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 02-OCT-2024, entry version 157. 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}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 13. 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 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: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. PE 1: Evidence at protein level; KW Disease variant; Glycoprotein; Hypogonadotropic hypogonadism; KW Kallmann syndrome; Neurogenesis; Proteomics identification; KW Reference proteome; Repeat; Secreted; 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 //