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   27-MAR-2024, entry version 154.
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   GlyCosmos; Q8TB73; 1 site, No reported glycans.
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; 9606-ENSP00000369014; -.
DR   PeptideAtlas; Q8TB73; -.
DR   ProteomicsDB; 73973; -.
DR   TopDownProteomics; Q8TB73; -.
DR   Antibodypedia; 52933; 110 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   AGR; HGNC:26256; -.
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; KFCIYRK; -.
DR   OrthoDB; 2876995at2759; -.
DR   PhylomeDB; Q8TB73; -.
DR   TreeFam; TF313245; -.
DR   PathwayCommons; Q8TB73; -.
DR   SignaLink; Q8TB73; -.
DR   BioGRID-ORCS; 79625; 15 hits in 1145 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 164 other cell types or tissues.
DR   ExpressionAtlas; Q8TB73; baseline and differential.
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; Immunoglobulins; 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; NEURON-DERIVED NEUROTROPHIC FACTOR; 1.
DR   PANTHER; PTHR14619:SF1; PROTEIN NDNF; 1.
DR   Pfam; PF10179; NDNF; 1.
DR   Pfam; PF19433; NDNF_C; 1.
DR   SMART; SM00060; FN3; 2.
DR   SUPFAM; SSF49265; Fibronectin type III; 1.
DR   Genevisible; Q8TB73; HS.
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
//