Full text data of NNT
NNT
[Confidence: low (only semi-automatic identification from reviews)]
NAD(P) transhydrogenase, mitochondrial; 1.6.1.2 (Nicotinamide nucleotide transhydrogenase; Pyridine nucleotide transhydrogenase; Flags: Precursor)
NAD(P) transhydrogenase, mitochondrial; 1.6.1.2 (Nicotinamide nucleotide transhydrogenase; Pyridine nucleotide transhydrogenase; Flags: Precursor)
UniProt
Q13423
ID NNTM_HUMAN Reviewed; 1086 AA.
AC Q13423; Q16796; Q2TB60; Q8N3V4;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-AUG-2004, sequence version 3.
DT 22-JAN-2014, entry version 139.
DE RecName: Full=NAD(P) transhydrogenase, mitochondrial;
DE EC=1.6.1.2;
DE AltName: Full=Nicotinamide nucleotide transhydrogenase;
DE AltName: Full=Pyridine nucleotide transhydrogenase;
DE Flags: Precursor;
GN Name=NNT;
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].
RX PubMed=9524818;
RA Ware J., Zieger B.;
RT "Cloning and deduced amino acid sequence of human nicotinamide
RT nucleotide transhydrogenase.";
RL DNA Seq. 7:369-374(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Heart;
RX PubMed=8616157; DOI=10.1016/0005-2728(95)00159-X;
RA Lagberg E.M., Betsholtz C., Rydstrom J.;
RT "The cDNA sequence of proton-pumping nicotinamide nucleotide
RT transhydrogenase from man and mouse.";
RL Biochim. Biophys. Acta 1273:203-205(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-70 AND LYS-397, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [7]
RP FUNCTION, TISSUE SPECIFICITY, AND VARIANTS GCCD4 ASN-193; ALA-357;
RP PRO-365; LEU-437; VAL-533; ARG-664; ARG-678; ASP-862; PRO-977;
RP PRO-1008 AND LYS-1009.
RX PubMed=22634753; DOI=10.1038/ng.2299;
RA Meimaridou E., Kowalczyk J., Guasti L., Hughes C.R., Wagner F.,
RA Frommolt P., Nurnberg P., Mann N.P., Banerjee R., Saka H.N.,
RA Chapple J.P., King P.J., Clark A.J., Metherell L.A.;
RT "Mutations in NNT encoding nicotinamide nucleotide transhydrogenase
RT cause familial glucocorticoid deficiency.";
RL Nat. Genet. 44:740-742(2012).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 880-1086 IN COMPLEX WITH
RP NADP.
RX PubMed=10673423; DOI=10.1016/S0969-2126(00)00075-7;
RA White S.A., Peake S.J., McSweeney S., Leonard G., Cotton N.P.J.,
RA Jackson J.B.;
RT "The high-resolution structure of the NADP(H)-binding component (dIII)
RT of proton-translocating transhydrogenase from human heart
RT mitochondria.";
RL Structure 8:1-12(2000).
CC -!- FUNCTION: The transhydrogenation between NADH and NADP is coupled
CC to respiration and ATP hydrolysis and functions as a proton pump
CC across the membrane. May play a role in reactive oxygen species
CC (ROS) detoxification in the adrenal gland.
CC -!- CATALYTIC ACTIVITY: NADPH + NAD(+) = NADP(+) + NADH.
CC -!- SUBUNIT: Homodimer (By similarity).
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane; Multi-pass
CC membrane protein; Matrix side (Potential).
CC -!- TISSUE SPECIFICITY: Widely expressed with expression most readily
CC detectable in adrenal, heart, kidney, thyroid and adipose tissues.
CC -!- DISEASE: Glucocorticoid deficiency 4 (GCCD4) [MIM:614736]: A rare,
CC potentially lethal, autosomal recessive disorder characterized by
CC resistance to ACTH action on the adrenal cortex, adrenal
CC insufficiency and an inability of the adrenal cortex to produce
CC cortisol. It usually presents in the neonatal period or in early
CC childhood with episodes of hypoglycemia and other symptoms related
CC to cortisol deficiency, including failure to thrive, recurrent
CC illnesses or infections, convulsions, and shock. In a small number
CC of patients hypoglycemia can be sufficiently severe and persistent
CC that it leads to serious long-term neurological damage or death.
CC The diagnosis is readily confirmed with a low plasma cortisol
CC measurement in the presence of an elevated ACTH level, and normal
CC aldosterone and plasma renin measurements. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: In the N-terminal section; belongs to the AlaDH/PNT
CC family.
CC -!- SIMILARITY: In the C-terminal section; belongs to the PNT beta
CC subunit family.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; U40490; AAC51914.1; -; mRNA.
DR EMBL; Z50101; CAA90428.1; -; mRNA.
DR EMBL; AL831822; CAD38536.1; -; mRNA.
DR EMBL; BC110543; AAI10544.1; -; mRNA.
DR PIR; G02257; G02257.
DR RefSeq; NP_036475.3; NM_012343.3.
DR RefSeq; NP_892022.2; NM_182977.2.
DR RefSeq; XP_005248331.1; XM_005248274.1.
DR UniGene; Hs.482043; -.
DR PDB; 1DJL; X-ray; 2.00 A; A/B=880-1086.
DR PDB; 1PT9; X-ray; 2.42 A; A/B=880-1086.
DR PDB; 1U31; X-ray; 2.20 A; A/B=880-1086.
DR PDBsum; 1DJL; -.
DR PDBsum; 1PT9; -.
DR PDBsum; 1U31; -.
DR ProteinModelPortal; Q13423; -.
DR SMR; Q13423; 59-439, 902-1083.
DR IntAct; Q13423; 2.
DR MINT; MINT-3027647; -.
DR STRING; 9606.ENSP00000264663; -.
DR DrugBank; DB00157; NADH.
DR PhosphoSite; Q13423; -.
DR DMDM; 51338801; -.
DR PaxDb; Q13423; -.
DR PeptideAtlas; Q13423; -.
DR PRIDE; Q13423; -.
DR DNASU; 23530; -.
DR Ensembl; ENST00000264663; ENSP00000264663; ENSG00000112992.
DR Ensembl; ENST00000344920; ENSP00000343873; ENSG00000112992.
DR GeneID; 23530; -.
DR KEGG; hsa:23530; -.
DR UCSC; uc003joe.3; human.
DR CTD; 23530; -.
DR GeneCards; GC05P043638; -.
DR H-InvDB; HIX0032203; -.
DR HGNC; HGNC:7863; NNT.
DR HPA; CAB004975; -.
DR HPA; HPA004829; -.
DR MIM; 607878; gene.
DR MIM; 614736; phenotype.
DR neXtProt; NX_Q13423; -.
DR Orphanet; 361; Familial glucocorticoid deficiency.
DR PharmGKB; PA31667; -.
DR eggNOG; COG1282; -.
DR HOGENOM; HOG000160623; -.
DR HOVERGEN; HBG006511; -.
DR InParanoid; Q13423; -.
DR KO; K00323; -.
DR OMA; KPGIPYK; -.
DR OrthoDB; EOG722J7T; -.
DR PhylomeDB; Q13423; -.
DR Reactome; REACT_111217; Metabolism.
DR EvolutionaryTrace; Q13423; -.
DR GeneWiki; NNT_(gene); -.
DR GenomeRNAi; 23530; -.
DR NextBio; 46004; -.
DR PRO; PR:Q13423; -.
DR ArrayExpress; Q13423; -.
DR Bgee; Q13423; -.
DR CleanEx; HS_NNT; -.
DR Genevestigator; Q13423; -.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005746; C:mitochondrial respiratory chain; TAS:UniProtKB.
DR GO; GO:0051287; F:NAD binding; TAS:UniProtKB.
DR GO; GO:0008750; F:NAD(P)+ transhydrogenase (AB-specific) activity; IEA:UniProtKB-EC.
DR GO; GO:0003957; F:NAD(P)+ transhydrogenase (B-specific) activity; TAS:UniProtKB.
DR GO; GO:0050661; F:NADP binding; IDA:UniProtKB.
DR GO; GO:0072593; P:reactive oxygen species metabolic process; IMP:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0006099; P:tricarboxylic acid cycle; TAS:UniProtKB.
DR InterPro; IPR008142; Ala_DH/PNT_CS1.
DR InterPro; IPR008143; Ala_DH/PNT_CS2.
DR InterPro; IPR007886; AlaDH/PNT_N.
DR InterPro; IPR007698; AlaDH/PNT_NAD(H)-bd.
DR InterPro; IPR012136; NADH_DH_b.
DR InterPro; IPR026255; NADP_transhyd_a.
DR InterPro; IPR024605; NADP_transhyd_a_C.
DR Pfam; PF01262; AlaDh_PNT_C; 1.
DR Pfam; PF05222; AlaDh_PNT_N; 1.
DR Pfam; PF12769; DUF3814; 1.
DR Pfam; PF02233; PNTB; 1.
DR SMART; SM01002; AlaDh_PNT_C; 1.
DR SMART; SM01003; AlaDh_PNT_N; 1.
DR TIGRFAMs; TIGR00561; pntA; 1.
DR PROSITE; PS00836; ALADH_PNT_1; 1.
DR PROSITE; PS00837; ALADH_PNT_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Disease mutation;
KW Membrane; Mitochondrion; Mitochondrion inner membrane; NAD; NADP;
KW Oxidoreductase; Reference proteome; Transit peptide; Transmembrane;
KW Transmembrane helix.
FT TRANSIT 1 43 Mitochondrion (By similarity).
FT CHAIN 44 1086 NAD(P) transhydrogenase, mitochondrial.
FT /FTId=PRO_0000001055.
FT TOPO_DOM 44 474 Mitochondrial matrix.
FT TRANSMEM 475 493 Helical; (Potential).
FT TRANSMEM 501 521 Helical; (Potential).
FT TRANSMEM 527 546 Helical; (Potential).
FT TRANSMEM 558 578 Helical; (Potential).
FT TOPO_DOM 579 595 Mitochondrial matrix.
FT TRANSMEM 596 616 Helical; (Potential).
FT TRANSMEM 622 642 Helical; (Potential).
FT TRANSMEM 646 666 Helical; (Potential).
FT TRANSMEM 672 691 Helical; (Potential).
FT TRANSMEM 702 722 Helical; (Potential).
FT TOPO_DOM 723 739 Cytoplasmic.
FT TRANSMEM 740 760 Helical; (Potential).
FT TRANSMEM 778 797 Helical; (Potential).
FT TRANSMEM 801 819 Helical; (Potential).
FT TRANSMEM 833 853 Helical; (Potential).
FT TRANSMEM 857 879 Helical; (Potential).
FT TOPO_DOM 880 1086 Mitochondrial matrix.
FT NP_BIND 229 259 NAD (By similarity).
FT NP_BIND 965 970 NADP.
FT NP_BIND 1007 1011 NADP.
FT NP_BIND 1042 1049 NADP.
FT NP_BIND 1068 1069 NADP.
FT BINDING 933 933 NADP; via amide nitrogen.
FT MOD_RES 70 70 N6-acetyllysine.
FT MOD_RES 397 397 N6-acetyllysine.
FT VARIANT 193 193 S -> N (in GCCD4).
FT /FTId=VAR_068781.
FT VARIANT 357 357 T -> A (in GCCD4).
FT /FTId=VAR_068782.
FT VARIANT 365 365 H -> P (in GCCD4).
FT /FTId=VAR_068783.
FT VARIANT 437 437 P -> L (in GCCD4).
FT /FTId=VAR_068784.
FT VARIANT 533 533 A -> V (in GCCD4).
FT /FTId=VAR_068785.
FT VARIANT 664 664 G -> R (in GCCD4).
FT /FTId=VAR_068786.
FT VARIANT 678 678 G -> R (in GCCD4).
FT /FTId=VAR_068787.
FT VARIANT 862 862 G -> D (in GCCD4).
FT /FTId=VAR_068788.
FT VARIANT 977 977 L -> P (in GCCD4).
FT /FTId=VAR_068789.
FT VARIANT 1008 1008 A -> P (in GCCD4).
FT /FTId=VAR_068790.
FT VARIANT 1009 1009 N -> K (in GCCD4).
FT /FTId=VAR_068791.
FT CONFLICT 176 176 A -> T (in Ref. 2; CAA90428).
FT CONFLICT 212 212 G -> E (in Ref. 3; CAD38536).
FT CONFLICT 246 246 A -> E (in Ref. 1; AAC51914).
FT CONFLICT 262 262 A -> S (in Ref. 1; AAC51914).
FT CONFLICT 706 706 F -> S (in Ref. 1; AAC51914).
FT CONFLICT 731 731 T -> P (in Ref. 1; AAC51914).
FT CONFLICT 810 810 S -> A (in Ref. 2; CAA90428).
FT CONFLICT 824 824 A -> P (in Ref. 2; CAA90428).
FT CONFLICT 871 871 I -> P (in Ref. 1; AAC51914).
FT CONFLICT 929 929 I -> F (in Ref. 1; AAC51914).
FT CONFLICT 1059 1059 K -> R (in Ref. 3; CAD38536).
FT HELIX 914 923
FT STRAND 925 931
FT HELIX 933 938
FT HELIX 941 953
FT STRAND 957 962
FT STRAND 967 969
FT HELIX 972 979
FT HELIX 984 986
FT STRAND 987 989
FT HELIX 990 993
FT HELIX 994 999
FT STRAND 1001 1007
FT HELIX 1010 1012
FT HELIX 1015 1018
FT TURN 1023 1026
FT HELIX 1032 1034
FT STRAND 1035 1045
FT HELIX 1055 1058
FT STRAND 1062 1067
FT HELIX 1069 1081
SQ SEQUENCE 1086 AA; 113896 MW; 8A437658CA0EB41B CRC64;
MANLLKTVVT GCSCPLLSNL GSCKGLRVKK DFLRTFYTHQ ELWCKAPVKP GIPYKQLTVG
VPKEIFQNEK RVALSPAGVQ NLVKQGFNVV VESGAGEASK FSDDHYRVAG AQIQGAKEVL
ASDLVVKVRA PMVNPTLGVH EADLLKTSGT LISFIYPAQN PELLNKLSQR KTTVLAMDQV
PRVTIAQGYD ALSSMANIAG YKAVVLAANH FGRFFTGQIT AAGKVPPAKI LIVGGGVAGL
ASAGAAKSMG AIVRGFDTRA AALEQFKSLG AEPLEVDLKE SGEGQGGYAK EMSKEFIEAE
MKLFAQQCKE VDILISTALI PGKKAPVLFN KEMIESMKEG SVVVDLAAEA GGNFETTKPG
ELYIHKGITH IGYTDLPSRM ATQASTLYSN NITKLLKAIS PDKDNFYFDV KDDFDFGTMG
HVIRGTVVMK DGKVIFPAPT PKNIPQGAPV KQKTVAELEA EKAATITPFR KTMSTASAYT
AGLTGILGLG IAAPNLAFSQ MVTTFGLAGI VGYHTVWGVT PALHSPLMSV TNAISGLTAV
GGLALMGGHL YPSTTSQGLA ALAAFISSVN IAGGFLVTQR MLDMFKRPTD PPEYNYLYLL
PAGTFVGGYL AALYSGYNIE QIMYLGSGLC CVGALAGLST QGTARLGNAL GMIGVAGGLA
ATLGVLKPGP ELLAQMSGAM ALGGTIGLTI AKRIQISDLP QLVAAFHSLV GLAAVLTCIA
EYIIEYPHFA TDAAANLTKI VAYLGTYIGG VTFSGSLIAY GKLQGLLKSA PLLLPGRHLL
NAGLLAASVG GIIPFMVDPS FTTGITCLGS VSALSAVMGV TLTAAIGGAD MPVVITVLNS
YSGWALCAEG FLLNNNLLTI VGALIGSSGA ILSYIMCVAM NRSLANVILG GYGTTSTAGG
KPMEISGTHT EINLDNAIDM IREANSIIIT PGYGLCAAKA QYPIADLVKM LTEQGKKVRF
GIHPVAGRMP GQLNVLLAEA GVPYDIVLEM DEINHDFPDT DLVLVIGAND TVNSAAQEDP
NSIIAGMPVL EVWKSKQVIV MKRSLGVGYA AVDNPIFYKP NTAMLLGDAK KTCDALQAKV
RESYQK
//
ID NNTM_HUMAN Reviewed; 1086 AA.
AC Q13423; Q16796; Q2TB60; Q8N3V4;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-AUG-2004, sequence version 3.
DT 22-JAN-2014, entry version 139.
DE RecName: Full=NAD(P) transhydrogenase, mitochondrial;
DE EC=1.6.1.2;
DE AltName: Full=Nicotinamide nucleotide transhydrogenase;
DE AltName: Full=Pyridine nucleotide transhydrogenase;
DE Flags: Precursor;
GN Name=NNT;
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].
RX PubMed=9524818;
RA Ware J., Zieger B.;
RT "Cloning and deduced amino acid sequence of human nicotinamide
RT nucleotide transhydrogenase.";
RL DNA Seq. 7:369-374(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Heart;
RX PubMed=8616157; DOI=10.1016/0005-2728(95)00159-X;
RA Lagberg E.M., Betsholtz C., Rydstrom J.;
RT "The cDNA sequence of proton-pumping nicotinamide nucleotide
RT transhydrogenase from man and mouse.";
RL Biochim. Biophys. Acta 1273:203-205(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-70 AND LYS-397, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [7]
RP FUNCTION, TISSUE SPECIFICITY, AND VARIANTS GCCD4 ASN-193; ALA-357;
RP PRO-365; LEU-437; VAL-533; ARG-664; ARG-678; ASP-862; PRO-977;
RP PRO-1008 AND LYS-1009.
RX PubMed=22634753; DOI=10.1038/ng.2299;
RA Meimaridou E., Kowalczyk J., Guasti L., Hughes C.R., Wagner F.,
RA Frommolt P., Nurnberg P., Mann N.P., Banerjee R., Saka H.N.,
RA Chapple J.P., King P.J., Clark A.J., Metherell L.A.;
RT "Mutations in NNT encoding nicotinamide nucleotide transhydrogenase
RT cause familial glucocorticoid deficiency.";
RL Nat. Genet. 44:740-742(2012).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 880-1086 IN COMPLEX WITH
RP NADP.
RX PubMed=10673423; DOI=10.1016/S0969-2126(00)00075-7;
RA White S.A., Peake S.J., McSweeney S., Leonard G., Cotton N.P.J.,
RA Jackson J.B.;
RT "The high-resolution structure of the NADP(H)-binding component (dIII)
RT of proton-translocating transhydrogenase from human heart
RT mitochondria.";
RL Structure 8:1-12(2000).
CC -!- FUNCTION: The transhydrogenation between NADH and NADP is coupled
CC to respiration and ATP hydrolysis and functions as a proton pump
CC across the membrane. May play a role in reactive oxygen species
CC (ROS) detoxification in the adrenal gland.
CC -!- CATALYTIC ACTIVITY: NADPH + NAD(+) = NADP(+) + NADH.
CC -!- SUBUNIT: Homodimer (By similarity).
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane; Multi-pass
CC membrane protein; Matrix side (Potential).
CC -!- TISSUE SPECIFICITY: Widely expressed with expression most readily
CC detectable in adrenal, heart, kidney, thyroid and adipose tissues.
CC -!- DISEASE: Glucocorticoid deficiency 4 (GCCD4) [MIM:614736]: A rare,
CC potentially lethal, autosomal recessive disorder characterized by
CC resistance to ACTH action on the adrenal cortex, adrenal
CC insufficiency and an inability of the adrenal cortex to produce
CC cortisol. It usually presents in the neonatal period or in early
CC childhood with episodes of hypoglycemia and other symptoms related
CC to cortisol deficiency, including failure to thrive, recurrent
CC illnesses or infections, convulsions, and shock. In a small number
CC of patients hypoglycemia can be sufficiently severe and persistent
CC that it leads to serious long-term neurological damage or death.
CC The diagnosis is readily confirmed with a low plasma cortisol
CC measurement in the presence of an elevated ACTH level, and normal
CC aldosterone and plasma renin measurements. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: In the N-terminal section; belongs to the AlaDH/PNT
CC family.
CC -!- SIMILARITY: In the C-terminal section; belongs to the PNT beta
CC subunit family.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; U40490; AAC51914.1; -; mRNA.
DR EMBL; Z50101; CAA90428.1; -; mRNA.
DR EMBL; AL831822; CAD38536.1; -; mRNA.
DR EMBL; BC110543; AAI10544.1; -; mRNA.
DR PIR; G02257; G02257.
DR RefSeq; NP_036475.3; NM_012343.3.
DR RefSeq; NP_892022.2; NM_182977.2.
DR RefSeq; XP_005248331.1; XM_005248274.1.
DR UniGene; Hs.482043; -.
DR PDB; 1DJL; X-ray; 2.00 A; A/B=880-1086.
DR PDB; 1PT9; X-ray; 2.42 A; A/B=880-1086.
DR PDB; 1U31; X-ray; 2.20 A; A/B=880-1086.
DR PDBsum; 1DJL; -.
DR PDBsum; 1PT9; -.
DR PDBsum; 1U31; -.
DR ProteinModelPortal; Q13423; -.
DR SMR; Q13423; 59-439, 902-1083.
DR IntAct; Q13423; 2.
DR MINT; MINT-3027647; -.
DR STRING; 9606.ENSP00000264663; -.
DR DrugBank; DB00157; NADH.
DR PhosphoSite; Q13423; -.
DR DMDM; 51338801; -.
DR PaxDb; Q13423; -.
DR PeptideAtlas; Q13423; -.
DR PRIDE; Q13423; -.
DR DNASU; 23530; -.
DR Ensembl; ENST00000264663; ENSP00000264663; ENSG00000112992.
DR Ensembl; ENST00000344920; ENSP00000343873; ENSG00000112992.
DR GeneID; 23530; -.
DR KEGG; hsa:23530; -.
DR UCSC; uc003joe.3; human.
DR CTD; 23530; -.
DR GeneCards; GC05P043638; -.
DR H-InvDB; HIX0032203; -.
DR HGNC; HGNC:7863; NNT.
DR HPA; CAB004975; -.
DR HPA; HPA004829; -.
DR MIM; 607878; gene.
DR MIM; 614736; phenotype.
DR neXtProt; NX_Q13423; -.
DR Orphanet; 361; Familial glucocorticoid deficiency.
DR PharmGKB; PA31667; -.
DR eggNOG; COG1282; -.
DR HOGENOM; HOG000160623; -.
DR HOVERGEN; HBG006511; -.
DR InParanoid; Q13423; -.
DR KO; K00323; -.
DR OMA; KPGIPYK; -.
DR OrthoDB; EOG722J7T; -.
DR PhylomeDB; Q13423; -.
DR Reactome; REACT_111217; Metabolism.
DR EvolutionaryTrace; Q13423; -.
DR GeneWiki; NNT_(gene); -.
DR GenomeRNAi; 23530; -.
DR NextBio; 46004; -.
DR PRO; PR:Q13423; -.
DR ArrayExpress; Q13423; -.
DR Bgee; Q13423; -.
DR CleanEx; HS_NNT; -.
DR Genevestigator; Q13423; -.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005746; C:mitochondrial respiratory chain; TAS:UniProtKB.
DR GO; GO:0051287; F:NAD binding; TAS:UniProtKB.
DR GO; GO:0008750; F:NAD(P)+ transhydrogenase (AB-specific) activity; IEA:UniProtKB-EC.
DR GO; GO:0003957; F:NAD(P)+ transhydrogenase (B-specific) activity; TAS:UniProtKB.
DR GO; GO:0050661; F:NADP binding; IDA:UniProtKB.
DR GO; GO:0072593; P:reactive oxygen species metabolic process; IMP:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0006099; P:tricarboxylic acid cycle; TAS:UniProtKB.
DR InterPro; IPR008142; Ala_DH/PNT_CS1.
DR InterPro; IPR008143; Ala_DH/PNT_CS2.
DR InterPro; IPR007886; AlaDH/PNT_N.
DR InterPro; IPR007698; AlaDH/PNT_NAD(H)-bd.
DR InterPro; IPR012136; NADH_DH_b.
DR InterPro; IPR026255; NADP_transhyd_a.
DR InterPro; IPR024605; NADP_transhyd_a_C.
DR Pfam; PF01262; AlaDh_PNT_C; 1.
DR Pfam; PF05222; AlaDh_PNT_N; 1.
DR Pfam; PF12769; DUF3814; 1.
DR Pfam; PF02233; PNTB; 1.
DR SMART; SM01002; AlaDh_PNT_C; 1.
DR SMART; SM01003; AlaDh_PNT_N; 1.
DR TIGRFAMs; TIGR00561; pntA; 1.
DR PROSITE; PS00836; ALADH_PNT_1; 1.
DR PROSITE; PS00837; ALADH_PNT_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Disease mutation;
KW Membrane; Mitochondrion; Mitochondrion inner membrane; NAD; NADP;
KW Oxidoreductase; Reference proteome; Transit peptide; Transmembrane;
KW Transmembrane helix.
FT TRANSIT 1 43 Mitochondrion (By similarity).
FT CHAIN 44 1086 NAD(P) transhydrogenase, mitochondrial.
FT /FTId=PRO_0000001055.
FT TOPO_DOM 44 474 Mitochondrial matrix.
FT TRANSMEM 475 493 Helical; (Potential).
FT TRANSMEM 501 521 Helical; (Potential).
FT TRANSMEM 527 546 Helical; (Potential).
FT TRANSMEM 558 578 Helical; (Potential).
FT TOPO_DOM 579 595 Mitochondrial matrix.
FT TRANSMEM 596 616 Helical; (Potential).
FT TRANSMEM 622 642 Helical; (Potential).
FT TRANSMEM 646 666 Helical; (Potential).
FT TRANSMEM 672 691 Helical; (Potential).
FT TRANSMEM 702 722 Helical; (Potential).
FT TOPO_DOM 723 739 Cytoplasmic.
FT TRANSMEM 740 760 Helical; (Potential).
FT TRANSMEM 778 797 Helical; (Potential).
FT TRANSMEM 801 819 Helical; (Potential).
FT TRANSMEM 833 853 Helical; (Potential).
FT TRANSMEM 857 879 Helical; (Potential).
FT TOPO_DOM 880 1086 Mitochondrial matrix.
FT NP_BIND 229 259 NAD (By similarity).
FT NP_BIND 965 970 NADP.
FT NP_BIND 1007 1011 NADP.
FT NP_BIND 1042 1049 NADP.
FT NP_BIND 1068 1069 NADP.
FT BINDING 933 933 NADP; via amide nitrogen.
FT MOD_RES 70 70 N6-acetyllysine.
FT MOD_RES 397 397 N6-acetyllysine.
FT VARIANT 193 193 S -> N (in GCCD4).
FT /FTId=VAR_068781.
FT VARIANT 357 357 T -> A (in GCCD4).
FT /FTId=VAR_068782.
FT VARIANT 365 365 H -> P (in GCCD4).
FT /FTId=VAR_068783.
FT VARIANT 437 437 P -> L (in GCCD4).
FT /FTId=VAR_068784.
FT VARIANT 533 533 A -> V (in GCCD4).
FT /FTId=VAR_068785.
FT VARIANT 664 664 G -> R (in GCCD4).
FT /FTId=VAR_068786.
FT VARIANT 678 678 G -> R (in GCCD4).
FT /FTId=VAR_068787.
FT VARIANT 862 862 G -> D (in GCCD4).
FT /FTId=VAR_068788.
FT VARIANT 977 977 L -> P (in GCCD4).
FT /FTId=VAR_068789.
FT VARIANT 1008 1008 A -> P (in GCCD4).
FT /FTId=VAR_068790.
FT VARIANT 1009 1009 N -> K (in GCCD4).
FT /FTId=VAR_068791.
FT CONFLICT 176 176 A -> T (in Ref. 2; CAA90428).
FT CONFLICT 212 212 G -> E (in Ref. 3; CAD38536).
FT CONFLICT 246 246 A -> E (in Ref. 1; AAC51914).
FT CONFLICT 262 262 A -> S (in Ref. 1; AAC51914).
FT CONFLICT 706 706 F -> S (in Ref. 1; AAC51914).
FT CONFLICT 731 731 T -> P (in Ref. 1; AAC51914).
FT CONFLICT 810 810 S -> A (in Ref. 2; CAA90428).
FT CONFLICT 824 824 A -> P (in Ref. 2; CAA90428).
FT CONFLICT 871 871 I -> P (in Ref. 1; AAC51914).
FT CONFLICT 929 929 I -> F (in Ref. 1; AAC51914).
FT CONFLICT 1059 1059 K -> R (in Ref. 3; CAD38536).
FT HELIX 914 923
FT STRAND 925 931
FT HELIX 933 938
FT HELIX 941 953
FT STRAND 957 962
FT STRAND 967 969
FT HELIX 972 979
FT HELIX 984 986
FT STRAND 987 989
FT HELIX 990 993
FT HELIX 994 999
FT STRAND 1001 1007
FT HELIX 1010 1012
FT HELIX 1015 1018
FT TURN 1023 1026
FT HELIX 1032 1034
FT STRAND 1035 1045
FT HELIX 1055 1058
FT STRAND 1062 1067
FT HELIX 1069 1081
SQ SEQUENCE 1086 AA; 113896 MW; 8A437658CA0EB41B CRC64;
MANLLKTVVT GCSCPLLSNL GSCKGLRVKK DFLRTFYTHQ ELWCKAPVKP GIPYKQLTVG
VPKEIFQNEK RVALSPAGVQ NLVKQGFNVV VESGAGEASK FSDDHYRVAG AQIQGAKEVL
ASDLVVKVRA PMVNPTLGVH EADLLKTSGT LISFIYPAQN PELLNKLSQR KTTVLAMDQV
PRVTIAQGYD ALSSMANIAG YKAVVLAANH FGRFFTGQIT AAGKVPPAKI LIVGGGVAGL
ASAGAAKSMG AIVRGFDTRA AALEQFKSLG AEPLEVDLKE SGEGQGGYAK EMSKEFIEAE
MKLFAQQCKE VDILISTALI PGKKAPVLFN KEMIESMKEG SVVVDLAAEA GGNFETTKPG
ELYIHKGITH IGYTDLPSRM ATQASTLYSN NITKLLKAIS PDKDNFYFDV KDDFDFGTMG
HVIRGTVVMK DGKVIFPAPT PKNIPQGAPV KQKTVAELEA EKAATITPFR KTMSTASAYT
AGLTGILGLG IAAPNLAFSQ MVTTFGLAGI VGYHTVWGVT PALHSPLMSV TNAISGLTAV
GGLALMGGHL YPSTTSQGLA ALAAFISSVN IAGGFLVTQR MLDMFKRPTD PPEYNYLYLL
PAGTFVGGYL AALYSGYNIE QIMYLGSGLC CVGALAGLST QGTARLGNAL GMIGVAGGLA
ATLGVLKPGP ELLAQMSGAM ALGGTIGLTI AKRIQISDLP QLVAAFHSLV GLAAVLTCIA
EYIIEYPHFA TDAAANLTKI VAYLGTYIGG VTFSGSLIAY GKLQGLLKSA PLLLPGRHLL
NAGLLAASVG GIIPFMVDPS FTTGITCLGS VSALSAVMGV TLTAAIGGAD MPVVITVLNS
YSGWALCAEG FLLNNNLLTI VGALIGSSGA ILSYIMCVAM NRSLANVILG GYGTTSTAGG
KPMEISGTHT EINLDNAIDM IREANSIIIT PGYGLCAAKA QYPIADLVKM LTEQGKKVRF
GIHPVAGRMP GQLNVLLAEA GVPYDIVLEM DEINHDFPDT DLVLVIGAND TVNSAAQEDP
NSIIAGMPVL EVWKSKQVIV MKRSLGVGYA AVDNPIFYKP NTAMLLGDAK KTCDALQAKV
RESYQK
//
MIM
607878
*RECORD*
*FIELD* NO
607878
*FIELD* TI
*607878 NICOTINAMIDE NUCLEOTIDE TRANSHYDROGENASE; NNT
*FIELD* TX
DESCRIPTION
NNT is a pyridine nucleotide transhydrogenase (EC 1.6.1.1). These
read moreintegral inner mitochondrial membrane proteins are part of the
energy-transfer system of the respiratory chain and catalyze the
transfer of a hydride ion between nicotinamide adenine dinucleotide,
NAD(H), and oxidized nicotinamide dinucleotide phosphate, NADP(H)
(summary by Zieger and Ware, 1997).
CLONING
Using bovine Nnt as probe, Arkblad et al. (1996) cloned NNT from a heart
cDNA library, and they cloned mouse Nnt from a mouse liver cDNA library.
The deduced 1,086-amino acid NNT protein has a 43-amino acid
presequence, 10 membrane-spanning alpha helices, and substrate-binding
sites for NAD(H) and NADP(H). It shares 97% amino acid identity with
bovine Nnt and 94% identity with mouse Nnt. A hypervariable region is
located in the first transmembrane helix, and the presequences are less
conserved.
Zieger and Ware (1997) cloned NNT from a cell line established from a
solid tumor in a patient with megakaryoblastic leukemia.
Meimaridou et al. (2012) found wide expression of NNT in humans, with
expression most readily detectable in adrenal, heart, kidney, thyroid,
and adipose tissues.
MAPPING
By FISH, Arkblad et al. (1997) mapped the NNT gene to chromosome
5p13.1-cen. They mapped the mouse Nnt gene to chromosome 13D2.
GENE FUNCTION
Meimaridou et al. (2012) studied the adrenal glands from Nnt-deficient
mice and observed slightly disorganized zonae fasciculatae with higher
levels of apoptosis than wildtype mice. There were no observable
differences in the levels of the steroidogenic enzymes CYP11A1 (118485)
and CYP11B1 (610613) between wildtype and mutant mice; however, the
mutant mice did have lower basal and stimulated levels of corticosterone
than their wildtype counterparts. Knockdown of NNT in the human
adrenocortical H295R cell line by short hairpin RNA not only increased
the levels of mitochondrial reactive oxygen species and apoptosis but
also lowered the glutathione (GSH; see 601002)/glutathione disulfide
(GSSG) ratio, implying that these cells also have impaired redox
potential.
MOLECULAR GENETICS
In 3 kindreds with glucocorticoid deficiency mapping to chromosome
5p13-q12 (GCCD4; 614736), Meimaridou et al. (2012) identified
homozygosity for 3 different mutations in the NNT gene
(607878.0001-607878.0003) that segregated with disease in each family
and were not found in controls. Subsequent analysis of the NNT gene in
100 individuals with GCCD of unknown etiology revealed homozygosity or
compound heterozygosity for 18 more mutations in 12 kindreds (see, e.g.,
607878.0004-607878.0006). The mutations were spread throughout the NNT
gene and included a mutation that destroyed the translation-initiating
methionine, 2 additional splice site mutations, and many missense and
nonsense changes.
*FIELD* AV
.0001
GLUCOCORTICOID DEFICIENCY 4
NNT, ALA533VAL
In a patient with glucocorticoid deficiency (GCCD4; 614736), who
presented at 9 months of age with hypoglycemia, hyperpigmentation, a low
cortisol level, and elevated ACTH, Meimaridou et al. (2012) identified
homozygosity for a 1598C-T transition in exon 11 of the NNT gene,
resulting in an ala533-to-val (A533V) substitution at a highly conserved
residue in the transmembrane domain. The mutation was found in
heterozygosity in the unaffected parents and was absent from controls.
.0002
GLUCOCORTICOID DEFICIENCY 4
NNT, 1-BP DEL, 600G
In a patient with glucocorticoid deficiency (GCCD4; 614736), who
presented at 18 months of age with hypoglycemia, hyperpigmentation, a
low cortisol level, and elevated ACTH, Meimaridou et al. (2012)
identified homozygosity for a 1-bp deletion (600delG) at the splice
junction of intron 4 and exon 5 of the NNT gene, causing a frameshift
predicted to result in premature termination at residue 202. The
mutation was not found in controls.
.0003
GLUCOCORTICOID DEFICIENCY 4
NNT, LEU977PRO
In a patient with glucocorticoid deficiency (GCCD4; 614736) who had a
low cortisol level and elevated ACTH, Meimaridou et al. (2012)
identified homozygosity for a 2930T-C transition in exon 20 of the NNT
gene, resulting in a leu977-to-pro (L977P) substitution at a highly
conserved residue in the nucleotide-binding domain. The mutation was not
found in controls.
.0004
GLUCOCORTICOID DEFICIENCY 4
NNT, 4-BP DEL, 1107TCAC
In a patient with glucocorticoid deficiency (GCCD4; 614736), who
presented at 12 months of age with exhaustion, lack of appetite, a
low-normal cortisol level, and elevated ACTH, Meimaridou et al. (2012)
identified compound heterozygosity for a 4-bp deletion (1107delTCAC) in
exon 9 of the NNT gene, causing a frameshift predicted to result in
premature termination at residue 370, and a 3027T-G transversion in exon
19, resulting in an asn1009-to-lys (N1009K; 607878.0005) substitution at
a highly conserved residue in the nucleotide-binding domain. Neither
mutation was found in controls.
.0005
GLUCOCORTICOID DEFICIENCY 4
NNT, ASN1009LYS
See 607878.0004 and Meimaridou et al. (2012).
.0006
GLUCOCORTICOID DEFICIENCY 4
NNT, ALA1008PRO
In a patient with glucocorticoid deficiency (GCCD4; 614736), who
presented at 3.25 years of age with hypoglycemic seizures, an
undetectable cortisol level, and elevated ACTH, Meimaridou et al. (2012)
identified homozygosity for a 3022G-C transversion in exon 21 of the NNT
gene, resulting in an ala1008-to-pro (A1008P) substitution at a highly
conserved residue in the nucleotide-binding domain. The mutation was not
found in controls.
*FIELD* RF
1. Arkblad, E. L.; Betsholtz, C.; Rydstrom, J.: The cDNA sequence
of proton-pumping nicotinamide nucleotide transhydrogenase from man
and mouse. Biochim. Biophys. Acta 1273: 203-205, 1996.
2. Arkblad, E. L.; Helou, K.; Levan, G.; Rydstrom, J.: Mapping of
the rat and mouse nicotinamide nucleotide transhydrogenase gene. Mammalian
Genome 8: 703 only, 1997.
3. Meimaridou, E.; Kowalczyk, J.; Guasti, L.; Hughes, C. R.; Wagner,
F.; Frommolt, P.; Nurnberg, P.; Mann, N. P.; Banerjee, R.; Saka, H.
N.; Chapple, J. P.; King, P. J.; Clark, A. J. L.; Metherell, L. A.
: Mutations in NNT encoding nicotinamide nucleotide transhydrogenase
cause familial glucocorticoid deficiency. Nature Genet. 44: 740-742,
2012.
4. Zieger, B.; Ware, J.: Cloning and deduced amino acid sequence
of human nicotinamide nucleotide transhydrogenase. DNA Seq. 7: 369-373,
1997.
*FIELD* CN
Marla J. F. O'Neill - updated: 7/20/2012
*FIELD* CD
Patricia A. Hartz: 6/12/2003
*FIELD* ED
carol: 08/30/2013
carol: 7/20/2012
mgross: 6/12/2003
*RECORD*
*FIELD* NO
607878
*FIELD* TI
*607878 NICOTINAMIDE NUCLEOTIDE TRANSHYDROGENASE; NNT
*FIELD* TX
DESCRIPTION
NNT is a pyridine nucleotide transhydrogenase (EC 1.6.1.1). These
read moreintegral inner mitochondrial membrane proteins are part of the
energy-transfer system of the respiratory chain and catalyze the
transfer of a hydride ion between nicotinamide adenine dinucleotide,
NAD(H), and oxidized nicotinamide dinucleotide phosphate, NADP(H)
(summary by Zieger and Ware, 1997).
CLONING
Using bovine Nnt as probe, Arkblad et al. (1996) cloned NNT from a heart
cDNA library, and they cloned mouse Nnt from a mouse liver cDNA library.
The deduced 1,086-amino acid NNT protein has a 43-amino acid
presequence, 10 membrane-spanning alpha helices, and substrate-binding
sites for NAD(H) and NADP(H). It shares 97% amino acid identity with
bovine Nnt and 94% identity with mouse Nnt. A hypervariable region is
located in the first transmembrane helix, and the presequences are less
conserved.
Zieger and Ware (1997) cloned NNT from a cell line established from a
solid tumor in a patient with megakaryoblastic leukemia.
Meimaridou et al. (2012) found wide expression of NNT in humans, with
expression most readily detectable in adrenal, heart, kidney, thyroid,
and adipose tissues.
MAPPING
By FISH, Arkblad et al. (1997) mapped the NNT gene to chromosome
5p13.1-cen. They mapped the mouse Nnt gene to chromosome 13D2.
GENE FUNCTION
Meimaridou et al. (2012) studied the adrenal glands from Nnt-deficient
mice and observed slightly disorganized zonae fasciculatae with higher
levels of apoptosis than wildtype mice. There were no observable
differences in the levels of the steroidogenic enzymes CYP11A1 (118485)
and CYP11B1 (610613) between wildtype and mutant mice; however, the
mutant mice did have lower basal and stimulated levels of corticosterone
than their wildtype counterparts. Knockdown of NNT in the human
adrenocortical H295R cell line by short hairpin RNA not only increased
the levels of mitochondrial reactive oxygen species and apoptosis but
also lowered the glutathione (GSH; see 601002)/glutathione disulfide
(GSSG) ratio, implying that these cells also have impaired redox
potential.
MOLECULAR GENETICS
In 3 kindreds with glucocorticoid deficiency mapping to chromosome
5p13-q12 (GCCD4; 614736), Meimaridou et al. (2012) identified
homozygosity for 3 different mutations in the NNT gene
(607878.0001-607878.0003) that segregated with disease in each family
and were not found in controls. Subsequent analysis of the NNT gene in
100 individuals with GCCD of unknown etiology revealed homozygosity or
compound heterozygosity for 18 more mutations in 12 kindreds (see, e.g.,
607878.0004-607878.0006). The mutations were spread throughout the NNT
gene and included a mutation that destroyed the translation-initiating
methionine, 2 additional splice site mutations, and many missense and
nonsense changes.
*FIELD* AV
.0001
GLUCOCORTICOID DEFICIENCY 4
NNT, ALA533VAL
In a patient with glucocorticoid deficiency (GCCD4; 614736), who
presented at 9 months of age with hypoglycemia, hyperpigmentation, a low
cortisol level, and elevated ACTH, Meimaridou et al. (2012) identified
homozygosity for a 1598C-T transition in exon 11 of the NNT gene,
resulting in an ala533-to-val (A533V) substitution at a highly conserved
residue in the transmembrane domain. The mutation was found in
heterozygosity in the unaffected parents and was absent from controls.
.0002
GLUCOCORTICOID DEFICIENCY 4
NNT, 1-BP DEL, 600G
In a patient with glucocorticoid deficiency (GCCD4; 614736), who
presented at 18 months of age with hypoglycemia, hyperpigmentation, a
low cortisol level, and elevated ACTH, Meimaridou et al. (2012)
identified homozygosity for a 1-bp deletion (600delG) at the splice
junction of intron 4 and exon 5 of the NNT gene, causing a frameshift
predicted to result in premature termination at residue 202. The
mutation was not found in controls.
.0003
GLUCOCORTICOID DEFICIENCY 4
NNT, LEU977PRO
In a patient with glucocorticoid deficiency (GCCD4; 614736) who had a
low cortisol level and elevated ACTH, Meimaridou et al. (2012)
identified homozygosity for a 2930T-C transition in exon 20 of the NNT
gene, resulting in a leu977-to-pro (L977P) substitution at a highly
conserved residue in the nucleotide-binding domain. The mutation was not
found in controls.
.0004
GLUCOCORTICOID DEFICIENCY 4
NNT, 4-BP DEL, 1107TCAC
In a patient with glucocorticoid deficiency (GCCD4; 614736), who
presented at 12 months of age with exhaustion, lack of appetite, a
low-normal cortisol level, and elevated ACTH, Meimaridou et al. (2012)
identified compound heterozygosity for a 4-bp deletion (1107delTCAC) in
exon 9 of the NNT gene, causing a frameshift predicted to result in
premature termination at residue 370, and a 3027T-G transversion in exon
19, resulting in an asn1009-to-lys (N1009K; 607878.0005) substitution at
a highly conserved residue in the nucleotide-binding domain. Neither
mutation was found in controls.
.0005
GLUCOCORTICOID DEFICIENCY 4
NNT, ASN1009LYS
See 607878.0004 and Meimaridou et al. (2012).
.0006
GLUCOCORTICOID DEFICIENCY 4
NNT, ALA1008PRO
In a patient with glucocorticoid deficiency (GCCD4; 614736), who
presented at 3.25 years of age with hypoglycemic seizures, an
undetectable cortisol level, and elevated ACTH, Meimaridou et al. (2012)
identified homozygosity for a 3022G-C transversion in exon 21 of the NNT
gene, resulting in an ala1008-to-pro (A1008P) substitution at a highly
conserved residue in the nucleotide-binding domain. The mutation was not
found in controls.
*FIELD* RF
1. Arkblad, E. L.; Betsholtz, C.; Rydstrom, J.: The cDNA sequence
of proton-pumping nicotinamide nucleotide transhydrogenase from man
and mouse. Biochim. Biophys. Acta 1273: 203-205, 1996.
2. Arkblad, E. L.; Helou, K.; Levan, G.; Rydstrom, J.: Mapping of
the rat and mouse nicotinamide nucleotide transhydrogenase gene. Mammalian
Genome 8: 703 only, 1997.
3. Meimaridou, E.; Kowalczyk, J.; Guasti, L.; Hughes, C. R.; Wagner,
F.; Frommolt, P.; Nurnberg, P.; Mann, N. P.; Banerjee, R.; Saka, H.
N.; Chapple, J. P.; King, P. J.; Clark, A. J. L.; Metherell, L. A.
: Mutations in NNT encoding nicotinamide nucleotide transhydrogenase
cause familial glucocorticoid deficiency. Nature Genet. 44: 740-742,
2012.
4. Zieger, B.; Ware, J.: Cloning and deduced amino acid sequence
of human nicotinamide nucleotide transhydrogenase. DNA Seq. 7: 369-373,
1997.
*FIELD* CN
Marla J. F. O'Neill - updated: 7/20/2012
*FIELD* CD
Patricia A. Hartz: 6/12/2003
*FIELD* ED
carol: 08/30/2013
carol: 7/20/2012
mgross: 6/12/2003
MIM
614736
*RECORD*
*FIELD* NO
614736
*FIELD* TI
#614736 GLUCOCORTICOID DEFICIENCY 4; GCCD4
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreglucocorticoid deficiency-4 (GCCD4) is caused by homozygous or compound
heterozygous mutation in the NNT gene (607878) on chromosome 5p12.
DESCRIPTION
Familial glucocorticoid deficiency is a rare autosomal recessive
disorder characterized by an inability of the adrenal cortex to produce
cortisol in response to stimulation by adrenocorticotropic hormone
(ACTH). Affected individuals typically present within the first few
months of life with symptoms related to cortisol deficiency, including
failure to thrive, recurrent illnesses or infections, hypoglycemia,
convulsions, and shock. The disease is life-threatening if untreated
(summary by Meimaridou et al., 2012).
For a discussion of genetic heterogeneity of familial glucocorticoid
deficiency, see GCCD1 (202200).
CLINICAL FEATURES
Meimaridou et al. (2012) studied patients from 15 families with
glucocorticoid deficiency (GCCD), all of whom were negative for mutation
in genes known to cause GCCD. The patients, who were diagnosed between 6
months and 40 months of age, presented with hyperpigmentation, high ACTH
levels, and low cortisol levels, but with normal renin and aldosterone
levels. All patients in whom an ACTH stimulation test was performed
failed to mount a suitable response.
MAPPING
Meimaridou et al. (2012) performed SNP array genotyping in 9 probands
from consanguineous families with glucocorticoid deficiency who were
known to be negative for mutation in the MC2R (607397), MRAP (609196),
and STAR (600617) genes. They found linkage to chromosome 5p13-q12 in 3
families, which was confirmed by genotyping of microsatellite markers.
MOLECULAR GENETICS
In the proband of a family with glucocorticoid deficiency (GCCD) mapping
to chromosome 5p13-q12, Meimaridou et al. (2012) performed targeted
exome sequencing followed by filtration, which yielded 5 variants for
validation; only 1, a missense mutation in the NNT gene (607878.0001),
was homozygous in the affected individual, heterozygous in the
unaffected parents, and absent in controls. Homozygosity for a 1-bp
deletion or a missense mutation in NNT (607878.0002 and 607878.0003,
respectively) was identified in affected individuals from 2 more
families with GCCD mapping to chromosome 5. Sequencing the NNT gene in
100 individuals with GCCD of unknown etiology revealed homozygosity or
compound heterozygosity for 18 more mutations in 12 kindreds (see, e.g.,
607878.0004-607878.0006). Functional analysis in mutant mice suggested
that impaired adrenal steroidogenesis and the development of GCCD are
due to defective oxidative stress responses.
*FIELD* RF
1. Meimaridou, E.; Kowalczyk, J.; Guasti, L.; Hughes, C. R.; Wagner,
F.; Frommolt, P.; Nurnberg, P.; Mann, N. P.; Banerjee, R.; Saka, H.
N.; Chapple, J. P.; King, P. J.; Clark, A. J. L.; Metherell, L. A.
: Mutations in NNT encoding nicotinamide nucleotide transhydrogenase
cause familial glucocorticoid deficiency. Nature Genet. 44: 740-742,
2012.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
Failure to thrive
SKIN, NAILS, HAIR:
[Skin];
Hyperpigmentation
NEUROLOGIC:
[Central nervous system];
Seizures, hypoglycemic (in some patients)
METABOLIC FEATURES:
Hypoglycemia
LABORATORY ABNORMALITIES:
Low cortisol level;
Elevated ACTH;
Unresponsive to ACTH stimulation;
Normal renin level;
Normal aldosterone level
MISCELLANEOUS:
Patients may present with recurrent illnesses or infections, or shock;
Disease is life-threatening if untreated
MOLECULAR BASIS:
Caused by mutation in the nicotinamide nucleotide transhydrogenase
gene (NNT, 607878.0001)
*FIELD* CD
Marla J. F. O'Neill: 7/20/2012
*FIELD* ED
joanna: 07/20/2012
*FIELD* CD
Marla J. F. O'Neill: 7/19/2012
*FIELD* ED
carol: 07/20/2012
*RECORD*
*FIELD* NO
614736
*FIELD* TI
#614736 GLUCOCORTICOID DEFICIENCY 4; GCCD4
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreglucocorticoid deficiency-4 (GCCD4) is caused by homozygous or compound
heterozygous mutation in the NNT gene (607878) on chromosome 5p12.
DESCRIPTION
Familial glucocorticoid deficiency is a rare autosomal recessive
disorder characterized by an inability of the adrenal cortex to produce
cortisol in response to stimulation by adrenocorticotropic hormone
(ACTH). Affected individuals typically present within the first few
months of life with symptoms related to cortisol deficiency, including
failure to thrive, recurrent illnesses or infections, hypoglycemia,
convulsions, and shock. The disease is life-threatening if untreated
(summary by Meimaridou et al., 2012).
For a discussion of genetic heterogeneity of familial glucocorticoid
deficiency, see GCCD1 (202200).
CLINICAL FEATURES
Meimaridou et al. (2012) studied patients from 15 families with
glucocorticoid deficiency (GCCD), all of whom were negative for mutation
in genes known to cause GCCD. The patients, who were diagnosed between 6
months and 40 months of age, presented with hyperpigmentation, high ACTH
levels, and low cortisol levels, but with normal renin and aldosterone
levels. All patients in whom an ACTH stimulation test was performed
failed to mount a suitable response.
MAPPING
Meimaridou et al. (2012) performed SNP array genotyping in 9 probands
from consanguineous families with glucocorticoid deficiency who were
known to be negative for mutation in the MC2R (607397), MRAP (609196),
and STAR (600617) genes. They found linkage to chromosome 5p13-q12 in 3
families, which was confirmed by genotyping of microsatellite markers.
MOLECULAR GENETICS
In the proband of a family with glucocorticoid deficiency (GCCD) mapping
to chromosome 5p13-q12, Meimaridou et al. (2012) performed targeted
exome sequencing followed by filtration, which yielded 5 variants for
validation; only 1, a missense mutation in the NNT gene (607878.0001),
was homozygous in the affected individual, heterozygous in the
unaffected parents, and absent in controls. Homozygosity for a 1-bp
deletion or a missense mutation in NNT (607878.0002 and 607878.0003,
respectively) was identified in affected individuals from 2 more
families with GCCD mapping to chromosome 5. Sequencing the NNT gene in
100 individuals with GCCD of unknown etiology revealed homozygosity or
compound heterozygosity for 18 more mutations in 12 kindreds (see, e.g.,
607878.0004-607878.0006). Functional analysis in mutant mice suggested
that impaired adrenal steroidogenesis and the development of GCCD are
due to defective oxidative stress responses.
*FIELD* RF
1. Meimaridou, E.; Kowalczyk, J.; Guasti, L.; Hughes, C. R.; Wagner,
F.; Frommolt, P.; Nurnberg, P.; Mann, N. P.; Banerjee, R.; Saka, H.
N.; Chapple, J. P.; King, P. J.; Clark, A. J. L.; Metherell, L. A.
: Mutations in NNT encoding nicotinamide nucleotide transhydrogenase
cause familial glucocorticoid deficiency. Nature Genet. 44: 740-742,
2012.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
Failure to thrive
SKIN, NAILS, HAIR:
[Skin];
Hyperpigmentation
NEUROLOGIC:
[Central nervous system];
Seizures, hypoglycemic (in some patients)
METABOLIC FEATURES:
Hypoglycemia
LABORATORY ABNORMALITIES:
Low cortisol level;
Elevated ACTH;
Unresponsive to ACTH stimulation;
Normal renin level;
Normal aldosterone level
MISCELLANEOUS:
Patients may present with recurrent illnesses or infections, or shock;
Disease is life-threatening if untreated
MOLECULAR BASIS:
Caused by mutation in the nicotinamide nucleotide transhydrogenase
gene (NNT, 607878.0001)
*FIELD* CD
Marla J. F. O'Neill: 7/20/2012
*FIELD* ED
joanna: 07/20/2012
*FIELD* CD
Marla J. F. O'Neill: 7/19/2012
*FIELD* ED
carol: 07/20/2012