA Kuang X.L., Zhao X.M., Xu H.F., Shi Y.Y., Deng J.B., Sun G.T.;
RT "Spatio-temporal expression of a novel neuron-derived neurotrophic factor
RT (NDNF) in mouse brains during development.";
RL BMC Neurosci. 11:137-137(2010).
RN [6]
RP SUBCELLULAR LOCATION, INDUCTION, AND FUNCTION.
RX PubMed=24706764; DOI=10.1074/jbc.m114.555789;
RA Ohashi K., Enomoto T., Joki Y., Shibata R., Ogura Y., Kataoka Y.,
RA Shimizu Y., Kambara T., Uemura Y., Yuasa D., Matsuo K., Hayakawa S.,
RA Hiramatsu-Ito M., Murohara T., Ouchi N.;
RT "Neuron-derived neurotrophic factor functions as a novel modulator that
RT enhances endothelial cell function and revascularization processes.";
RL J. Biol. Chem. 289:14132-14144(2014).
RN [7]
RP INVOLVEMENT IN HH25, VARIANTS HH25 62-LYS--CYS-568 DEL; SER-201 AND
RP 469-TRP--CYS-568 DEL, CHARACTERIZATION OF VARIANTS HH25 62-LYS--CYS-568
RP DEL; SER-201 AND 469-TRP--CYS-568 DEL, FUNCTION, SUBCELLULAR LOCATION, AND
RP TISSUE SPECIFICITY.
RX PubMed=31883645; DOI=10.1016/j.ajhg.2019.12.003;
RA Messina A., Pulli K., Santini S., Acierno J., Kaensaekoski J.,
RA Cassatella D., Xu C., Casoni F., Malone S.A., Ternier G., Conte D.,
RA Sidis Y., Tommiska J., Vaaralahti K., Dwyer A., Gothilf Y., Merlo G.R.,
RA Santoni F., Niederlaender N.J., Giacobini P., Raivio T., Pitteloud N.;
RT "Neuron-derived neurotrophic factor is mutated in congenital
RT hypogonadotropic hypogonadism.";
RL Am. J. Hum. Genet. 106:58-70(2020).
CC -!- FUNCTION: Secretory protein that plays a role in various cellular
CC processes (PubMed:20969804, PubMed:24706764, PubMed:31883645). Acts as
CC a chemorepellent acting on gonadotropin-releasing hormone (GnRH)
CC expressing neurons regulating their migration to the hypothalamus
CC (PubMed:31883645). Also promotes neuron migration, growth and survival
CC as well as neurite outgrowth and is involved in the development of the
CC olfactory system (PubMed:20969804, PubMed:31883645). May also act
CC through the regulation of growth factors activity and downstream
CC signaling (PubMed:31883645). Also regulates extracellular matrix
CC assembly and cell adhesiveness (By similarity). Promotes endothelial
CC cell survival, vessel formation and plays an important role in the
CC process of revascularization through NOS3-dependent mechanisms
CC (PubMed:24706764). {ECO:0000250|UniProtKB:Q8C119,
CC ECO:0000269|PubMed:20969804, ECO:0000269|PubMed:24706764,
CC ECO:0000269|PubMed:31883645}.
CC -!- SUBUNIT: Binds heparin and chondroitin sulfate.
CC {ECO:0000250|UniProtKB:Q8C119}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:20969804,
CC ECO:0000269|PubMed:24706764, ECO:0000269|PubMed:31883645}.
CC -!- TISSUE SPECIFICITY: Expressed in neurons along the gonadotropin-
CC releasing hormone (GnRH) expressing neurons migratory route.
CC {ECO:0000269|PubMed:31883645}.
CC -!- INDUCTION: Up-regulated by hypoxia (at protein level).
CC {ECO:0000269|PubMed:20969804}.
CC -!- PTM: O-glycosylated; contains heparan sulfate and chondroitin sulfate.
CC {ECO:0000250|UniProtKB:Q8C119}.
CC -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:Q8C119}.
CC -!- DISEASE: Hypogonadotropic hypogonadism 25 with anosmia (HH25)
CC [MIM:618841]: A form of hypogonadotropic hypogonadism, a group of
CC disorders characterized by absent or incomplete sexual maturation by
CC the age of 18 years, in conjunction with low levels of circulating
CC gonadotropins and testosterone, and no other abnormalities of the
CC hypothalamic-pituitary axis. In some cases, it is associated with non-
CC reproductive phenotypes, such as anosmia, cleft palate, and
CC sensorineural hearing loss. Anosmia or hyposmia is related to the
CC absence or hypoplasia of the olfactory bulbs and tracts. In the
CC presence of anosmia, idiopathic hypogonadotropic hypogonadism is
CC referred to as Kallmann syndrome, whereas in the presence of a normal
CC sense of smell, it has been termed normosmic idiopathic
CC hypogonadotropic hypogonadism (nIHH). HH25 is an autosomal dominant
CC form with anosmia, characterized by intrafamilial variable expressivity
CC and incomplete penetrance. {ECO:0000269|PubMed:31883645}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB15573.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAB15573.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AY358821; AAQ89180.1; -; mRNA.
DR EMBL; AK026844; BAB15573.1; ALT_SEQ; mRNA.
DR EMBL; AK289615; BAF82304.1; -; mRNA.
DR EMBL; CH471056; EAX05266.1; -; Genomic_DNA.
DR EMBL; BC019351; AAH19351.2; -; mRNA.
DR CCDS; CCDS3717.2; -.
DR RefSeq; NP_078850.3; NM_024574.3.
DR AlphaFoldDB; Q8TB73; -.
DR BioGRID; 122755; 15.
DR IntAct; Q8TB73; 4.
DR STRING; 9606.ENSP00000369014; -.
DR GlyGen; Q8TB73; 1 site.
DR iPTMnet; Q8TB73; -.
DR PhosphoSitePlus; Q8TB73; -.
DR BioMuta; NDNF; -.
DR DMDM; 121949126; -.
DR EPD; Q8TB73; -.
DR jPOST; Q8TB73; -.
DR MassIVE; Q8TB73; -.
DR PaxDb; Q8TB73; -.
DR PeptideAtlas; Q8TB73; -.
DR PRIDE; Q8TB73; -.
DR ProteomicsDB; 73973; -.
DR TopDownProteomics; Q8TB73; -.
DR Antibodypedia; 52933; 92 antibodies from 17 providers.
DR DNASU; 79625; -.
DR Ensembl; ENST00000379692.9; ENSP00000369014.4; ENSG00000173376.14.
DR GeneID; 79625; -.
DR KEGG; hsa:79625; -.
DR MANE-Select; ENST00000379692.9; ENSP00000369014.4; NM_024574.4; NP_078850.3.
DR UCSC; uc003idq.2; human.
DR CTD; 79625; -.
DR DisGeNET; 79625; -.
DR GeneCards; NDNF; -.
DR HGNC; HGNC:26256; NDNF.
DR HPA; ENSG00000173376; Tissue enhanced (lung, placenta, retina).
DR MalaCards; NDNF; -.
DR MIM; 616506; gene.
DR MIM; 618841; phenotype.
DR neXtProt; NX_Q8TB73; -.
DR OpenTargets; ENSG00000173376; -.
DR Orphanet; 478; Kallmann syndrome.
DR PharmGKB; PA147358639; -.
DR VEuPathDB; HostDB:ENSG00000173376; -.
DR eggNOG; KOG4806; Eukaryota.
DR GeneTree; ENSGT00390000007586; -.
DR HOGENOM; CLU_041753_0_0_1; -.
DR InParanoid; Q8TB73; -.
DR OMA; YCVVINR; -.
DR OrthoDB; 294977at2759; -.
DR PhylomeDB; Q8TB73; -.
DR TreeFam; TF313245; -.
DR PathwayCommons; Q8TB73; -.
DR SignaLink; Q8TB73; -.
DR BioGRID-ORCS; 79625; 12 hits in 1062 CRISPR screens.
DR ChiTaRS; NDNF; human.
DR GenomeRNAi; 79625; -.
DR Pharos; Q8TB73; Tbio.
DR PRO; PR:Q8TB73; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q8TB73; protein.
DR Bgee; ENSG00000173376; Expressed in renal glomerulus and 162 other tissues.
DR ExpressionAtlas; Q8TB73; baseline and differential.
DR Genevisible; Q8TB73; HS.
DR GO; GO:0031012; C:extracellular matrix; ISS:UniProtKB.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0005539; F:glycosaminoglycan binding; ISS:UniProtKB.
DR GO; GO:0008201; F:heparin binding; ISS:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IDA:UniProtKB.
DR GO; GO:0044344; P:cellular response to fibroblast growth factor stimulus; IMP:UniProtKB.
DR GO; GO:0071456; P:cellular response to hypoxia; IDA:UniProtKB.
DR GO; GO:0030198; P:extracellular matrix organization; ISS:UniProtKB.
DR GO; GO:0021828; P:gonadotrophin-releasing hormone neuronal migration to the hypothalamus; ISS:UniProtKB.
DR GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; IDA:UniProtKB.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:UniProtKB.
DR GO; GO:0001764; P:neuron migration; IDA:UniProtKB.
DR GO; GO:0007263; P:nitric oxide mediated signal transduction; IDA:UniProtKB.
DR GO; GO:0019800; P:peptide cross-linking via chondroitin 4-sulfate glycosaminoglycan; ISS:UniProtKB.
DR GO; GO:0010811; P:positive regulation of cell-substrate adhesion; ISS:UniProtKB.
DR GO; GO:0010976; P:positive regulation of neuron projection development; IDA:UniProtKB.
DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
DR GO; GO:0061042; P:vascular wound healing; ISS:UniProtKB.
DR Gene3D; 2.60.40.10; -; 1.
DR InterPro; IPR003961; FN3_dom.
DR InterPro; IPR036116; FN3_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR019326; NDNF.
DR InterPro; IPR045805; NDNF_C.
DR PANTHER; PTHR14619; PTHR14619; 1.
DR Pfam; PF10179; NDNF; 1.
DR Pfam; PF19433; NDNF_C; 1.
DR SMART; SM00060; FN3; 2.
DR SUPFAM; SSF49265; SSF49265; 1.
PE 1: Evidence at protein level;
KW Disease variant; Glycoprotein; Hypogonadotropic hypogonadism;
KW Kallmann syndrome; Neurogenesis; Reference proteome; Repeat; Secreted;
KW Signal.
FT SIGNAL 1..19
FT /evidence="ECO:0000255"
FT CHAIN 20..568
FT /note="Protein NDNF"
FT /id="PRO_0000301965"
FT DOMAIN 261..331
FT /note="Fibronectin type-III 1"
FT DOMAIN 445..564
FT /note="Fibronectin type-III 2"
FT CARBOHYD 322
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VARIANT 62..568
FT /note="Missing (in HH25; loss of protein expression)"
FT /evidence="ECO:0000269|PubMed:31883645"
FT /id="VAR_084037"
FT VARIANT 201
FT /note="T -> S (in HH25; no effect on protein abundance; no
FT effect on function in cellular response to fibroblast
FT growth factor stimulus; dbSNP:rs200466645)"
FT /evidence="ECO:0000269|PubMed:31883645"
FT /id="VAR_084038"
FT VARIANT 469..568
FT /note="Missing (in HH25; no effect on protein abundance;
FT decreased secretion; loss of function in cellular response
FT to fibroblast growth factor stimulus)"
FT /evidence="ECO:0000269|PubMed:31883645"
FT /id="VAR_084039"
FT CONFLICT 119
FT /note="N -> S (in Ref. 2; BAF82304)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 568 AA; 64673 MW; 140498575659675F CRC64;
MVLLHWCLLW LLFPLSSRTQ KLPTRDEELF QMQIRDKAFF HDSSVIPDGA EISSYLFRDT
PKRYFFVVEE DNTPLSVTVT PCDAPLEWKL SLQELPEDRS GEGSGDLEPL EQQKQQIINE
EGTELFSYKG NDVEYFISSS SPSGLYQLDL LSTEKDTHFK VYATTTPESD QPYPELPYDP
RVDVTSLGRT TVTLAWKPSP TASLLKQPIQ YCVVINKEHN FKSLCAVEAK LSADDAFMMA
PKPGLDFSPF DFAHFGFPSD NSGKERSFQA KPSPKLGRHV YSRPKVDIQK ICIGNKNIFT
VSDLKPDTQY YFDVFVVNIN SNMSTAYVGT FARTKEEAKQ KTVELKDGKI TDVFVKRKGA
KFLRFAPVSS HQKVTFFIHS CLDAVQIQVR RDGKLLLSQN VEGIQQFQLR GKPKAKYLVR
LKGNKKGASM LKILATTRPT KQSFPSLPED TRIKAFDKLR TCSSATVAWL GTQERNKFCI
YKKEVDDNYN EDQKKREQNQ CLGPDIRKKS EKVLCKYFHS QNLQKAVTTE TIKGLQPGKS
YLLDVYVIGH GGHSVKYQSK VVKTRKFC
