Full text data of NSMF
NSMF
(NELF)
[Confidence: low (only semi-automatic identification from reviews)]
NMDA receptor synaptonuclear signaling and neuronal migration factor (Nasal embryonic luteinizing hormone-releasing hormone factor; Nasal embryonic LHRH factor)
NMDA receptor synaptonuclear signaling and neuronal migration factor (Nasal embryonic luteinizing hormone-releasing hormone factor; Nasal embryonic LHRH factor)
UniProt
Q6X4W1
ID NSMF_HUMAN Reviewed; 530 AA.
AC Q6X4W1; Q2TB96; Q6X4V7; Q6X4V8; Q6X4V9; Q8N2M2; Q96SY1; Q9NPM4;
read moreAC Q9NPP3; Q9NPS3;
DT 19-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 22-JAN-2014, entry version 87.
DE RecName: Full=NMDA receptor synaptonuclear signaling and neuronal migration factor;
DE AltName: Full=Nasal embryonic luteinizing hormone-releasing hormone factor;
DE Short=Nasal embryonic LHRH factor;
GN Name=NSMF; Synonyms=NELF;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 4 AND 5), TISSUE
RP SPECIFICITY, AND VARIANT HH9 ALA-480.
RC TISSUE=Brain;
RX PubMed=15362570; DOI=10.1007/s10038-004-0137-4;
RA Miura K., Acierno J.S. Jr., Seminara S.B.;
RT "Characterization of the human nasal embryonic LHRH factor gene, NELF,
RT and a mutation screening among 65 patients with idiopathic
RT hypogonadotropic hypogonadism (IHH).";
RL J. Hum. Genet. 49:265-268(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Embryo;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 6).
RC TISSUE=Brain, and Colon;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 241-530.
RG The European IMAGE consortium;
RL Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP FUNCTION, MUTAGENESIS OF 247-ARG--ARG-250 AND 263-ARG-LYS-264,
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=20025934; DOI=10.1016/j.mce.2009.11.016;
RA Xu N., Bhagavath B., Kim H.G., Halvorson L., Podolsky R.S.,
RA Chorich L.P., Prasad P., Xiong W.C., Cameron R.S., Layman L.C.;
RT "NELF is a nuclear protein involved in hypothalamic GnRH neuronal
RT migration.";
RL Mol. Cell. Endocrinol. 319:47-55(2010).
RN [7]
RP VARIANT HH9 ALA-480.
RX PubMed=21700882; DOI=10.1073/pnas.1102284108;
RA Tornberg J., Sykiotis G.P., Keefe K., Plummer L., Hoang X., Hall J.E.,
RA Quinton R., Seminara S.B., Hughes V., Van Vliet G., Van Uum S.,
RA Crowley W.F., Habuchi H., Kimata K., Pitteloud N., Bulow H.E.;
RT "Heparan sulfate 6-O-sulfotransferase 1, a gene involved in
RT extracellular sugar modifications, is mutated in patients with
RT idiopathic hypogonadotrophic hypogonadism.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:11524-11529(2011).
RN [8]
RP VARIANT HH9 HIS-196.
RX PubMed=23643382; DOI=10.1016/j.ajhg.2013.04.008;
RA Miraoui H., Dwyer A.A., Sykiotis G.P., Plummer L., Chung W., Feng B.,
RA Beenken A., Clarke J., Pers T.H., Dworzynski P., Keefe K.,
RA Niedziela M., Raivio T., Crowley W.F. Jr., Seminara S.B., Quinton R.,
RA Hughes V.A., Kumanov P., Young J., Yialamas M.A., Hall J.E.,
RA Van Vliet G., Chanoine J.P., Rubenstein J., Mohammadi M., Tsai P.S.,
RA Sidis Y., Lage K., Pitteloud N.;
RT "Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in
RT individuals with congenital hypogonadotropic hypogonadism.";
RL Am. J. Hum. Genet. 92:725-743(2013).
CC -!- FUNCTION: Couples NMDA-sensitive glutamate receptor signaling to
CC the nucleus and triggers long-lasting changes in the
CC cytoarchitecture of dendrites and spine synapse processes. Part of
CC the cAMP response element-binding protein (CREB) shut-off
CC signaling pathway. Stimulates outgrowth of olfactory axons and
CC migration of gonadotropin-releasing hormone (GnRH) and
CC luteinizing-hormone-releasing hormone (LHRH) neuronal cells.
CC -!- SUBUNIT: Interacts with KPNA1; the interaction occurs in a
CC calcium-independent manner after synaptic NMDA receptor
CC stimulation and is required for nuclear import of NSMF but is
CC competed by CABP1. Interacts (via the central NLS-containing motif
CC region) with CABP1 (via EF-hands 1 and 2); the interaction occurs
CC in a calcium-dependent manner after synaptic NMDA receptor
CC stimulation and prevents the nuclear import of NSMF. Cannot be
CC competed by calmodulin (By similarity).
CC -!- SUBCELLULAR LOCATION: Nucleus. Nucleus envelope (By similarity).
CC Nucleus membrane (By similarity). Nucleus matrix (By similarity).
CC Cytoplasm. Cytoplasm, cell cortex (By similarity). Cytoplasm,
CC cytoskeleton (By similarity). Cell membrane; Peripheral membrane
CC protein. Cell projection, dendrite (By similarity). Cell junction,
CC synapse (By similarity). Cell junction, synapse, synaptosome (By
CC similarity). Cell junction, synapse, postsynaptic cell membrane,
CC postsynaptic density (By similarity). Membrane (By similarity).
CC Note=Found on the outside of the luteinizing-hormone-releasing
CC hormone (LHRH) cell membrane and axons projecting from the
CC olfactory pit and epithelium. Associates with transcriptionally
CC active chromatin regions. Detected at the nuclear membranes of CA1
CC neurons. Cortical cytoskeleton. Localized in proximal apical
CC dendrites. Colocalizes with CABP1 in dendrites and dendritic
CC spines. Myristoylation is a prerequisite for extranuclear
CC localization. Translocates from dendrites to the nucleus during
CC NMDA receptor-dependent long-term potentiation (LTP) induction of
CC synaptic transmission at Schaffer collateral/CA1 synapses of
CC hippocampal primary neurons and in a importin-dependent manner (By
CC similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=NELF-v1;
CC IsoId=Q6X4W1-1; Sequence=Displayed;
CC Name=2; Synonyms=NELF-v2;
CC IsoId=Q6X4W1-2; Sequence=VSP_014759;
CC Name=3; Synonyms=NELF-v3;
CC IsoId=Q6X4W1-3; Sequence=VSP_014760;
CC Name=4; Synonyms=NELF-v4;
CC IsoId=Q6X4W1-4; Sequence=VSP_014761;
CC Name=5; Synonyms=NELF-v5;
CC IsoId=Q6X4W1-5; Sequence=VSP_014762, VSP_014763;
CC Name=6;
CC IsoId=Q6X4W1-6; Sequence=VSP_014759, VSP_014760;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Highly expressed in adult and fetal brain.
CC Weakly expressed in heart, liver, spleen, testis, small intestine,
CC skeletal muscle, peripheral white blood cells and kidney.
CC -!- PTM: Proteolytically processed after NMDA receptor activation.
CC Cleaved in a calcium-dependent and calpain-sensitive manner.
CC Calpain cleavage is essential for the translocation process from
CC dendrites to the nucleus (By similarity).
CC -!- DISEASE: Hypogonadotropic hypogonadism 9 with or without anosmia
CC (HH9) [MIM:614838]: A disorder characterized by absent or
CC incomplete sexual maturation by the age of 18 years, in
CC conjunction with low levels of circulating gonadotropins and
CC testosterone and no other abnormalities of the hypothalamic-
CC 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.
CC Hypogonadism is due to deficiency in gonadotropin-releasing
CC hormone and probably results from a failure of embryonic migration
CC of gonadotropin-releasing hormone-synthesizing neurons. In the
CC presence of anosmia, idiopathic hypogonadotropic hypogonadism is
CC referred to as Kallmann syndrome, whereas in the presence of a
CC normal sense of smell, it has been termed normosmic idiopathic
CC hypogonadotropic hypogonadism (nIHH). Note=The disease is caused
CC by mutations affecting distinct genetic loci, including the gene
CC represented in this entry. The genetics of hypogonadotropic
CC hypogonadism involves various modes of transmission. Oligogenic
CC inheritance has been reported in some patients carrying mutations
CC in NSMF as well as in other HH-associated genes including FGFR1
CC (PubMed:23643382).
CC -!- MISCELLANEOUS: NSMF mRNAs expressed in the hippocampus exhibit a
CC prominent dendritic localization which is mediated by a dendritic
CC targeting element (DTE) residing in the 3'-untranslated region
CC (3'UTR). Transport from dendrites to the nucleus is induced by
CC NMDA receptor activation and results in a rapid stripping of
CC synaptic contacts and a reduction of dendritic complexity (By
CC similarity).
CC -!- SIMILARITY: Belongs to the NSMF family.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB55139.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=CAI14577.1; Type=Erroneous gene model prediction;
CC Sequence=CAI14578.1; Type=Erroneous gene model prediction;
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DR EMBL; AY255128; AAP83576.1; -; mRNA.
DR EMBL; AY255129; AAP83577.1; -; mRNA.
DR EMBL; AY255130; AAP83578.1; -; mRNA.
DR EMBL; AY255131; AAP83579.1; -; mRNA.
DR EMBL; AY255132; AAP83580.1; -; mRNA.
DR EMBL; AK027474; BAB55139.1; ALT_INIT; mRNA.
DR EMBL; AK074602; BAC11086.1; -; mRNA.
DR EMBL; AL365502; CAI14577.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AL365502; CAI14578.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BC072412; AAH72412.1; -; mRNA.
DR EMBL; BC110498; AAI10499.1; -; mRNA.
DR EMBL; AL389944; CAB97524.1; -; mRNA.
DR EMBL; AL389946; CAB97525.1; -; mRNA.
DR EMBL; AL389945; CAB97542.1; -; mRNA.
DR PIR; T17341; T17341.
DR RefSeq; NP_001124441.1; NM_001130969.1.
DR RefSeq; NP_001124442.1; NM_001130970.1.
DR RefSeq; NP_001124443.1; NM_001130971.1.
DR RefSeq; NP_001171535.1; NM_001178064.1.
DR RefSeq; NP_056352.3; NM_015537.4.
DR UniGene; Hs.455336; -.
DR ProteinModelPortal; Q6X4W1; -.
DR IntAct; Q6X4W1; 1.
DR MINT; MINT-1371927; -.
DR PhosphoSite; Q6X4W1; -.
DR DMDM; 71152011; -.
DR PaxDb; Q6X4W1; -.
DR PRIDE; Q6X4W1; -.
DR Ensembl; ENST00000265663; ENSP00000265663; ENSG00000165802.
DR Ensembl; ENST00000339554; ENSP00000342966; ENSG00000165802.
DR Ensembl; ENST00000371472; ENSP00000360527; ENSG00000165802.
DR Ensembl; ENST00000371473; ENSP00000360528; ENSG00000165802.
DR Ensembl; ENST00000371474; ENSP00000360529; ENSG00000165802.
DR Ensembl; ENST00000371475; ENSP00000360530; ENSG00000165802.
DR Ensembl; ENST00000437259; ENSP00000412007; ENSG00000165802.
DR GeneID; 26012; -.
DR KEGG; hsa:26012; -.
DR UCSC; uc004cna.3; human.
DR CTD; 26012; -.
DR GeneCards; GC09M140343; -.
DR HGNC; HGNC:29843; NSMF.
DR HPA; HPA044316; -.
DR MIM; 608137; gene.
DR MIM; 614838; phenotype.
DR neXtProt; NX_Q6X4W1; -.
DR Orphanet; 478; Kallmann syndrome.
DR Orphanet; 432; Normosmic congenital hypogonadotropic hypogonadism.
DR PharmGKB; PA134917144; -.
DR eggNOG; NOG42206; -.
DR HOGENOM; HOG000231556; -.
DR HOVERGEN; HBG080324; -.
DR InParanoid; Q6X4W1; -.
DR OMA; DIPIRTW; -.
DR OrthoDB; EOG7M98G2; -.
DR GeneWiki; Nasal_embryonic_LHRH_factor; -.
DR GenomeRNAi; 26012; -.
DR NextBio; 47766; -.
DR PRO; PR:Q6X4W1; -.
DR ArrayExpress; Q6X4W1; -.
DR Bgee; Q6X4W1; -.
DR Genevestigator; Q6X4W1; -.
DR GO; GO:0097440; C:apical dendrite; ISS:UniProtKB.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
DR GO; GO:0030863; C:cortical cytoskeleton; ISS:UniProtKB.
DR GO; GO:0005719; C:nuclear euchromatin; ISS:UniProtKB.
DR GO; GO:0016363; C:nuclear matrix; ISS:UniProtKB.
DR GO; GO:0031965; C:nuclear membrane; ISS:UniProtKB.
DR GO; GO:0043204; C:perikaryon; ISS:UniProtKB.
DR GO; GO:0014069; C:postsynaptic density; ISS:UniProtKB.
DR GO; GO:0045211; C:postsynaptic membrane; IEA:UniProtKB-KW.
DR GO; GO:0048306; F:calcium-dependent protein binding; ISS:UniProtKB.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; ISS:UniProtKB.
DR GO; GO:0071257; P:cellular response to electrical stimulus; ISS:UniProtKB.
DR GO; GO:0071371; P:cellular response to gonadotropin stimulus; ISS:UniProtKB.
DR GO; GO:2001224; P:positive regulation of neuron migration; IMP:UniProtKB.
DR GO; GO:0035307; P:positive regulation of protein dephosphorylation; ISS:UniProtKB.
DR GO; GO:0048814; P:regulation of dendrite morphogenesis; ISS:UniProtKB.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:0048168; P:regulation of neuronal synaptic plasticity; ISS:UniProtKB.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell junction; Cell membrane; Cell projection;
KW Complete proteome; Cytoplasm; Cytoskeleton; Disease mutation;
KW Hypogonadotropic hypogonadism; Kallmann syndrome; Lipoprotein;
KW Membrane; Myristate; Nucleus; Polymorphism;
KW Postsynaptic cell membrane; Reference proteome; Synapse; Synaptosome.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 530 NMDA receptor synaptonuclear signaling
FT and neuronal migration factor.
FT /FTId=PRO_0000096778.
FT REGION 2 233 Necessary and sufficient to elicit
FT dendritic processes and synaptic contacts
FT (By similarity).
FT MOTIF 247 250 Nuclear localization signal.
FT LIPID 2 2 N-myristoyl glycine (By similarity).
FT VAR_SEQ 236 237 Missing (in isoform 2 and isoform 6).
FT /FTId=VSP_014759.
FT VAR_SEQ 238 260 Missing (in isoform 3 and isoform 6).
FT /FTId=VSP_014760.
FT VAR_SEQ 278 307 Missing (in isoform 4).
FT /FTId=VSP_014761.
FT VAR_SEQ 350 402 LISSKVPKAEYIPTIIRRDDPSIIPILYDHEHATFEDILEE
FT IERKLNVYHKGA -> VRPSPGSAPLHPEQDSAPTRVQPAL
FT PGTTQPSPAAWGRVSHRAIPLGCLAARR (in isoform
FT 5).
FT /FTId=VSP_014762.
FT VAR_SEQ 403 530 Missing (in isoform 5).
FT /FTId=VSP_014763.
FT VARIANT 196 196 R -> H (in HH9; phenotype consistent with
FT Kallmann syndrome; the patient also
FT carries a mutation in FGFR1).
FT /FTId=VAR_069967.
FT VARIANT 480 480 T -> A (in HH9; sporadic case).
FT /FTId=VAR_023003.
FT VARIANT 511 511 L -> V (in dbSNP:rs34177733).
FT /FTId=VAR_059699.
FT MUTAGEN 247 250 RRKR->AAKA: Localizes predominantly in
FT the cytoplasm.
FT MUTAGEN 263 264 RK->AA: Localizes both in the cytoplasm
FT and the nucleus.
SQ SEQUENCE 530 AA; 60143 MW; 7A18FDFD1F21A2D9 CRC64;
MGAAASRRRA LRSEAMSSVA AKVRAARAFG EYLSQSHPEN RNGADHLLAD AYSGHDGSPE
MQPAPQNKRR LSLVSNGCYE GSLSEEPSIR KPAGEGPQPR VYTISGEPAL LPSPEAEAIE
LAVVKGRRQR HPHHHSQPLR ASPGGSREDV SRPCQSWAGS RQGSKECPGC AQLAPGPTPR
AFGLDQPPLP ETSGRRKKLE RMYSVDRVSD DIPIRTWFPK ENLFSFQTAT TTMQAISVFR
GYAERKRRKR ENDSASVIQR NFRKHLRMVG SRRVKAQTFA ERRERSFSRS WSDPTPMKAD
TSHDSRDSSD LQSSHCTLDE AFEDLDWDTE KGLEAVACDT EGFVPPKVML ISSKVPKAEY
IPTIIRRDDP SIIPILYDHE HATFEDILEE IERKLNVYHK GAKIWKMLIF CQGGPGHLYL
LKNKVATFAK VEKEEDMIHF WKRLSRLMSK VNPEPNVIHI MGCYILGNPN GEKLFQNLRT
LMTPYRVTFE SPLELSAQGK QMIETYFDFR LYRLWKSRQH SKLLDFDDVL
//
ID NSMF_HUMAN Reviewed; 530 AA.
AC Q6X4W1; Q2TB96; Q6X4V7; Q6X4V8; Q6X4V9; Q8N2M2; Q96SY1; Q9NPM4;
read moreAC Q9NPP3; Q9NPS3;
DT 19-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 22-JAN-2014, entry version 87.
DE RecName: Full=NMDA receptor synaptonuclear signaling and neuronal migration factor;
DE AltName: Full=Nasal embryonic luteinizing hormone-releasing hormone factor;
DE Short=Nasal embryonic LHRH factor;
GN Name=NSMF; Synonyms=NELF;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 4 AND 5), TISSUE
RP SPECIFICITY, AND VARIANT HH9 ALA-480.
RC TISSUE=Brain;
RX PubMed=15362570; DOI=10.1007/s10038-004-0137-4;
RA Miura K., Acierno J.S. Jr., Seminara S.B.;
RT "Characterization of the human nasal embryonic LHRH factor gene, NELF,
RT and a mutation screening among 65 patients with idiopathic
RT hypogonadotropic hypogonadism (IHH).";
RL J. Hum. Genet. 49:265-268(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Embryo;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 6).
RC TISSUE=Brain, and Colon;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 241-530.
RG The European IMAGE consortium;
RL Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP FUNCTION, MUTAGENESIS OF 247-ARG--ARG-250 AND 263-ARG-LYS-264,
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=20025934; DOI=10.1016/j.mce.2009.11.016;
RA Xu N., Bhagavath B., Kim H.G., Halvorson L., Podolsky R.S.,
RA Chorich L.P., Prasad P., Xiong W.C., Cameron R.S., Layman L.C.;
RT "NELF is a nuclear protein involved in hypothalamic GnRH neuronal
RT migration.";
RL Mol. Cell. Endocrinol. 319:47-55(2010).
RN [7]
RP VARIANT HH9 ALA-480.
RX PubMed=21700882; DOI=10.1073/pnas.1102284108;
RA Tornberg J., Sykiotis G.P., Keefe K., Plummer L., Hoang X., Hall J.E.,
RA Quinton R., Seminara S.B., Hughes V., Van Vliet G., Van Uum S.,
RA Crowley W.F., Habuchi H., Kimata K., Pitteloud N., Bulow H.E.;
RT "Heparan sulfate 6-O-sulfotransferase 1, a gene involved in
RT extracellular sugar modifications, is mutated in patients with
RT idiopathic hypogonadotrophic hypogonadism.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:11524-11529(2011).
RN [8]
RP VARIANT HH9 HIS-196.
RX PubMed=23643382; DOI=10.1016/j.ajhg.2013.04.008;
RA Miraoui H., Dwyer A.A., Sykiotis G.P., Plummer L., Chung W., Feng B.,
RA Beenken A., Clarke J., Pers T.H., Dworzynski P., Keefe K.,
RA Niedziela M., Raivio T., Crowley W.F. Jr., Seminara S.B., Quinton R.,
RA Hughes V.A., Kumanov P., Young J., Yialamas M.A., Hall J.E.,
RA Van Vliet G., Chanoine J.P., Rubenstein J., Mohammadi M., Tsai P.S.,
RA Sidis Y., Lage K., Pitteloud N.;
RT "Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in
RT individuals with congenital hypogonadotropic hypogonadism.";
RL Am. J. Hum. Genet. 92:725-743(2013).
CC -!- FUNCTION: Couples NMDA-sensitive glutamate receptor signaling to
CC the nucleus and triggers long-lasting changes in the
CC cytoarchitecture of dendrites and spine synapse processes. Part of
CC the cAMP response element-binding protein (CREB) shut-off
CC signaling pathway. Stimulates outgrowth of olfactory axons and
CC migration of gonadotropin-releasing hormone (GnRH) and
CC luteinizing-hormone-releasing hormone (LHRH) neuronal cells.
CC -!- SUBUNIT: Interacts with KPNA1; the interaction occurs in a
CC calcium-independent manner after synaptic NMDA receptor
CC stimulation and is required for nuclear import of NSMF but is
CC competed by CABP1. Interacts (via the central NLS-containing motif
CC region) with CABP1 (via EF-hands 1 and 2); the interaction occurs
CC in a calcium-dependent manner after synaptic NMDA receptor
CC stimulation and prevents the nuclear import of NSMF. Cannot be
CC competed by calmodulin (By similarity).
CC -!- SUBCELLULAR LOCATION: Nucleus. Nucleus envelope (By similarity).
CC Nucleus membrane (By similarity). Nucleus matrix (By similarity).
CC Cytoplasm. Cytoplasm, cell cortex (By similarity). Cytoplasm,
CC cytoskeleton (By similarity). Cell membrane; Peripheral membrane
CC protein. Cell projection, dendrite (By similarity). Cell junction,
CC synapse (By similarity). Cell junction, synapse, synaptosome (By
CC similarity). Cell junction, synapse, postsynaptic cell membrane,
CC postsynaptic density (By similarity). Membrane (By similarity).
CC Note=Found on the outside of the luteinizing-hormone-releasing
CC hormone (LHRH) cell membrane and axons projecting from the
CC olfactory pit and epithelium. Associates with transcriptionally
CC active chromatin regions. Detected at the nuclear membranes of CA1
CC neurons. Cortical cytoskeleton. Localized in proximal apical
CC dendrites. Colocalizes with CABP1 in dendrites and dendritic
CC spines. Myristoylation is a prerequisite for extranuclear
CC localization. Translocates from dendrites to the nucleus during
CC NMDA receptor-dependent long-term potentiation (LTP) induction of
CC synaptic transmission at Schaffer collateral/CA1 synapses of
CC hippocampal primary neurons and in a importin-dependent manner (By
CC similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=NELF-v1;
CC IsoId=Q6X4W1-1; Sequence=Displayed;
CC Name=2; Synonyms=NELF-v2;
CC IsoId=Q6X4W1-2; Sequence=VSP_014759;
CC Name=3; Synonyms=NELF-v3;
CC IsoId=Q6X4W1-3; Sequence=VSP_014760;
CC Name=4; Synonyms=NELF-v4;
CC IsoId=Q6X4W1-4; Sequence=VSP_014761;
CC Name=5; Synonyms=NELF-v5;
CC IsoId=Q6X4W1-5; Sequence=VSP_014762, VSP_014763;
CC Name=6;
CC IsoId=Q6X4W1-6; Sequence=VSP_014759, VSP_014760;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Highly expressed in adult and fetal brain.
CC Weakly expressed in heart, liver, spleen, testis, small intestine,
CC skeletal muscle, peripheral white blood cells and kidney.
CC -!- PTM: Proteolytically processed after NMDA receptor activation.
CC Cleaved in a calcium-dependent and calpain-sensitive manner.
CC Calpain cleavage is essential for the translocation process from
CC dendrites to the nucleus (By similarity).
CC -!- DISEASE: Hypogonadotropic hypogonadism 9 with or without anosmia
CC (HH9) [MIM:614838]: A disorder characterized by absent or
CC incomplete sexual maturation by the age of 18 years, in
CC conjunction with low levels of circulating gonadotropins and
CC testosterone and no other abnormalities of the hypothalamic-
CC 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.
CC Hypogonadism is due to deficiency in gonadotropin-releasing
CC hormone and probably results from a failure of embryonic migration
CC of gonadotropin-releasing hormone-synthesizing neurons. In the
CC presence of anosmia, idiopathic hypogonadotropic hypogonadism is
CC referred to as Kallmann syndrome, whereas in the presence of a
CC normal sense of smell, it has been termed normosmic idiopathic
CC hypogonadotropic hypogonadism (nIHH). Note=The disease is caused
CC by mutations affecting distinct genetic loci, including the gene
CC represented in this entry. The genetics of hypogonadotropic
CC hypogonadism involves various modes of transmission. Oligogenic
CC inheritance has been reported in some patients carrying mutations
CC in NSMF as well as in other HH-associated genes including FGFR1
CC (PubMed:23643382).
CC -!- MISCELLANEOUS: NSMF mRNAs expressed in the hippocampus exhibit a
CC prominent dendritic localization which is mediated by a dendritic
CC targeting element (DTE) residing in the 3'-untranslated region
CC (3'UTR). Transport from dendrites to the nucleus is induced by
CC NMDA receptor activation and results in a rapid stripping of
CC synaptic contacts and a reduction of dendritic complexity (By
CC similarity).
CC -!- SIMILARITY: Belongs to the NSMF family.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB55139.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=CAI14577.1; Type=Erroneous gene model prediction;
CC Sequence=CAI14578.1; Type=Erroneous gene model prediction;
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DR EMBL; AY255128; AAP83576.1; -; mRNA.
DR EMBL; AY255129; AAP83577.1; -; mRNA.
DR EMBL; AY255130; AAP83578.1; -; mRNA.
DR EMBL; AY255131; AAP83579.1; -; mRNA.
DR EMBL; AY255132; AAP83580.1; -; mRNA.
DR EMBL; AK027474; BAB55139.1; ALT_INIT; mRNA.
DR EMBL; AK074602; BAC11086.1; -; mRNA.
DR EMBL; AL365502; CAI14577.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AL365502; CAI14578.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BC072412; AAH72412.1; -; mRNA.
DR EMBL; BC110498; AAI10499.1; -; mRNA.
DR EMBL; AL389944; CAB97524.1; -; mRNA.
DR EMBL; AL389946; CAB97525.1; -; mRNA.
DR EMBL; AL389945; CAB97542.1; -; mRNA.
DR PIR; T17341; T17341.
DR RefSeq; NP_001124441.1; NM_001130969.1.
DR RefSeq; NP_001124442.1; NM_001130970.1.
DR RefSeq; NP_001124443.1; NM_001130971.1.
DR RefSeq; NP_001171535.1; NM_001178064.1.
DR RefSeq; NP_056352.3; NM_015537.4.
DR UniGene; Hs.455336; -.
DR ProteinModelPortal; Q6X4W1; -.
DR IntAct; Q6X4W1; 1.
DR MINT; MINT-1371927; -.
DR PhosphoSite; Q6X4W1; -.
DR DMDM; 71152011; -.
DR PaxDb; Q6X4W1; -.
DR PRIDE; Q6X4W1; -.
DR Ensembl; ENST00000265663; ENSP00000265663; ENSG00000165802.
DR Ensembl; ENST00000339554; ENSP00000342966; ENSG00000165802.
DR Ensembl; ENST00000371472; ENSP00000360527; ENSG00000165802.
DR Ensembl; ENST00000371473; ENSP00000360528; ENSG00000165802.
DR Ensembl; ENST00000371474; ENSP00000360529; ENSG00000165802.
DR Ensembl; ENST00000371475; ENSP00000360530; ENSG00000165802.
DR Ensembl; ENST00000437259; ENSP00000412007; ENSG00000165802.
DR GeneID; 26012; -.
DR KEGG; hsa:26012; -.
DR UCSC; uc004cna.3; human.
DR CTD; 26012; -.
DR GeneCards; GC09M140343; -.
DR HGNC; HGNC:29843; NSMF.
DR HPA; HPA044316; -.
DR MIM; 608137; gene.
DR MIM; 614838; phenotype.
DR neXtProt; NX_Q6X4W1; -.
DR Orphanet; 478; Kallmann syndrome.
DR Orphanet; 432; Normosmic congenital hypogonadotropic hypogonadism.
DR PharmGKB; PA134917144; -.
DR eggNOG; NOG42206; -.
DR HOGENOM; HOG000231556; -.
DR HOVERGEN; HBG080324; -.
DR InParanoid; Q6X4W1; -.
DR OMA; DIPIRTW; -.
DR OrthoDB; EOG7M98G2; -.
DR GeneWiki; Nasal_embryonic_LHRH_factor; -.
DR GenomeRNAi; 26012; -.
DR NextBio; 47766; -.
DR PRO; PR:Q6X4W1; -.
DR ArrayExpress; Q6X4W1; -.
DR Bgee; Q6X4W1; -.
DR Genevestigator; Q6X4W1; -.
DR GO; GO:0097440; C:apical dendrite; ISS:UniProtKB.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
DR GO; GO:0030863; C:cortical cytoskeleton; ISS:UniProtKB.
DR GO; GO:0005719; C:nuclear euchromatin; ISS:UniProtKB.
DR GO; GO:0016363; C:nuclear matrix; ISS:UniProtKB.
DR GO; GO:0031965; C:nuclear membrane; ISS:UniProtKB.
DR GO; GO:0043204; C:perikaryon; ISS:UniProtKB.
DR GO; GO:0014069; C:postsynaptic density; ISS:UniProtKB.
DR GO; GO:0045211; C:postsynaptic membrane; IEA:UniProtKB-KW.
DR GO; GO:0048306; F:calcium-dependent protein binding; ISS:UniProtKB.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; ISS:UniProtKB.
DR GO; GO:0071257; P:cellular response to electrical stimulus; ISS:UniProtKB.
DR GO; GO:0071371; P:cellular response to gonadotropin stimulus; ISS:UniProtKB.
DR GO; GO:2001224; P:positive regulation of neuron migration; IMP:UniProtKB.
DR GO; GO:0035307; P:positive regulation of protein dephosphorylation; ISS:UniProtKB.
DR GO; GO:0048814; P:regulation of dendrite morphogenesis; ISS:UniProtKB.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:0048168; P:regulation of neuronal synaptic plasticity; ISS:UniProtKB.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell junction; Cell membrane; Cell projection;
KW Complete proteome; Cytoplasm; Cytoskeleton; Disease mutation;
KW Hypogonadotropic hypogonadism; Kallmann syndrome; Lipoprotein;
KW Membrane; Myristate; Nucleus; Polymorphism;
KW Postsynaptic cell membrane; Reference proteome; Synapse; Synaptosome.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 530 NMDA receptor synaptonuclear signaling
FT and neuronal migration factor.
FT /FTId=PRO_0000096778.
FT REGION 2 233 Necessary and sufficient to elicit
FT dendritic processes and synaptic contacts
FT (By similarity).
FT MOTIF 247 250 Nuclear localization signal.
FT LIPID 2 2 N-myristoyl glycine (By similarity).
FT VAR_SEQ 236 237 Missing (in isoform 2 and isoform 6).
FT /FTId=VSP_014759.
FT VAR_SEQ 238 260 Missing (in isoform 3 and isoform 6).
FT /FTId=VSP_014760.
FT VAR_SEQ 278 307 Missing (in isoform 4).
FT /FTId=VSP_014761.
FT VAR_SEQ 350 402 LISSKVPKAEYIPTIIRRDDPSIIPILYDHEHATFEDILEE
FT IERKLNVYHKGA -> VRPSPGSAPLHPEQDSAPTRVQPAL
FT PGTTQPSPAAWGRVSHRAIPLGCLAARR (in isoform
FT 5).
FT /FTId=VSP_014762.
FT VAR_SEQ 403 530 Missing (in isoform 5).
FT /FTId=VSP_014763.
FT VARIANT 196 196 R -> H (in HH9; phenotype consistent with
FT Kallmann syndrome; the patient also
FT carries a mutation in FGFR1).
FT /FTId=VAR_069967.
FT VARIANT 480 480 T -> A (in HH9; sporadic case).
FT /FTId=VAR_023003.
FT VARIANT 511 511 L -> V (in dbSNP:rs34177733).
FT /FTId=VAR_059699.
FT MUTAGEN 247 250 RRKR->AAKA: Localizes predominantly in
FT the cytoplasm.
FT MUTAGEN 263 264 RK->AA: Localizes both in the cytoplasm
FT and the nucleus.
SQ SEQUENCE 530 AA; 60143 MW; 7A18FDFD1F21A2D9 CRC64;
MGAAASRRRA LRSEAMSSVA AKVRAARAFG EYLSQSHPEN RNGADHLLAD AYSGHDGSPE
MQPAPQNKRR LSLVSNGCYE GSLSEEPSIR KPAGEGPQPR VYTISGEPAL LPSPEAEAIE
LAVVKGRRQR HPHHHSQPLR ASPGGSREDV SRPCQSWAGS RQGSKECPGC AQLAPGPTPR
AFGLDQPPLP ETSGRRKKLE RMYSVDRVSD DIPIRTWFPK ENLFSFQTAT TTMQAISVFR
GYAERKRRKR ENDSASVIQR NFRKHLRMVG SRRVKAQTFA ERRERSFSRS WSDPTPMKAD
TSHDSRDSSD LQSSHCTLDE AFEDLDWDTE KGLEAVACDT EGFVPPKVML ISSKVPKAEY
IPTIIRRDDP SIIPILYDHE HATFEDILEE IERKLNVYHK GAKIWKMLIF CQGGPGHLYL
LKNKVATFAK VEKEEDMIHF WKRLSRLMSK VNPEPNVIHI MGCYILGNPN GEKLFQNLRT
LMTPYRVTFE SPLELSAQGK QMIETYFDFR LYRLWKSRQH SKLLDFDDVL
//
MIM
608137
*RECORD*
*FIELD* NO
608137
*FIELD* TI
*608137 NASAL EMBRYONIC LHRH FACTOR; NELF
;;NASAL EMBRYONIC LUTEINIZING HORMONE-RELEASING HORMONE FACTOR
read more*FIELD* TX
CLONING
Kramer and Wray (2000) cloned mouse Nelf by differential screening of
migrating (3.5 days in vitro) versus nonmigrating (10.5 days in vitro)
primary luteinizing hormone-releasing hormone (LHRH; 152760) neurons.
Nelf was expressed in peripheral and central nervous system tissues
during embryonic development, including olfactory sensory cells and LHRH
cells.
Using RT-PCR on a fetal brain cDNA library, Miura et al. (2004) detected
5 alternatively spliced variants of NELF. One of the variants, NELF-v1,
has 93 to 94% identity at the amino acid level to mouse and rat Nelf,
and 4 other transcripts are also highly conserved among human, rat, and
mouse. A 3.0-kb transcript is expressed most highly in the adult and
fetal brain, testis, and kidney, indicating that NELF plays a role in
the function of these tissues.
GENE FUNCTION
Kramer and Wray (2000) presented evidence that mouse Nelf is a guidance
molecule for olfactory axon projections and plays a role in the
neurophilic migration of LHRH cells.
GENE STRUCTURE
Miura et al. (2004) determined that the NELF gene contains 16 exons with
a 1,590-bp open reading frame encoding 530 amino acids.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the NELF
gene to chromosome 9 (TMAP IB1002).
Miura et al. (2004) stated that the NELF gene maps to 9q34.3.
MOLECULAR GENETICS
Because the mouse Nelf gene encodes a guidance molecule for the
migration of the olfactory axon and gonadotropin-releasing hormone
neurons, its human homolog is a candidate gene for hypogonadotropic
hypogonadism and Kallmann syndrome (see HH9, 614838). Miura et al.
(2004) reported studies of NELF, including mutation analysis, in 65
patients with hypogonadotropic hypogonadism. In one of the patients,
they identified a thr480-to-ala mutation in the NELF gene (608137.0001).
The mutation was not found in 100 normal control individuals.
In a family in which the proband had severe Kallmann syndrome, his
father had a history of delayed puberty and congenital anosmia, his
mother had clinodactyly and Duane ocular retraction syndrome (see
126800), his sister had midline defects with a bifid nose and
high-arched palate, and his brother had clinodactyly alone, Pitteloud et
al. (2007) identified heterozygosity for a missense mutation in the
FGFR1 gene (L342S; 136350.0017) in the proband, his father, and his
sister. Heterozygosity for an additional mutation, an 8-bp intronic
deletion in the NELF gene (608137.0002), was identified in the proband,
his mother, and his brother. Pitteloud et al. (2007) concluded that
mutations in 2 different genes can synergize to produce a more severe
phenotype in families with hypogonadotropic hypogonadism than either
alone, and that this digenic model may account for some of the
phenotypic heterogeneity seen in GnRH deficiency.
In a 44-year-old man with anosmic hypogonadotropic hypogonadism and in
his unaffected brother, Tornberg et al. (2011) identified heterozygosity
for a missense mutation in the HS6ST1 gene (604846.0001). Because of the
reduced penetrance displayed in the family and phenotypic variability
seen among other HH patients carrying the same HS6ST1 mutation, the
authors analyzed 8 additional known HH-associated genes and detected a
missense mutation in NELF that was present only in the affected brother
(608137.0001). Tornberg et al. (2011) concluded that HH is an oligogenic
disorder in which a limited number of genes contribute pathogenic
alleles to the genetic network responsible for neuroendocrine control of
human reproduction.
*FIELD* AV
.0001
HYPOGONADOTROPIC HYPOGONADISM 9 WITHOUT ANOSMIA, SUSCEPTIBILITY TO
NELF, THR480ALA
In a sporadic case of hypogonadotropic hypogonadism (HH9; 614838), Miura
et al. (2004) identified a heterozygous 1438A-G transition at the donor
splice site in exon 15 of the NELF gene, resulting in a thr480-to-ala
(T480A) mutation. This amino acid substitution switches from a polar
side chain in threonine to a nonpolar side chain in alanine. As the
mutation was not found in any of 100 control individuals, and thr480 is
highly conserved among mouse, rat, and human, Miura et al. (2004)
suggested that T480A was associated with the pathogenesis of
hypogonadotropic hypogonadism in this case.
In a 44-year-old man with anosmic hypogonadotropic hypogonadism and in
his unaffected brother, Tornberg et al. (2011) identified heterozygosity
for a missense mutation in the HS6ST1 gene (604846.0001). Because of the
reduced penetrance displayed in the family and phenotypic variability
seen among other HH patients carrying the same HS6ST1 mutation, the
authors analyzed 8 additional known HH-associated genes and detected the
T480A mutation in NELF in the affected brother but not in his unaffected
sib.
.0002
HYPOGONADOTROPIC HYPOGONADISM 9 WITH ANOSMIA, SUSCEPTIBILITY TO
NELF, 8-BP DEL, IVS9, -14
In a family in which the proband had severe Kallmann syndrome (614838),
his father had a history of delayed puberty and congenital anosmia, his
mother had clinodactyly and Duane ocular retraction syndrome, his sister
had midline defects with a bifid nose and high-arched palate, and his
brother had clinodactyly alone, Pitteloud et al. (2007) identified
heterozygosity for an intronic 8-bp deletion ending 14 bp before exon 10
(1159-14_-22del), resulting in a splicing defect of exon 10 and causing
a premature stop codon, in the proband, his mother, and his brother. The
deletion was not found in 384 controls. Heterozygosity for an additional
missense mutation in the FGFR1 gene (L342S; 136350.0017) was identified
in the proband, his father, and his sister. Pitteloud et al. (2007)
concluded that mutations in 2 different genes can synergize to produce a
more severe phenotype in families with hypogonadotropic hypogonadism
than either alone, and that this digenic model may account for some of
the phenotypic heterogeneity seen in GnRH deficiency.
*FIELD* RF
1. Kramer, P. R.; Wray, S.: Novel gene expressed in nasal region
influences outgrowth of olfactory axons and migration of luteinizing
hormone-releasing hormone (LHRH) neurons. Genes Dev. 14: 1824-1834,
2000.
2. Miura, K.; Acierno, J. S., Jr.; Seminara, S. B.: Characterization
of the human nasal embryonic LHRH factor gene, NELF, and a mutation
screening among 65 patients with idiopathic hypogonadotropic hypogonadism
(IHH). J. Hum. Genet. 49: 265-268, 2004.
3. Pitteloud, N.; Quinton, R.; Pearce, S.; Raivio, T.; Acierno, J.;
Dwyer, A.; Plummer, L.; Hughes, V.; Seminara, S.; Cheng, Y.-Z.; Li,
W.-P.; Maccoll, G.; Eliseenkova, A. V.; Olsen, S. K.; Ibrahimi, O.
A.; Hayes, F. J.; Boepple, P.; Hall, J. E.; Bouloux, P.; Mohammadi,
M.; Crowley, W., Jr.: Digenic mutations account for variable phenotypes
in idiopathic hypogonadotropic hypogonadism. J. Clin. Invest. 117:
457-463, 2007.
4. Tornberg, J.; Sykiotis, G. P.; Keefe, K.; Plummer, L.; Hoang, X.;
Hall, J. E.; Quinton, R.; Seminara, S. B.; Hughes, V.; Van Vliet,
G.; Van Uum, S.; Crowley, W. F.; Habuchi, H.; Kimata, K.; Pitteloud,
N.; Bulow, H. E.: Heparan sulfate 6-O-sulfotransferase 1, a gene
involved in extracellular sugar modifications, is mutated in patients
with idiopathic hypogonadotrophic hypogonadism. Proc. Nat. Acad.
Sci. 108: 11524-11529, 2011.
*FIELD* CN
Marla J. F. O'Neill - updated: 10/17/2012
Marla J. F. O'Neill - updated: 9/27/2012
Marla J. F. O'Neill - updated: 3/13/2007
Victor A. McKusick - updated: 7/9/2004
*FIELD* CD
Patricia A. Hartz: 9/30/2003
*FIELD* ED
carol: 10/17/2012
carol: 9/27/2012
carol: 3/14/2007
carol: 3/13/2007
tkritzer: 7/23/2004
tkritzer: 7/14/2004
terry: 7/9/2004
mgross: 9/30/2003
*RECORD*
*FIELD* NO
608137
*FIELD* TI
*608137 NASAL EMBRYONIC LHRH FACTOR; NELF
;;NASAL EMBRYONIC LUTEINIZING HORMONE-RELEASING HORMONE FACTOR
read more*FIELD* TX
CLONING
Kramer and Wray (2000) cloned mouse Nelf by differential screening of
migrating (3.5 days in vitro) versus nonmigrating (10.5 days in vitro)
primary luteinizing hormone-releasing hormone (LHRH; 152760) neurons.
Nelf was expressed in peripheral and central nervous system tissues
during embryonic development, including olfactory sensory cells and LHRH
cells.
Using RT-PCR on a fetal brain cDNA library, Miura et al. (2004) detected
5 alternatively spliced variants of NELF. One of the variants, NELF-v1,
has 93 to 94% identity at the amino acid level to mouse and rat Nelf,
and 4 other transcripts are also highly conserved among human, rat, and
mouse. A 3.0-kb transcript is expressed most highly in the adult and
fetal brain, testis, and kidney, indicating that NELF plays a role in
the function of these tissues.
GENE FUNCTION
Kramer and Wray (2000) presented evidence that mouse Nelf is a guidance
molecule for olfactory axon projections and plays a role in the
neurophilic migration of LHRH cells.
GENE STRUCTURE
Miura et al. (2004) determined that the NELF gene contains 16 exons with
a 1,590-bp open reading frame encoding 530 amino acids.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the NELF
gene to chromosome 9 (TMAP IB1002).
Miura et al. (2004) stated that the NELF gene maps to 9q34.3.
MOLECULAR GENETICS
Because the mouse Nelf gene encodes a guidance molecule for the
migration of the olfactory axon and gonadotropin-releasing hormone
neurons, its human homolog is a candidate gene for hypogonadotropic
hypogonadism and Kallmann syndrome (see HH9, 614838). Miura et al.
(2004) reported studies of NELF, including mutation analysis, in 65
patients with hypogonadotropic hypogonadism. In one of the patients,
they identified a thr480-to-ala mutation in the NELF gene (608137.0001).
The mutation was not found in 100 normal control individuals.
In a family in which the proband had severe Kallmann syndrome, his
father had a history of delayed puberty and congenital anosmia, his
mother had clinodactyly and Duane ocular retraction syndrome (see
126800), his sister had midline defects with a bifid nose and
high-arched palate, and his brother had clinodactyly alone, Pitteloud et
al. (2007) identified heterozygosity for a missense mutation in the
FGFR1 gene (L342S; 136350.0017) in the proband, his father, and his
sister. Heterozygosity for an additional mutation, an 8-bp intronic
deletion in the NELF gene (608137.0002), was identified in the proband,
his mother, and his brother. Pitteloud et al. (2007) concluded that
mutations in 2 different genes can synergize to produce a more severe
phenotype in families with hypogonadotropic hypogonadism than either
alone, and that this digenic model may account for some of the
phenotypic heterogeneity seen in GnRH deficiency.
In a 44-year-old man with anosmic hypogonadotropic hypogonadism and in
his unaffected brother, Tornberg et al. (2011) identified heterozygosity
for a missense mutation in the HS6ST1 gene (604846.0001). Because of the
reduced penetrance displayed in the family and phenotypic variability
seen among other HH patients carrying the same HS6ST1 mutation, the
authors analyzed 8 additional known HH-associated genes and detected a
missense mutation in NELF that was present only in the affected brother
(608137.0001). Tornberg et al. (2011) concluded that HH is an oligogenic
disorder in which a limited number of genes contribute pathogenic
alleles to the genetic network responsible for neuroendocrine control of
human reproduction.
*FIELD* AV
.0001
HYPOGONADOTROPIC HYPOGONADISM 9 WITHOUT ANOSMIA, SUSCEPTIBILITY TO
NELF, THR480ALA
In a sporadic case of hypogonadotropic hypogonadism (HH9; 614838), Miura
et al. (2004) identified a heterozygous 1438A-G transition at the donor
splice site in exon 15 of the NELF gene, resulting in a thr480-to-ala
(T480A) mutation. This amino acid substitution switches from a polar
side chain in threonine to a nonpolar side chain in alanine. As the
mutation was not found in any of 100 control individuals, and thr480 is
highly conserved among mouse, rat, and human, Miura et al. (2004)
suggested that T480A was associated with the pathogenesis of
hypogonadotropic hypogonadism in this case.
In a 44-year-old man with anosmic hypogonadotropic hypogonadism and in
his unaffected brother, Tornberg et al. (2011) identified heterozygosity
for a missense mutation in the HS6ST1 gene (604846.0001). Because of the
reduced penetrance displayed in the family and phenotypic variability
seen among other HH patients carrying the same HS6ST1 mutation, the
authors analyzed 8 additional known HH-associated genes and detected the
T480A mutation in NELF in the affected brother but not in his unaffected
sib.
.0002
HYPOGONADOTROPIC HYPOGONADISM 9 WITH ANOSMIA, SUSCEPTIBILITY TO
NELF, 8-BP DEL, IVS9, -14
In a family in which the proband had severe Kallmann syndrome (614838),
his father had a history of delayed puberty and congenital anosmia, his
mother had clinodactyly and Duane ocular retraction syndrome, his sister
had midline defects with a bifid nose and high-arched palate, and his
brother had clinodactyly alone, Pitteloud et al. (2007) identified
heterozygosity for an intronic 8-bp deletion ending 14 bp before exon 10
(1159-14_-22del), resulting in a splicing defect of exon 10 and causing
a premature stop codon, in the proband, his mother, and his brother. The
deletion was not found in 384 controls. Heterozygosity for an additional
missense mutation in the FGFR1 gene (L342S; 136350.0017) was identified
in the proband, his father, and his sister. Pitteloud et al. (2007)
concluded that mutations in 2 different genes can synergize to produce a
more severe phenotype in families with hypogonadotropic hypogonadism
than either alone, and that this digenic model may account for some of
the phenotypic heterogeneity seen in GnRH deficiency.
*FIELD* RF
1. Kramer, P. R.; Wray, S.: Novel gene expressed in nasal region
influences outgrowth of olfactory axons and migration of luteinizing
hormone-releasing hormone (LHRH) neurons. Genes Dev. 14: 1824-1834,
2000.
2. Miura, K.; Acierno, J. S., Jr.; Seminara, S. B.: Characterization
of the human nasal embryonic LHRH factor gene, NELF, and a mutation
screening among 65 patients with idiopathic hypogonadotropic hypogonadism
(IHH). J. Hum. Genet. 49: 265-268, 2004.
3. Pitteloud, N.; Quinton, R.; Pearce, S.; Raivio, T.; Acierno, J.;
Dwyer, A.; Plummer, L.; Hughes, V.; Seminara, S.; Cheng, Y.-Z.; Li,
W.-P.; Maccoll, G.; Eliseenkova, A. V.; Olsen, S. K.; Ibrahimi, O.
A.; Hayes, F. J.; Boepple, P.; Hall, J. E.; Bouloux, P.; Mohammadi,
M.; Crowley, W., Jr.: Digenic mutations account for variable phenotypes
in idiopathic hypogonadotropic hypogonadism. J. Clin. Invest. 117:
457-463, 2007.
4. Tornberg, J.; Sykiotis, G. P.; Keefe, K.; Plummer, L.; Hoang, X.;
Hall, J. E.; Quinton, R.; Seminara, S. B.; Hughes, V.; Van Vliet,
G.; Van Uum, S.; Crowley, W. F.; Habuchi, H.; Kimata, K.; Pitteloud,
N.; Bulow, H. E.: Heparan sulfate 6-O-sulfotransferase 1, a gene
involved in extracellular sugar modifications, is mutated in patients
with idiopathic hypogonadotrophic hypogonadism. Proc. Nat. Acad.
Sci. 108: 11524-11529, 2011.
*FIELD* CN
Marla J. F. O'Neill - updated: 10/17/2012
Marla J. F. O'Neill - updated: 9/27/2012
Marla J. F. O'Neill - updated: 3/13/2007
Victor A. McKusick - updated: 7/9/2004
*FIELD* CD
Patricia A. Hartz: 9/30/2003
*FIELD* ED
carol: 10/17/2012
carol: 9/27/2012
carol: 3/14/2007
carol: 3/13/2007
tkritzer: 7/23/2004
tkritzer: 7/14/2004
terry: 7/9/2004
mgross: 9/30/2003
MIM
614838
*RECORD*
*FIELD* NO
614838
*FIELD* TI
#614838 HYPOGONADOTROPIC HYPOGONADISM 9 WITH OR WITHOUT ANOSMIA; HH9
*FIELD* TX
A number sign (#) is used with this entry because autosomal dominant
read morehypogonadotropic hypogonadism-9 with or without anosmia (HH9) is caused
by heterozygous mutation in the NELF gene (608137) on chromosome 9q34,
sometimes in association with mutation in other genes, e.g., FGFR1
(136350) and HS6ST1 (604846).
DESCRIPTION
Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder
characterized by absent or incomplete sexual maturation by the age of 18
years, in conjunction with low levels of circulating gonadotropins and
testosterone and no other abnormalities of the hypothalamic-pituitary
axis. Idiopathic hypogonadotropic hypogonadism can be caused by an
isolated defect in gonadotropin-releasing hormone (GNRH; 152760)
release, action, or both. Other associated nonreproductive phenotypes,
such as anosmia, cleft palate, and sensorineural hearing loss, occur
with variable frequency. In the presence of anosmia, idiopathic
hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),'
whereas in the presence of a normal sense of smell, it has been termed
'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by
Raivio et al., 2007). Because families have been found to segregate both
KS and nIHH, the disorder is here referred to as 'hypogonadotropic
hypogonadism with or without anosmia (HH).'
For a discussion of genetic heterogeneity of hypogonadotropic
hypogonadism with or without anosmia, see 147950.
MOLECULAR GENETICS
In 1 of 65 patients with IHH, Miura et al. (2004) identified a
thr480-to-ala mutation in the NELF gene (T480A; 608137.0001). The
mutation was not found in 100 normal control individuals, suggesting
that it may be associated with IHH.
In a family in which the proband had severe Kallmann syndrome, his
father had a history of delayed puberty and congenital anosmia, his
mother had clinodactyly and Duane ocular retraction syndrome, his sister
had midline defects with a bifid nose and high-arched palate, and his
brother had clinodactyly alone, Pitteloud et al. (2007) identified
heterozygosity for a missense mutation in the FGFR1 gene (L342S;
136350.0017) in the proband, his father, and his sister. Heterozygosity
for an additional mutation, an 8-bp deletion in the NELF gene
(608137.0002), was identified in the proband, his mother, and his
brother. The mother and both sibs of the proband had normal puberty and
a normal sense of smell by formal testing. Pitteloud et al. (2007)
concluded that mutations in 2 different genes can synergize to produce a
more severe phenotype in families with hypogonadotropic hypogonadism
than either alone, and that this digenic model may account for some of
the phenotypic heterogeneity seen in GnRH deficiency.
In a 44-year-old man with anosmic hypogonadotropic hypogonadism and in
his unaffected brother, Tornberg et al. (2011) identified heterozygosity
for a missense mutation in the HS6ST1 gene (604846.0001). Because of the
reduced penetrance displayed in the family and phenotypic variability
seen among other HH patients carrying the same HS6ST1 mutation, the
authors analyzed 8 additional known HH-associated genes and detected the
T480A NELF missense mutation in the affected brother. Tornberg et al.
(2011) concluded that HH is an oligogenic disorder in which a limited
number of genes contribute pathogenic alleles to the genetic network
responsible for neuroendocrine control of human reproduction.
*FIELD* RF
1. Miura, K.; Acierno, J. S., Jr.; Seminara, S. B.: Characterization
of the human nasal embryonic LHRH factor gene, NELF, and a mutation
screening among 65 patients with idiopathic hypogonadotropic hypogonadism
(IHH). J. Hum. Genet. 49: 265-268, 2004.
2. Pitteloud, N.; Quinton, R.; Pearce, S.; Raivio, T.; Acierno, J.;
Dwyer, A.; Plummer, L.; Hughes, V.; Seminara, S.; Cheng, Y.-Z.; Li,
W.-P.; Maccoll, G.; Eliseenkova, A. V.; Olsen, S. K.; Ibrahimi, O.
A.; Hayes, F. J.; Boepple, P.; Hall, J. E.; Bouloux, P.; Mohammadi,
M.; Crowley, W., Jr.: Digenic mutations account for variable phenotypes
in idiopathic hypogonadotropic hypogonadism. J. Clin. Invest. 117:
457-463, 2007.
3. Raivio, T.; Falardeau, J.; Dwyer, A.; Quinton, R.; Hayes, F. J.;
Hughes, V. A.; Cole, L. W.; Pearce, S. H.; Lee, H.; Boepple, P.; Crowley,
W. F., Jr.; Pitteloud, N.: Reversal of idiopathic hypogonadotropic
hypogonadism. New Eng. J. Med. 357: 863-873, 2007.
4. Tornberg, J.; Sykiotis, G. P.; Keefe, K.; Plummer, L.; Hoang, X.;
Hall, J. E.; Quinton, R.; Seminara, S. B.; Hughes, V.; Van Vliet,
G.; Van Uum, S.; Crowley, W. F.; Habuchi, H.; Kimata, K.; Pitteloud,
N.; Bulow, H. E.: Heparan sulfate 6-O-sulfotransferase 1, a gene
involved in extracellular sugar modifications, is mutated in patients
with idiopathic hypogonadotrophic hypogonadism. Proc. Nat. Acad.
Sci. 108: 11524-11529, 2011.
*FIELD* CN
Marla J. F. O'Neill - updated: 10/17/2012
*FIELD* CD
Marla J. F. O'Neill: 9/27/2012
*FIELD* ED
carol: 10/17/2012
carol: 9/27/2012
*RECORD*
*FIELD* NO
614838
*FIELD* TI
#614838 HYPOGONADOTROPIC HYPOGONADISM 9 WITH OR WITHOUT ANOSMIA; HH9
*FIELD* TX
A number sign (#) is used with this entry because autosomal dominant
read morehypogonadotropic hypogonadism-9 with or without anosmia (HH9) is caused
by heterozygous mutation in the NELF gene (608137) on chromosome 9q34,
sometimes in association with mutation in other genes, e.g., FGFR1
(136350) and HS6ST1 (604846).
DESCRIPTION
Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder
characterized by absent or incomplete sexual maturation by the age of 18
years, in conjunction with low levels of circulating gonadotropins and
testosterone and no other abnormalities of the hypothalamic-pituitary
axis. Idiopathic hypogonadotropic hypogonadism can be caused by an
isolated defect in gonadotropin-releasing hormone (GNRH; 152760)
release, action, or both. Other associated nonreproductive phenotypes,
such as anosmia, cleft palate, and sensorineural hearing loss, occur
with variable frequency. In the presence of anosmia, idiopathic
hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),'
whereas in the presence of a normal sense of smell, it has been termed
'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by
Raivio et al., 2007). Because families have been found to segregate both
KS and nIHH, the disorder is here referred to as 'hypogonadotropic
hypogonadism with or without anosmia (HH).'
For a discussion of genetic heterogeneity of hypogonadotropic
hypogonadism with or without anosmia, see 147950.
MOLECULAR GENETICS
In 1 of 65 patients with IHH, Miura et al. (2004) identified a
thr480-to-ala mutation in the NELF gene (T480A; 608137.0001). The
mutation was not found in 100 normal control individuals, suggesting
that it may be associated with IHH.
In a family in which the proband had severe Kallmann syndrome, his
father had a history of delayed puberty and congenital anosmia, his
mother had clinodactyly and Duane ocular retraction syndrome, his sister
had midline defects with a bifid nose and high-arched palate, and his
brother had clinodactyly alone, Pitteloud et al. (2007) identified
heterozygosity for a missense mutation in the FGFR1 gene (L342S;
136350.0017) in the proband, his father, and his sister. Heterozygosity
for an additional mutation, an 8-bp deletion in the NELF gene
(608137.0002), was identified in the proband, his mother, and his
brother. The mother and both sibs of the proband had normal puberty and
a normal sense of smell by formal testing. Pitteloud et al. (2007)
concluded that mutations in 2 different genes can synergize to produce a
more severe phenotype in families with hypogonadotropic hypogonadism
than either alone, and that this digenic model may account for some of
the phenotypic heterogeneity seen in GnRH deficiency.
In a 44-year-old man with anosmic hypogonadotropic hypogonadism and in
his unaffected brother, Tornberg et al. (2011) identified heterozygosity
for a missense mutation in the HS6ST1 gene (604846.0001). Because of the
reduced penetrance displayed in the family and phenotypic variability
seen among other HH patients carrying the same HS6ST1 mutation, the
authors analyzed 8 additional known HH-associated genes and detected the
T480A NELF missense mutation in the affected brother. Tornberg et al.
(2011) concluded that HH is an oligogenic disorder in which a limited
number of genes contribute pathogenic alleles to the genetic network
responsible for neuroendocrine control of human reproduction.
*FIELD* RF
1. Miura, K.; Acierno, J. S., Jr.; Seminara, S. B.: Characterization
of the human nasal embryonic LHRH factor gene, NELF, and a mutation
screening among 65 patients with idiopathic hypogonadotropic hypogonadism
(IHH). J. Hum. Genet. 49: 265-268, 2004.
2. Pitteloud, N.; Quinton, R.; Pearce, S.; Raivio, T.; Acierno, J.;
Dwyer, A.; Plummer, L.; Hughes, V.; Seminara, S.; Cheng, Y.-Z.; Li,
W.-P.; Maccoll, G.; Eliseenkova, A. V.; Olsen, S. K.; Ibrahimi, O.
A.; Hayes, F. J.; Boepple, P.; Hall, J. E.; Bouloux, P.; Mohammadi,
M.; Crowley, W., Jr.: Digenic mutations account for variable phenotypes
in idiopathic hypogonadotropic hypogonadism. J. Clin. Invest. 117:
457-463, 2007.
3. Raivio, T.; Falardeau, J.; Dwyer, A.; Quinton, R.; Hayes, F. J.;
Hughes, V. A.; Cole, L. W.; Pearce, S. H.; Lee, H.; Boepple, P.; Crowley,
W. F., Jr.; Pitteloud, N.: Reversal of idiopathic hypogonadotropic
hypogonadism. New Eng. J. Med. 357: 863-873, 2007.
4. Tornberg, J.; Sykiotis, G. P.; Keefe, K.; Plummer, L.; Hoang, X.;
Hall, J. E.; Quinton, R.; Seminara, S. B.; Hughes, V.; Van Vliet,
G.; Van Uum, S.; Crowley, W. F.; Habuchi, H.; Kimata, K.; Pitteloud,
N.; Bulow, H. E.: Heparan sulfate 6-O-sulfotransferase 1, a gene
involved in extracellular sugar modifications, is mutated in patients
with idiopathic hypogonadotrophic hypogonadism. Proc. Nat. Acad.
Sci. 108: 11524-11529, 2011.
*FIELD* CN
Marla J. F. O'Neill - updated: 10/17/2012
*FIELD* CD
Marla J. F. O'Neill: 9/27/2012
*FIELD* ED
carol: 10/17/2012
carol: 9/27/2012