RBCC Red Blood Cell Collection

HNF4A (HNF4, NR2A1, TCF14) [Confidence: low (only semi-automatic identification from reviews)]
Hepatocyte nuclear factor 4-alpha; HNF-4-alpha (Nuclear receptor subfamily 2 group A member 1; Transcription factor 14; TCF-14; Transcription factor HNF-4)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P41235
ID HNF4A_HUMAN Reviewed; 474 AA.
AC P41235; A5JW41; B2RPP8; O00659; O00723; Q14540; Q5QPB8; Q6B4V5;
read moreAC Q6B4V6; Q6B4V7; Q92653; Q92654; Q92655; Q99864; Q9NQH0;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 29-MAY-2007, sequence version 3.
DT 22-JAN-2014, entry version 166.
DE RecName: Full=Hepatocyte nuclear factor 4-alpha;
DE Short=HNF-4-alpha;
DE AltName: Full=Nuclear receptor subfamily 2 group A member 1;
DE AltName: Full=Transcription factor 14;
DE Short=TCF-14;
DE AltName: Full=Transcription factor HNF-4;
GN Name=HNF4A; Synonyms=HNF4, NR2A1, TCF14;
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 HNF4-ALPHA-1; HNF4-ALPHA-2 AND
RP HNF4-ALPHA-3), AND VARIANT SER-445.
RC TISSUE=Liver;
RX PubMed=8964514; DOI=10.1016/0378-1119(96)00183-7;
RA Kritis A.A., Argyrokastritis A., Moschonas N.K., Power S.,
RA Katrakili N., Zannis V.I., Cereghini S., Talianidis I.;
RT "Isolation and characterization of a third isoform of human hepatocyte
RT nuclear factor 4.";
RL Gene 173:275-280(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND ALTERNATIVE SPLICING.
RC TISSUE=Kidney;
RX PubMed=8622695;
RA Drewes T., Senkel S., Holewa B., Ryffel G.U.;
RT "Human hepatocyte nuclear factor 4 isoforms are encoded by distinct
RT and differentially expressed genes.";
RL Mol. Cell. Biol. 16:925-931(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8945471; DOI=10.1038/384458a0;
RA Yamagata K., Furuta H., Oda N., Kaisaki P.J., Menzel S., Cox N.J.,
RA Fajans S.S., Signorini S., Stoffel M., Bell G.I.;
RT "Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-
RT onset diabetes of the young (MODY1).";
RL Nature 384:458-460(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND ALTERNATIVE PROMOTER USAGE (ISOFORMS
RP HNF4-ALPHA-7; HNF4-ALPHA-8 AND HNF4-ALPHA-9).
RA Tanaka T., Jiang S., Hotta H., Takano K., Iwanari H., Hirayama Y.,
RA Midorikawa Y., Hippo Y., Watanabe A., Yamashita H., Kumakura J.,
RA Uchiyama Y., Hasegawa G., Aburatani H., Hamakubo T., Naito M.,
RA Sakai J., Kodama T.;
RT "Variation in P1 and P2 promoter-driven hepatocyte nuclear factor-4a
RT (HNF4a) expression in human tissues: implications for
RT carcinogenesis.";
RL Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ILE-139 AND ILE-453.
RG SeattleSNPs variation discovery resource;
RL Submitted (MAY-2007) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M.,
RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H.,
RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM HNF4-ALPHA-3).
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 [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 4-474, AND ALTERNATIVE SPLICING.
RC TISSUE=Liver;
RX PubMed=7926813; DOI=10.1016/0378-1119(94)90079-5;
RA Chartier F.L., Bossu J.-P., Laudet V., Fruchart J.-C., Laine B.;
RT "Cloning and sequencing of cDNAs encoding the human hepatocyte nuclear
RT factor 4 indicate the presence of two isoforms in human liver.";
RL Gene 147:269-272(1994).
RN [10]
RP PHOSPHORYLATION.
RX PubMed=7568236; DOI=10.1073/pnas.92.21.9876;
RA Ktistaki E., Ktistakis N.T., Papadogeorgaki E., Talianidis I.;
RT "Recruitment of hepatocyte nuclear factor 4 into specific intranuclear
RT compartments depends on tyrosine phosphorylation that affects its DNA-
RT binding and transactivation potential.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:9876-9880(1995).
RN [11]
RP PHOSPHORYLATION AT SER-313, AND MUTAGENESIS OF SER-313.
RX PubMed=12740371; DOI=10.1074/jbc.M304112200;
RA Hong Y.H., Varanasi U.S., Yang W., Leff T.;
RT "AMP-activated protein kinase regulates HNF4alpha transcriptional
RT activity by inhibiting dimer formation and decreasing protein
RT stability.";
RL J. Biol. Chem. 278:27495-27501(2003).
RN [12]
RP PHOSPHORYLATION AT SER-142; THR-166; SER-167; THR-432 AND SER-436,
RP UBIQUITINATION AT LYS-234 AND LYS-307, AND ACETYLATION AT LYS-458.
RX PubMed=21708125; DOI=10.1016/j.bbrc.2011.06.033;
RA Yokoyama A., Katsura S., Ito R., Hashiba W., Sekine H., Fujiki R.,
RA Kato S.;
RT "Multiple post-translational modifications in hepatocyte nuclear
RT factor 4alpha.";
RL Biochem. Biophys. Res. Commun. 410:749-753(2011).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 142-378, AND FATTY ACID
RP BINDING.
RX PubMed=14982928; DOI=10.1074/jbc.M400864200;
RA Duda K., Chi Y.-I., Shoelson S.E.;
RT "Structural basis for HNF-4alpha activation by ligand and coactivator
RT binding.";
RL J. Biol. Chem. 279:23311-23316(2004).
RN [14]
RP VARIANT MODY1 TRP-136.
RX PubMed=9313765; DOI=10.2337/diacare.46.10.1652;
RA Furuta H., Iwasaki N., Oda N., Hinokio Y., Horikawa Y., Yamagata K.,
RA Yano N., Sugahiro J., Ogata M., Ohgawara H., Omori Y., Iwamoto Y.,
RA Bell G.I.;
RT "Organization and partial sequence of the hepatocyte nuclear factor-4-
RT alpha/MODY1 gene and identification of a missense mutation, R127W, in
RT a Japanese family with MODY.";
RL Diabetes 46:1652-1657(1997).
RN [15]
RP VARIANT MODY1 GLN-285.
RX PubMed=9243109; DOI=10.1007/s001250050760;
RA Bulman M.P., Dronsfield M.J., Frayling T.M., Appleton M., Bain S.C.,
RA Ellard S., Hattersley A.T.;
RT "A missense mutation in the hepatocyte nuclear factor 4 alpha gene in
RT a UK pedigree with maturity-onset diabetes of the young.";
RL Diabetologia 40:859-862(1997).
RN [16]
RP VARIANTS ILE-139 AND MET-264.
RX PubMed=9267996; DOI=10.1007/s001250050778;
RA Moeller A.M., Urhammer S.A., Dalgaard L.T., Reneland R., Berglund L.,
RA Hansen T., Clausen J.O., Lithell H., Pedersen O.;
RT "Studies of the genetic variability of the coding region of the
RT hepatocyte nuclear factor-4alpha in Caucasians with maturity onset
RT NIDDM.";
RL Diabetologia 40:980-983(1997).
RN [17]
RP VARIANT NIDDM ILE-402.
RX PubMed=9449683; DOI=10.1172/JCI1403;
RA Hani E.H., Suaud L., Boutin P., Chevre J.-C., Durand E., Philippi A.,
RA Demenais F., Vionnet N., Furuta H., Velho G., Bell G.I., Laine B.,
RA Froguel P.;
RT "A missense mutation in hepatocyte nuclear factor-4-alpha, resulting
RT in a reduced transactivation activity, in human late-onset non-
RT insulin-dependent diabetes mellitus.";
RL J. Clin. Invest. 101:521-526(1998).
RN [18]
RP CHARACTERIZATION OF MET-264, AND CHARACTERIZATION OF VARIANT MODY1
RP GLN-285.
RX PubMed=10389854; DOI=10.2337/diabetes.48.7.1459;
RA Navas M.A., Munoz-Elias E.J., Kim J., Shih D., Stoffel M.;
RT "Functional characterization of the MODY1 gene mutations HNF4(R127W),
RT HNF4(V255M), and HNF4(E276Q).";
RL Diabetes 48:1459-1465(1999).
CC -!- FUNCTION: Transcriptionally controlled transcription factor. Binds
CC to DNA sites required for the transcription of alpha 1-
CC antitrypsin, apolipoprotein CIII, transthyretin genes and HNF1-
CC alpha. May be essential for development of the liver, kidney and
CC intestine.
CC -!- SUBUNIT: Homodimerization is required for HNF4-alpha to bind to
CC its recognition site.
CC -!- INTERACTION:
CC Q99967:CITED2; NbExp=3; IntAct=EBI-1049011, EBI-937732;
CC A8MYZ6:FOXO6; NbExp=2; IntAct=EBI-1049011, EBI-8531039;
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage, Alternative splicing; Named isoforms=7;
CC Comment=Additional isoforms seem to exist;
CC Name=HNF4-Alpha-1; Synonyms=HNF-4B;
CC IsoId=P41235-1; Sequence=Displayed;
CC Note=Produced by alternative promoter usage;
CC Name=HNF4-Alpha-2; Synonyms=HNF4-A;
CC IsoId=P41235-2; Sequence=VSP_003674;
CC Note=Produced by alternative splicing of isoform HNF4-Alpha-1;
CC Name=HNF4-Alpha-3; Synonyms=HNF4-C;
CC IsoId=P41235-3; Sequence=VSP_003675;
CC Note=Produced by alternative splicing of isoform HNF4-Alpha-1;
CC Name=HNF4-Alpha-4;
CC IsoId=P41235-4; Sequence=VSP_003673;
CC Note=Produced by alternative splicing of isoform HNF4-Alpha-1;
CC Name=HNF4-Alpha-7;
CC IsoId=P41235-5; Sequence=VSP_026030;
CC Note=Produced by alternative promoter usage;
CC Name=HNF4-Alpha-8;
CC IsoId=P41235-6; Sequence=VSP_026030, VSP_003674;
CC Note=Produced by alternative splicing of isoform HNF4-Alpha-7;
CC Name=HNF4-Alpha-9;
CC IsoId=P41235-7; Sequence=VSP_026030, VSP_003675;
CC Note=Produced by alternative splicing of isoform HNF4-Alpha-7;
CC -!- PTM: Phosphorylated on tyrosine residue(s); phosphorylation is
CC important for its DNA-binding activity. Phosphorylation may
CC directly or indirectly play a regulatory role in the subnuclear
CC distribution. Phosphorylation at Ser-313 by AMPK reduces the
CC ability to form homodimers and bind DNA.
CC -!- PTM: Acetylation at Lys-458 lowers transcriptional activation by
CC about two-fold.
CC -!- DISEASE: Maturity-onset diabetes of the young 1 (MODY1)
CC [MIM:125850]: A form of diabetes that is characterized by an
CC autosomal dominant mode of inheritance, onset in childhood or
CC early adulthood (usually before 25 years of age), a primary defect
CC in insulin secretion and frequent insulin-independence at the
CC beginning of the disease. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM)
CC [MIM:125853]: A multifactorial disorder of glucose homeostasis
CC caused by a lack of sensitivity to the body's own insulin.
CC Affected individuals usually have an obese body habitus and
CC manifestations of a metabolic syndrome characterized by diabetes,
CC insulin resistance, hypertension and hypertriglyceridemia. The
CC disease results in long-term complications that affect the eyes,
CC kidneys, nerves, and blood vessels. Note=Disease susceptibility
CC may be associated with variations affecting the gene represented
CC in this entry.
CC -!- MISCELLANEOUS: Binds fatty acids.
CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR2
CC subfamily.
CC -!- SIMILARITY: Contains 1 nuclear receptor DNA-binding domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA54248.1; Type=Erroneous initiation;
CC Sequence=CAA61133.1; Type=Frameshift; Positions=2, 7;
CC Sequence=CAA61134.1; Type=Frameshift; Positions=2, 7;
CC Sequence=CAA61135.1; Type=Frameshift; Positions=2, 7;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/HNF4A";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Hepatocyte nuclear factors
CC entry;
CC URL="http://en.wikipedia.org/wiki/Hepatocyte_nuclear_factors";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/hnf4a/";
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DR EMBL; X87870; CAA61133.1; ALT_FRAME; mRNA.
DR EMBL; X87871; CAA61134.1; ALT_FRAME; mRNA.
DR EMBL; X87872; CAA61135.1; ALT_FRAME; mRNA.
DR EMBL; Z49825; CAA89989.1; -; mRNA.
DR EMBL; AY680696; AAT91237.1; -; mRNA.
DR EMBL; AY680697; AAT91238.1; -; mRNA.
DR EMBL; AY680698; AAT91239.1; -; mRNA.
DR EMBL; U72969; AAB48082.1; ALT_SEQ; Genomic_DNA.
DR EMBL; U72959; AAB48082.1; JOINED; Genomic_DNA.
DR EMBL; U72961; AAB48082.1; JOINED; Genomic_DNA.
DR EMBL; U72962; AAB48082.1; JOINED; Genomic_DNA.
DR EMBL; U72963; AAB48082.1; JOINED; Genomic_DNA.
DR EMBL; U72964; AAB48082.1; JOINED; Genomic_DNA.
DR EMBL; U72965; AAB48082.1; JOINED; Genomic_DNA.
DR EMBL; U72966; AAB48082.1; JOINED; Genomic_DNA.
DR EMBL; U72967; AAB48082.1; JOINED; Genomic_DNA.
DR EMBL; U72968; AAB48082.1; JOINED; Genomic_DNA.
DR EMBL; U72967; AAB48083.1; -; Genomic_DNA.
DR EMBL; U72959; AAB48083.1; JOINED; Genomic_DNA.
DR EMBL; U72961; AAB48083.1; JOINED; Genomic_DNA.
DR EMBL; U72962; AAB48083.1; JOINED; Genomic_DNA.
DR EMBL; U72963; AAB48083.1; JOINED; Genomic_DNA.
DR EMBL; U72964; AAB48083.1; JOINED; Genomic_DNA.
DR EMBL; U72965; AAB48083.1; JOINED; Genomic_DNA.
DR EMBL; U72966; AAB48083.1; JOINED; Genomic_DNA.
DR EMBL; EF591040; ABQ52204.1; -; Genomic_DNA.
DR EMBL; AL132772; CAC01303.1; -; Genomic_DNA.
DR EMBL; AL132772; CAI18856.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW75924.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW75925.1; -; Genomic_DNA.
DR EMBL; BC137539; AAI37540.1; -; mRNA.
DR EMBL; BC137540; AAI37541.1; -; mRNA.
DR EMBL; X76930; CAA54248.1; ALT_INIT; mRNA.
DR PIR; JC4937; JC4937.
DR PIR; JC4938; JC4938.
DR PIR; JC6096; JC6096.
DR RefSeq; NP_000448.3; NM_000457.4.
DR RefSeq; NP_001025174.1; NM_001030003.2.
DR RefSeq; NP_001025175.1; NM_001030004.2.
DR RefSeq; NP_001245284.1; NM_001258355.1.
DR RefSeq; NP_787110.2; NM_175914.4.
DR RefSeq; NP_849181.1; NM_178850.2.
DR UniGene; Hs.116462; -.
DR PDB; 1PZL; X-ray; 2.10 A; A=142-378.
DR PDB; 3CBB; X-ray; 2.00 A; A/B=58-135.
DR PDB; 3FS1; X-ray; 2.20 A; A=148-377.
DR PDB; 4B7W; X-ray; 4.00 A; A/B/C/D=142-377.
DR PDB; 4IQR; X-ray; 2.90 A; A/B/E/F=55-377.
DR PDBsum; 1PZL; -.
DR PDBsum; 3CBB; -.
DR PDBsum; 3FS1; -.
DR PDBsum; 4B7W; -.
DR PDBsum; 4IQR; -.
DR ProteinModelPortal; P41235; -.
DR SMR; P41235; 58-377.
DR DIP; DIP-499N; -.
DR IntAct; P41235; 3.
DR MINT; MINT-269829; -.
DR BindingDB; P41235; -.
DR ChEMBL; CHEMBL5398; -.
DR GuidetoPHARMACOLOGY; 608; -.
DR PhosphoSite; P41235; -.
DR DMDM; 148886624; -.
DR PaxDb; P41235; -.
DR PRIDE; P41235; -.
DR Ensembl; ENST00000316099; ENSP00000312987; ENSG00000101076.
DR Ensembl; ENST00000316673; ENSP00000315180; ENSG00000101076.
DR Ensembl; ENST00000415691; ENSP00000412111; ENSG00000101076.
DR Ensembl; ENST00000443598; ENSP00000410911; ENSG00000101076.
DR Ensembl; ENST00000457232; ENSP00000396216; ENSG00000101076.
DR GeneID; 3172; -.
DR KEGG; hsa:3172; -.
DR UCSC; uc002xma.4; human.
DR CTD; 3172; -.
DR GeneCards; GC20P042984; -.
DR HGNC; HGNC:5024; HNF4A.
DR HPA; CAB019417; -.
DR HPA; HPA004712; -.
DR MIM; 125850; phenotype.
DR MIM; 125853; phenotype.
DR MIM; 600281; gene.
DR MIM; 606391; phenotype.
DR neXtProt; NX_P41235; -.
DR Orphanet; 263455; Hyperinsulinism due to HNF4A deficiency.
DR Orphanet; 552; MODY syndrome.
DR PharmGKB; PA29349; -.
DR eggNOG; NOG241134; -.
DR HOVERGEN; HBG005606; -.
DR KO; K07292; -.
DR OMA; ANTMPSH; -.
DR OrthoDB; EOG7K3TKX; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_71; Gene Expression.
DR SignaLink; P41235; -.
DR EvolutionaryTrace; P41235; -.
DR GeneWiki; Hepatocyte_nuclear_factor_4_alpha; -.
DR GenomeRNAi; 3172; -.
DR NextBio; 12578; -.
DR PRO; PR:P41235; -.
DR ArrayExpress; P41235; -.
DR Bgee; P41235; -.
DR Genevestigator; P41235; -.
DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005504; F:fatty acid binding; IDA:BHF-UCL.
DR GO; GO:0004879; F:ligand-activated sequence-specific DNA binding RNA polymerase II transcription factor activity; IEA:InterPro.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:BHF-UCL.
DR GO; GO:0005102; F:receptor binding; IDA:BHF-UCL.
DR GO; GO:0001102; F:RNA polymerase II activating transcription factor binding; ISS:BHF-UCL.
DR GO; GO:0001077; F:RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription; ISS:BHF-UCL.
DR GO; GO:0003705; F:RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity; IEA:Ensembl.
DR GO; GO:0043565; F:sequence-specific DNA binding; IEA:Ensembl.
DR GO; GO:0003707; F:steroid hormone receptor activity; IEA:InterPro.
DR GO; GO:0044212; F:transcription regulatory region DNA binding; IDA:BHF-UCL.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0007596; P:blood coagulation; IDA:BHF-UCL.
DR GO; GO:0031018; P:endocrine pancreas development; TAS:Reactome.
DR GO; GO:0042593; P:glucose homeostasis; ISS:BHF-UCL.
DR GO; GO:0030522; P:intracellular receptor signaling pathway; IEA:GOC.
DR GO; GO:0006629; P:lipid metabolic process; IEA:Ensembl.
DR GO; GO:0030308; P:negative regulation of cell growth; IMP:BHF-UCL.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IMP:BHF-UCL.
DR GO; GO:0006591; P:ornithine metabolic process; IMP:BHF-UCL.
DR GO; GO:0055091; P:phospholipid homeostasis; ISS:BHF-UCL.
DR GO; GO:2000189; P:positive regulation of cholesterol homeostasis; ISS:BHF-UCL.
DR GO; GO:0010470; P:regulation of gastrulation; IEA:Ensembl.
DR GO; GO:0060398; P:regulation of growth hormone receptor signaling pathway; NAS:BHF-UCL.
DR GO; GO:0050796; P:regulation of insulin secretion; ISS:BHF-UCL.
DR GO; GO:0019216; P:regulation of lipid metabolic process; IDA:BHF-UCL.
DR GO; GO:0009749; P:response to glucose stimulus; ISS:BHF-UCL.
DR GO; GO:0007548; P:sex differentiation; IEA:Ensembl.
DR GO; GO:0023019; P:signal transduction involved in regulation of gene expression; IEA:Ensembl.
DR GO; GO:0060395; P:SMAD protein signal transduction; IEA:Ensembl.
DR GO; GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0070328; P:triglyceride homeostasis; ISS:BHF-UCL.
DR GO; GO:0006805; P:xenobiotic metabolic process; IMP:BHF-UCL.
DR Gene3D; 1.10.565.10; -; 1.
DR Gene3D; 3.30.50.10; -; 1.
DR InterPro; IPR003068; COUP_TF.
DR InterPro; IPR008946; Nucl_hormone_rcpt_ligand-bd.
DR InterPro; IPR000536; Nucl_hrmn_rcpt_lig-bd_core.
DR InterPro; IPR001723; Str_hrmn_rcpt.
DR InterPro; IPR001628; Znf_hrmn_rcpt.
DR InterPro; IPR013088; Znf_NHR/GATA.
DR Pfam; PF00104; Hormone_recep; 1.
DR Pfam; PF00105; zf-C4; 1.
DR PRINTS; PR01282; COUPTNFACTOR.
DR PRINTS; PR00398; STRDHORMONER.
DR PRINTS; PR00047; STROIDFINGER.
DR SMART; SM00430; HOLI; 1.
DR SMART; SM00399; ZnF_C4; 1.
DR SUPFAM; SSF48508; SSF48508; 1.
DR PROSITE; PS00031; NUCLEAR_REC_DBD_1; 1.
DR PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative promoter usage;
KW Alternative splicing; Complete proteome; Diabetes mellitus;
KW Disease mutation; DNA-binding; Isopeptide bond; Metal-binding;
KW Nucleus; Phosphoprotein; Polymorphism; Receptor; Reference proteome;
KW Transcription; Transcription regulation; Ubl conjugation; Zinc;
KW Zinc-finger.
FT CHAIN 1 474 Hepatocyte nuclear factor 4-alpha.
FT /FTId=PRO_0000053558.
FT DNA_BIND 57 132 Nuclear receptor.
FT ZN_FING 60 80 NR C4-type.
FT ZN_FING 96 120 NR C4-type.
FT MOD_RES 142 142 Phosphoserine.
FT MOD_RES 166 166 Phosphothreonine.
FT MOD_RES 167 167 Phosphoserine.
FT MOD_RES 313 313 Phosphoserine; by AMPK.
FT MOD_RES 429 429 Phosphothreonine (By similarity).
FT MOD_RES 432 432 Phosphothreonine.
FT MOD_RES 436 436 Phosphoserine.
FT MOD_RES 458 458 N6-acetyllysine.
FT CROSSLNK 234 234 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 307 307 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VAR_SEQ 1 38 MRLSKTLVDMDMADYSAALDPAYTTLEFENVQVLTMGN ->
FT MVSVNAPLGAPVESSY (in isoform HNF4-Alpha-
FT 7, isoform HNF4-Alpha-8 and isoform HNF4-
FT Alpha-9).
FT /FTId=VSP_026030.
FT VAR_SEQ 38 38 N -> NDLLPLRLARLRHPLRHHWSISGGVDSSPQG (in
FT isoform HNF4-Alpha-4).
FT /FTId=VSP_003673.
FT VAR_SEQ 378 474 SPSDAPHAHHPLHPHLMQEHMGTNVIVANTMPTHLSNGQMC
FT EWPRPRGQAATPETPQPSPPGGSGSEPYKLLPGAVATIVKP
FT LSAIPQPTITKQEVI -> PCQAQEGRGWSGDSPGDRPHTV
FT SSPLSSLASPLCRFGQVA (in isoform HNF4-
FT Alpha-3 and isoform HNF4-Alpha-9).
FT /FTId=VSP_003675.
FT VAR_SEQ 418 428 CEWPRPRGQAA -> S (in isoform HNF4-Alpha-2
FT and isoform HNF4-Alpha-8).
FT /FTId=VSP_003674.
FT VARIANT 136 136 R -> W (in MODY1; dbSNP:rs137853336).
FT /FTId=VAR_004668.
FT VARIANT 139 139 T -> I (in dbSNP:rs1800961).
FT /FTId=VAR_004669.
FT VARIANT 264 264 V -> M (rare polymorphism found in a
FT patient with non-insulin-dependent
FT diabetes mellitus; does not affect
FT activity; dbSNP:rs139779712).
FT /FTId=VAR_010600.
FT VARIANT 285 285 E -> Q (in MODY1; results in loss of
FT function).
FT /FTId=VAR_010601.
FT VARIANT 402 402 V -> I (in NIDDM; reduced transactivation
FT activity; dbSNP:rs137853337).
FT /FTId=VAR_004670.
FT VARIANT 445 445 P -> S (in dbSNP:rs1063239).
FT /FTId=VAR_011785.
FT VARIANT 453 453 V -> I.
FT /FTId=VAR_062267.
FT MUTAGEN 313 313 S->A: Abolishes AMPK-mediated
FT phosphorylation.
FT MUTAGEN 313 313 S->D: Phosphomimetic mutant that leads to
FT reduced ability to bind DNA.
FT CONFLICT 440 440 G -> A (in Ref. 9; CAA54248).
FT TURN 61 63
FT STRAND 64 66
FT STRAND 69 71
FT HELIX 78 89
FT STRAND 97 100
FT TURN 106 111
FT HELIX 113 123
FT HELIX 127 129
FT HELIX 149 153
FT HELIX 155 163
FT TURN 176 178
FT HELIX 184 202
FT HELIX 206 209
FT HELIX 213 222
FT HELIX 224 236
FT STRAND 239 244
FT STRAND 250 254
FT HELIX 256 261
FT HELIX 262 271
FT HELIX 273 279
FT HELIX 283 294
FT HELIX 305 324
FT STRAND 325 328
FT HELIX 333 338
FT HELIX 340 360
FT HELIX 368 374
SQ SEQUENCE 474 AA; 52785 MW; 5F1309B89D95DCAF CRC64;
MRLSKTLVDM DMADYSAALD PAYTTLEFEN VQVLTMGNDT SPSEGTNLNA PNSLGVSALC
AICGDRATGK HYGASSCDGC KGFFRRSVRK NHMYSCRFSR QCVVDKDKRN QCRYCRLKKC
FRAGMKKEAV QNERDRISTR RSSYEDSSLP SINALLQAEV LSRQITSPVS GINGDIRAKK
IASIADVCES MKEQLLVLVE WAKYIPAFCE LPLDDQVALL RAHAGEHLLL GATKRSMVFK
DVLLLGNDYI VPRHCPELAE MSRVSIRILD ELVLPFQELQ IDDNEYAYLK AIIFFDPDAK
GLSDPGKIKR LRSQVQVSLE DYINDRQYDS RGRFGELLLL LPTLQSITWQ MIEQIQFIKL
FGMAKIDNLL QEMLLGGSPS DAPHAHHPLH PHLMQEHMGT NVIVANTMPT HLSNGQMCEW
PRPRGQAATP ETPQPSPPGG SGSEPYKLLP GAVATIVKPL SAIPQPTITK QEVI
//

MIM 125850
*RECORD*
*FIELD* NO
125850
*FIELD* TI
#125850 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 1; MODY1
;;MODY, TYPE 1;;
MILD JUVENILE DIABETES MELLITUS
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that type
1 maturity-onset diabetes of the young (MODY) can be caused by mutation
in the gene encoding hepatocyte nuclear factor-4-alpha (HNF4A; 600281)
on chromosome 20.

Fajans et al. (2001) reported that mutation in the HNF4A gene is a
relatively uncommon cause of MODY. They stated that only 13 families had
been identified as having this form of MODY.

CLINICAL FEATURES

In their review of MODY, Fajans et al. (2001) stated that, not
unexpectedly, the pathophysiologic mechanisms of MODY due to mutations
in HNF4A (MODY1) and MODY due to mutations in the HNF1A gene (MODY3;
142410) are very similar since HNF4-alpha regulates the expression of
HNF1-alpha. Patients with mutations in these genes may present with a
mild form of diabetes. Despite similarly mild elevations in fasting
plasma glucose concentrations, patients with mutations in HNF4A or HNF1A
have significantly higher plasma glucose concentrations 2 hours after
glucose administration than do persons with glucokinase mutations
(MODY2; 125851). The hyperglycinemia in patients with MODY1 and MODY3
tends to increase over time, resulting in the need for treatment with
oral hypoglycemic drugs or insulin in many of these patients (30 to 40%
require insulin). These forms of MODY are associated with a progressive
decrease in insulin secretion. In most populations, mutations in the
HNF1A gene are the most common cause of MODY. Patients with MODY1 or
MODY3 may have the full spectrum of complications of diabetes.
Microvascular complications, particularly those involving the retina or
kidneys, are as common in these patients as in patients with type 1 or
type 2 diabetes (matched according to the duration of diabetes and the
degree of glycemic control) and are probably determined by the degree of
glycemic control. Patients with MODY1 lose the glucose priming effect of
mild hyperglycemia on insulin secretion. Both prediabetic and diabetic
persons with mutations in the HNF4A gene secrete decreased amounts of
insulin in response to glucose and in response to arginine and also have
an impairment of glucagon secretion in response to arginine.
Furthermore, a defect in the hypoglycemia-induced secretion of
pancreatic polypeptide has been found in prediabetic and diabetic
persons who have mutations in the gene for HNF4A. These findings
suggested that a deficiency of HNF4A resulting from mutations in this
gene may affect the function of the beta, alpha, and pancreatic
polypeptide cells within pancreatic islets. Patients with mutations in
HNF1A have decreased renal absorption of glucose (i.e., a low renal
threshold for glucose) and glycosuria. A deficiency of HNF4A affects
triglyceride and apolipoprotein biosynthesis and is associated with a
50% reduction in serum triglyceride concentrations and a 25% reduction
in serum concentrations of apolipoproteins AII and CIII and Lp(a).

Most of the diabetic subjects in the well-studied R-W pedigree with MODY
reported by Fajans (1989, 1990) had a reduced and delayed secretory
response to glucose. A similar secretory response to glucose has been
observed in many patients with late-age-of-onset forms of
noninsulin-dependent diabetes mellitus (NIDDM) in the absence of
islet-cell antibodies. Other MODY families have a 'hyperinsulinemic'
response to glucose (Fajans, 1987) as is seen in the majority of NIDDM
patients early in the natural history of their disease. Byrne et al.
(1995) concluded that members of the R-W family who inherited the
at-risk allele of the MODY1 gene have a characteristic pattern of
altered insulin secretory responses to glucose. These alterations are
present before the onset of hyperglycemia, suggesting a unique mechanism
of beta-cell dysfunction different from the defect in MODY subjects with
glucokinase mutation.

MAPPING

In the well-studied R-W pedigree with MODY reported by Fajans (1989,
1990), Bell et al. (1991) found linkage with a DNA polymorphism in the
adenosine deaminase gene (608958); maximum lod = 5.25 at theta = 0.00.
This places the MODY gene on chromosome 20q, probably in 20q13.

Bowden et al. (1992) reported an Edinburgh family and a Wisconsin family
in which MODY was not linked to chromosome 20 markers. Furthermore, they
observed a large multigeneration kindred in which early-onset
noninsulin-dependent diabetes mellitus was linked to markers on
chromosome 20 in one branch, whereas no linkage to chromosome 20 markers
could be found in the NIDDM in 2 other branches.

Rothschild et al. (1993) reported multiple highly polymorphic markers in
the 20q12-q13.1 region useful in the study of MODY families and in the
further genetic and physical mapping of the region.

Stoffel et al. (1996) created a YAC contig consisting of 71 clones and
spanning a region of about 18 Mb, which represents about 40% of the
physical length of 20q. Using this physical map, they refined the
location of MODY1 to a 13-cM interval (approximately 7 Mb) between
D20S169 and D20S176.

MOLECULAR GENETICS

The R-W pedigree, which included more than 360 members spanning 6
generations and 74 members with diabetes, including those with MODY, had
been studied prospectively since 1958 (Fajans, 1989). The members of
this family were descendants of a couple that immigrated from East
Prussia to Detroit, Michigan in 1861 with their 4 sons, 3 of whom were
diabetic, and 5 daughters, 1 of whom was diabetic. Linkage studies, as
indicated earlier, showed that the gene responsible for MODY in this
family is tightly linked to 20q12-q13.1. The demonstration that the gene
for HNF1A is the site of mutations causing MODY3 prompted Yamagata et
al. (1996) to screen the gene for HNF4A, which is known to map to
chromosome 20, for a mutation in the R-W pedigree. A gln268-to-ter
nonsense mutation was demonstrated (600281.0001).

Lindner et al. (1997) observed an R154X mutation in HNF4-alpha
(600281.0002) in a 3-generation German family, Dresden-11. Lindner et
al. (1997) reported no abnormalities in liver or renal function, despite
severe diabetes requiring insulin or oral hypoglycemic agents, in 6
affected members of this pedigree. The phenotype was similar to that
seen in the R-W pedigree. The results suggested to the authors that
MODY1 is primarily a disorder of beta-cell function.

To determine the prevalence of MODY1, Moller et al. (1999) screened 10
Danish non-MODY3 probands for mutations in the minimal promoter and the
12 exons of the HNF4-alpha gene. They found a frameshift mutation
(phe75fsdelT; 600281.0005) in 1 proband. They concluded that defects in
the HNF4-alpha gene are a rare cause of MODY in Denmark.

Thomas et al. (2001) identified an alternative promoter of the
HNF4-alpha gene, P2, which is 46 kb 5-prime to the previously identified
P1 promoter of the human gene. Based on RT-PCR, this distant upstream P2
promoter represents the major transcription site in pancreatic
beta-cells, and is also used in hepatic cells. Transfection assays with
various deletions and mutants of the P2 promoter revealed functional
binding sites for HNF1-alpha, HNF1-beta, and IPF1 (600733), the other
transcription factors known to encode MODY genes. In a large MODY
family, a mutated IPF1 binding site in the P2 promoter of the HNF4-alpha
gene cosegregated with diabetes (lod score 3.25). The authors proposed a
regulatory network of the 4 MODY transcription factors interconnected at
the distant upstream P2 promoter of the HNF4-alpha gene.

Pearson et al. (2007) studied 108 members of 15 families with MODY1 and
found that birth weights were significantly higher in mutation carriers
(p less than 0.001), with 30 (56%) of 54 mutation-positive infants being
macrosomic compared to 7 (13%) of 54 mutation-negative infants (p less
than 0.001). In addition, 8 of 54 mutation-positive infants had
transient hypoglycemia versus none of the 54 mutation-negative infants
(p = 0.003), and inappropriate hyperinsulinemia was documented in all 3
hypoglycemic cases tested (see, e.g., 600281.0007). The authors
concluded that mutations in HNF4A are associated with increased birth
weight and macrosomia, and that the natural history of MODY1 includes
hyperinsulinemia at birth that evolves to decreased insulin secretion
and diabetes later in life.

GENOTYPE/PHENOTYPE CORRELATIONS

Barrio et al. (2002) estimated the prevalence of major MODY subtypes in
Spanish MODY families and analyzed genotype-phenotype correlations.
Twenty-two unrelated pediatric MODY patients and 97 relatives were
screened for mutations in the coding region of the GCK (138079), HNF1A,
and HNF4A genes using PCR-SSCP and/or direct sequencing. Mutations in
MODY genes were identified in 64% of the families. GCK/MODY2 mutations
were the most frequently found, in 41%: 7 novel and 2 theretofore
described mutations. Four pedigrees (18%) harbored mutations in the
HNF1A/MODY3 gene, including a previously unreported change. One family
(4%) carried a novel mutation in the HNF4A gene (IVS5-2delA;
600281.0006), representing the first report of a MODY1 pedigree in the
Spanish population. Clinical expression of MODY3 and MODY1 mutations,
the second and third most frequent groups of defects found, was more
severe, including the frequent development of chronic complications.

*FIELD* SA
Falk et al. (1978); Froguel and Velho (1999)
*FIELD* RF
1. Barrio, R.; Bellanne-Chantelot, C.; Moreno, J. C.; Morel, V.; Calle,
H.; Alonso, M.; Mustieles, C.: Nine novel mutations in maturity-onset
diabetes of the young (MODY) candidate genes in 22 Spanish families. J.
Clin. Endocr. Metab. 87: 2532-2539, 2002.

2. Bell, G. I.; Xiang, K.; Newman, M. V.; Wu, S.; Wright, L. G.; Fajans,
S. S.; Spielman, R. S.; Cox, N. J.: Gene for non-insulin-dependent
diabetes mellitus (maturity-onset diabetes of the young subtype) is
linked to DNA polymorphism on human chromosome 20q. Proc. Nat. Acad.
Sci. 88: 1484-1488, 1991.

3. Bowden, D. W.; Akots, G.; Rothschild, C. B.; Falls, K. F.; Sheehy,
M. J.; Hayward, C.; Mackie, A.; Baird, J.; Brock, D.; Antonarakis,
S. E.; Fajans, S. S.: Linkage analysis of maturity-onset diabetes
of the young (MODY): genetic heterogeneity and nonpenetrance. Am.
J. Hum. Genet. 50: 607-618, 1992.

4. Byrne, M. M.; Sturis, J.; Fajans, S. S.; Ortiz, F. J.; Stoltz,
A.; Stoffel, M.; Smith, M. J.; Bell, G. I.; Halter, J. B.; Polonsky,
K. S.: Altered insulin secretory responses to glucose in subjects
with a mutation in the MODY1 gene on chromosome 20. Diabetes 44:
699-704, 1995.

5. Fajans, S. S.: Maturity-onset diabetes of the young (MODY). Diabetes
Metab. Rev. 5: 579-606, 1989.

6. Fajans, S. S.: MODY: a model for understanding the pathogenesis
and natural history of type II diabetes. Hormone Metab. Res. 19:
591-599, 1987.

7. Fajans, S. S.: Scope and heterogeneous nature of MODY. Diabetes
Care 13: 49-64, 1990. Note: Erratum: Diabetes Care 13: following
Table of Contents, 1990; Diabetes Care 13: 910 only, 1990.

8. Fajans, S. S.; Bell, G. I.; Polonsky, K. S.: Molecular mechanisms
and clinical pathophysiology of maturity-onset diabetes of the young. New
Eng. J. Med. 345: 971-980, 2001.

9. Falk, C. T.; Suciu-Foca, N.; Rubinstein, P.: Possible localization
of the gene(s) for juvenile diabetes mellitus (JDM) to the HLA region
of chromosome 6. Cytogenet. Cell Genet. 22: 298-300, 1978.

10. Froguel, P.; Velho, G.: Molecular genetics of maturity-onset
diabetes of the young. Trends Endocr. Metab. 10: 142-146, 1999.

11. Lindner, T.; Gragnoli, C.; Furuta, H.; Cockburn, B. N.; Petzold,
C.; Rietzsch, H.; Weiss, U.; Schulze, J.; Bell, G. I.: Hepatic function
in a family with a nonsense mutation (R154X) in the hepatocyte nuclear
factor-4-alpha/MODY1 gene. J. Clin. Invest. 100: 1400-1405, 1997.

12. Moller, A. M.; Dalgaard, L. T.; Ambye, L.; Hansen, L.; Schmitz,
O.; Hansen, T.; Pedersen, O.: A novel Phe75fsdelT mutation in the
hepatocyte nuclear factor-4-alpha gene in a Danish pedigree with maturity-onset
diabetes of the young. J. Clin. Endocr. Metab. 84: 367-369, 1999.

13. Pearson, E. R.; Boj, S. F.; Steele, A. M.; Barrett, T.; Stals,
K.; Shield, J. P.; Ellard, S.; Ferrer, J.; Hattersley, A. T.: Macrosomia
and hyperinsulinaemic hypoglycaemia in patients with heterozygous
mutations in the HNF4A gene. PLoS Med. 4: e118, 2007. Note: Electronic
Article.

14. Rothschild, C. B.; Akots, G.; Hayworth, R.; Pettenati, M. J.;
Rao, P. N.; Wood, P.; Stolz, F.-M.; Hansmann, I.; Serino, K.; Keith,
T. P.; Fajans, S. S.; Bowden, D. W.: A genetic map of chromosome
20q12-q13.1: multiple highly polymorphic microsatellite and RFLP markers
linked to the maturity-onset diabetes of the young (MODY) locus. Am.
J. Hum. Genet. 52: 110-123, 1993.

15. Stoffel, M.; Le Beau, M. M.; Espinosa, R., III; Bohlander, S.
F.; Le Paslier, D.; Cohen, D.; Xiang, K.-S.; Cox, N. J.; Fajans, S.
S.; Bell, G. I.: A yeast artificial chromosome-based map of the region
of chromosome 20 containing the diabetes-susceptibility gene, MODY1,
and a myeloid leukemia related gene. Proc. Nat. Acad. Sci. 93: 3937-3941,
1996.

16. Thomas, H.; Jaschkowitz, K.; Bulman, M.; Frayling, T. M.; Mitchell,
S. M. S.; Roosen, S.; Lingott-Frieg, A.; Tack, C. J.; Ellard, S.;
Ryffel, G. U.; Hattersley, A. T.: A distant upstream promoter of
the HNF-4-alpha gene connects the transcription factors involved in
maturity-onset diabetes of the young. Hum. Molec. Genet. 10: 2089-2097,
2001.

17. Yamagata, K.; Furuta, H.; Oda, N.; Kalsaki, P. J.; Menzel, S.;
Cox, N. J.; Fajans, S. S.; Signorini, S.; Stoffel, M.; Bell, G. I.
: Mutations in the hepatocyte nuclear factor-4-alpha gene in maturity-onset
diabetes of the young (MODY1). Nature 384: 458-460, 1996.

*FIELD* CS

Endo:
Diabetes mellitus

Misc:
Early onset, mild and relatively uncomplicated course;
Chlorpropamide-alcohol flushing may be a marker for this form

Inheritance:
Autosomal dominant (20q12-q13.1)

*FIELD* CN
Marla J. F. O'Neill - updated: 5/6/2008
John A. Phillips, III - updated: 1/10/2003
George E. Tiller - updated: 2/8/2002
Ada Hamosh - updated: 10/18/2001
Victor A. McKusick - updated: 10/8/2001
John A. Phillips, III - updated: 9/29/2000
John A. Phillips, III - updated: 11/17/1999
Ada Hamosh - updated: 10/20/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
tpirozzi: 07/11/2013
carol: 4/16/2013
carol: 4/4/2013
terry: 4/19/2010
terry: 2/19/2009
carol: 2/16/2009
carol: 5/8/2008
terry: 5/6/2008
ckniffin: 10/28/2004
alopez: 1/10/2003
cwells: 2/19/2002
cwells: 2/8/2002
carol: 10/18/2001
carol: 10/16/2001
carol: 10/8/2001
alopez: 10/4/2000
mgross: 10/3/2000
terry: 9/29/2000
carol: 2/3/2000
alopez: 11/17/1999
alopez: 11/5/1999
mgross: 11/4/1999
alopez: 12/8/1997
alopez: 11/19/1997
alopez: 7/29/1997
alopez: 7/7/1997
mark: 1/3/1997
mark: 12/4/1996
terry: 12/3/1996
mark: 5/31/1996
terry: 5/28/1996
mark: 10/5/1995
mimadm: 6/25/1994
warfield: 4/8/1994
carol: 10/26/1993
carol: 3/1/1993
carol: 8/25/1992

MIM 125853
*RECORD*
*FIELD* NO
125853
*FIELD* TI
#125853 DIABETES MELLITUS, NONINSULIN-DEPENDENT; NIDDM
;;DIABETES MELLITUS, TYPE II; T2D;;
read moreNONINSULIN-DEPENDENT DIABETES MELLITUS;;
MATURITY-ONSET DIABETES
INSULIN RESISTANCE, SUSCEPTIBILITY TO, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that more
than one gene is involved in the causation of noninsulin-dependent
diabetes mellitus (NIDDM).

See 601283 for description of a form of NIDDM linked to 2q, which may be
caused by mutation in the gene encoding calpain-10 (CAPN10; 605286). See
601407 for description of a chromosome 12q locus, NIDDM2, found in a
Finnish population. See 603694 for description of a locus on chromosome
20, NIDDM3.

A mutation has been observed in hepatocyte nuclear factor-4-alpha
(HNF4A; 600281.0004) in a French family with NIDDM of late onset.
Mutations in the NEUROD1 gene (601724) on chromosome 2q32 were found to
cause type II diabetes mellitus in 2 families. Mutation in the GLUT4
glucose transporter was associated with NIDDM in 1 patient (138190.0001)
and in the GLUT2 glucose transporter in another (138160.0001). Mutation
in the MAPK8IP1 gene, which encodes the islet-brain-1 protein, was found
in a family with type II diabetes in individuals in 4 successive
generations (604641.0001). Polymorphism in the KCNJ11 gene (600937.0014)
confers susceptibility. In French white families, Vionnet et al. (2000)
found evidence for a susceptibility locus for type II diabetes on
3q27-qter. They confirmed the diabetes susceptibility locus on 1q21-q24
reported by Elbein et al. (1999) in whites and by Hanson et al. (1998)
in Pima Indians. A mutation in the GPD2 gene (138430.0001) on chromosome
2q24.1, encoding mitochondrial glycerophosphate dehydrogenase, was found
in a patient with type II diabetes mellitus and in his
glucose-intolerant half sister. Mutations in the PAX4 gene (167413) have
been identified in patients with type II diabetes. Triggs-Raine et al.
(2002) stated that in the Oji-Cree, a gly319-to-ser change in HNF1-alpha
(142410.0008) behaves as a susceptibility allele for type II diabetes.
Mutation in the HNF1B gene (189907.0007) was found in 2 Japanese
patients with typical late-onset type II diabetes. Mutations in the IRS1
gene (147545) have been found in patients with type II diabetes.
Reynisdottir et al. (2003) mapped a susceptibility locus for type II
diabetes to chromosome 5q34-q35.2 (NIDDM4; 608036). A missense mutation
in the AKT2 gene (164731.0001) caused autosomal dominant type II
diabetes in 1 family. A (single-nucleotide polymorphism) SNP in the
3-prime untranslated region of the resistin gene (605565.0001) was
associated with susceptibility to diabetes and to insulin
resistance-related hypertension in Chinese subjects. Susceptibility to
insulin resistance has been associated with polymorphism in the TCF1
(142410.0011), PPP1R3A (600917.0001), PTPN1 (176885.0001), ENPP1
(173335.0006), IRS1 (147545.0002), and EPHX2 (132811.0001) genes. The
K121Q polymorphism of ENPP1 (173335.0006) is associated with
susceptibility to type II diabetes; a haplotype defined by 3 SNPs of
this gene, including K121Q, is associated with obesity, glucose
intolerance, and type II diabetes. A SNP in the promoter region of the
hepatic lipase gene (151670.0004) predicts conversion from impaired
glucose tolerance to type II diabetes. Variants of transcription factor
7-like-2 (TCF7L2; 602228.0001), located on 10q, have also been found to
confer risk of type II diabetes. A common sequence variant, dbSNP
rs10811661, on chromosome 9p21 near the CDKN2A (600160) and CDKN2B
(600431) genes has been associated with risk of type II diabetes.
Variation in the PPARG gene (601487) has been associated with risk of
type 2 diabetes. A promoter polymorphism in the IL6 gene (147620) is
associated with susceptibility to NIDDM. Variation in the KCNJ15 gene
(602106) has been associated with T2DM in lean Asians. Variation in the
HMGA1 gene (600701.0001) is associated with an increased risk of type II
diabetes. Mutation in the MTNR1B gene (600804) is associated with
susceptibility to type 2 diabetes.

Noninsulin-dependent diabetes mellitus is distinct from MODY (606391) in
that it is polygenic, characterized by gene-gene and gene-environment
interactions with onset in adulthood, usually at age 40 to 60 but
occasionally in adolescence if a person is obese. The pedigrees are
rarely multigenerational. The penetrance is variable, possibly 10 to 40%
(Fajans et al., 2001). Persons with type II diabetes usually have an
obese body habitus and manifestations of the so-called metabolic
syndrome (see 605552), which is characterized by diabetes, insulin
resistance, hypertension, and hypertriglyceridemia.

INHERITANCE

In 3 families with MODY and 7 with 'common' type II diabetes mellitus,
O'Rahilly et al. (1992) excluded linkage to the INS locus (176730).
Exclusive of the mendelian forms of NIDDM represented by MODY, the high
incidence of diabetes in certain populations and among first-degree
relatives of type II diabetic patients, as well as the high concordance
in identical twins, provides strong evidence that genetic factors
underlie susceptibility to the common form of NIDDM which affects up to
6% of the United States population. Although defects in both insulin
secretion and insulin action may be necessary for disease expression in
groups with a high incidence of NIDDM, such as offspring of type II
diabetic parents and Pima Indians, insulin resistance and decreased
glucose disposal can be shown to precede and predict the onset of
diabetes (Martin et al., 1992; Bogardus et al., 1989). In both of these
groups, relatives and Pima Indians, there is evidence of familial
clustering of insulin sensitivity. Thus, insulin resistance appears to
be a central feature of NIDDM and may be an early and inherited marker
of the disorder.

Martinez-Marignac et al. (2007) analyzed and discussed the use of
admixture mapping of type 2 diabetes genetic risk factors in Mexico
City. Type 2 diabetes is at least twice as prevalent in Native American
populations as in populations of European ancestry. The authors
characterized the admixture proportions in a sample of 286 unrelated
type 2 diabetes patients and 275 controls from Mexico City. Admixture
proportions were estimated using 69 autosomal ancestry-informative
markers (AIMs). The average proportions of Native American, European,
and West African admixture were estimated as 65%, 30%, and 5%,
respectively. The contributions of Native American ancestors to maternal
and paternal lineages were estimated as 90% and 40%, respectively. In a
logistic model with higher educational status as dependent variable, the
odds ratio for higher educational status associated with an increase
from 0 to 1 in European admixture proportions was 9.4. This association
of socioeconomic status with individual admixture proportion showed that
genetic stratification in this population is paralleled, and possibly
maintained, by socioeconomic stratification. The effective number of
generations back to unadmixed ancestors was 6.7, from which
Martinez-Marignac et al. (2007) could estimate the number of evenly
distributed AIMs required to localize genes underlying disease risk
between populations of European and Native American ancestry, i.e.,
about 1,400. Sample sizes of about 2,000 cases would be required to
detect any locus that contributed an ancestry risk ratio of at least
1.5.

Kong et al. (2009) found 3 SNPs at 11p15 that had association with type
2 diabetes and parental origin specific effects; These were dbSNP
rs2237892, dbSNP rs231362, and dbSNP rs2334499. For dbSNP rs2334499 the
allele that confers risk when paternally inherited (T) is protective
when maternally inherited.

BIOCHEMICAL FEATURES

A subgroup of patients diagnosed with type II diabetes have circulating
antibodies to islet cell cytoplasmic antigens, most frequently to
glutamic acid decarboxylase (see GAD2; 138275). Among 1,122 type II
diabetic patients, Tuomi et al. (1999) found GAD antibody in 9.3%, a
significantly higher prevalence than that found in patients with
impaired glucose tolerance or in controls. The GADab+ patients had lower
fasting C-peptide concentration, lower insulin response to oral glucose,
and higher frequency of the high-risk HLA-DQB1*0201/0302 (see 604305)
genotype (though significantly lower than in patients with type I
diabetes) when compared with GADab- patients. Tuomi et al. (1999)
suggested the designation latent autoimmune diabetes in adults (LADA) to
define the subgroup of type II diabetes patients with GADab positivity
(greater than 5 relative units) and age at onset greater than 35 years.

Both defective insulin secretion and insulin resistance have been
reported in relatives of NIDDM subjects. Elbein et al. (1999) tested 120
members of 26 families containing an NIDDM sib pair with a
tolbutamide-modified, frequently sampled intravenous glucose tolerance
test to determine the insulin sensitivity index (SI) and acute insulin
response to glucose (AIRglucose). Both SI x AIRglucose and SI showed
strong negative genetic correlations with diabetes (-85 +/- 3% and -87
+/- 2%, respectively, for all family members), whereas AIRglucose did
not correlate with diabetes. The authors concluded that insulin
secretion, as measured by SI x AIRglucose, is decreased in nondiabetic
members of familial NIDDM kindreds; that SI x AIRglucose in these
high-risk families is highly heritable; and that the same polygenes may
determine diabetes status and a low SI x AIRglucose. They also suggested
that insulin secretion, when expressed as an index normalized for
insulin sensitivity, is more familial than either insulin sensitivity or
first-phase insulin secretion alone, and may be a very useful trait for
identifying genetic predisposition to NIDDM.

GENOTYPE/PHENOTYPE CORRELATIONS

Li et al. (2001) assessed the prevalence of families with both type I
and type II diabetes in Finland and studied, in patients with type II
diabetes, the association between a family history of type 1 diabetes,
GAD antibodies (GADab), and type I diabetes-associated HLA-DQB1
genotypes. Further, in mixed type I/type II diabetes families, they
investigated whether sharing an HLA haplotype with a family member with
type I diabetes influenced the manifestation of type II diabetes. Among
695 families with more than 1 patient with type II diabetes, 100 (14%)
also had members with type I diabetes. Type II diabetic patients from
the mixed families more often had GADab (18% vs 8%) and DQB1*0302/X
genotype (25% vs 12%) than patients from families with only type II
diabetes; however, they had a lower frequency of DQB1*02/0302 genotype
compared with adult-onset type I patients (4% vs 27%). In the mixed
families, the insulin response to oral glucose load was impaired in
patients who had HLA class II risk haplotypes, either
DR3(17)-DQA1*0501-DQB1*02 or DR4*0401/4-DQA1*0301-DQB1*0302, compared
with patients without such haplotypes. This finding was independent of
the presence of GADab. The authors concluded that type I and type II
diabetes cluster in the same families. A shared genetic background with
a patient with type I diabetes predisposes type II diabetic patients
both to autoantibody positivity and, irrespective of antibody
positivity, to impaired insulin secretion. Their findings also supported
a possible genetic interaction between type I and type II diabetes
mediated by the HLA locus.

CLINICAL MANAGEMENT

Fonseca et al. (1998) studied the effects of troglitazone monotherapy on
glycemic control in patients with NIDDM in 24 hospital and outpatient
clinics in the U.S. and Canada. Troglitazone 100, 200, 400, or 600 mg,
or placebo, was administered once daily with breakfast to 402 patients
with NIDDM and fasting serum glucose (FSG) greater than 140 mg/dL,
glycosylated hemoglobin (HbA1c) greater than 6.5%, and fasting C-peptide
greater than 1.5 ng/mL. Patients treated with 400 and 600 mg
troglitazone had significant decreases from baseline in mean FSG (-51
and -60 mg/dL, respectively) and HbA1c (-0.7% and -1.1%, respectively)
at month 6 compared to placebo-treated patients. In the diet-only
subset, 600 mg troglitazone therapy resulted in a significant (P less
than 0.05) reduction in HbA1c (-1.35%) and a significant reduction in
FSG (-42 mg/dL) compared with placebo. Patients previously treated with
sulfonylurea therapy had significant (P less than 0.05) decreases in
mean FSG with 200 to 600 mg troglitazone therapy compared with placebo
(-48, -61, and -66 mg/dL, respectively). The authors concluded that
troglitazone monotherapy significantly improves HbA1c and fasting serum
glucose, while lowering insulin and C-peptide in patients with NIDDM.

Chung et al. (2000) studied the effect of HMG-CoA reductase inhibitors
on bone mineral density (BMD) of type II diabetes mellitus by a
retrospective review of medical records. In the control group, BMD of
the spine significantly decreased after 14 months. In the treatment
group, BMD of the femoral neck significantly increased after 15 months.
In male subjects treated with HMG-CoA reductase inhibitors, there was a
significant increase in BMD of the femoral neck and femoral trochanter,
but in female subjects, only BMD of the femoral neck increased. The
authors concluded that HMG-CoA reductase inhibitors may increase BMD of
the femur in male patients with type II diabetes mellitus.

Aljada et al. (2001) investigated the effect of troglitazone on the
proinflammatory transcription factor NF-kappa-B (see 164011) and its
inhibitory protein I-kappa-B (see 164008) in mononuclear cells (MNC) in
obese patients with type II diabetes. Seven obese patients with type II
diabetes were treated with troglitazone (400 mg/day) for 4 weeks, and
blood samples were obtained at weekly intervals. NF-kappa-B binding
activity in MNC nuclear extracts was significantly inhibited after
troglitazone treatment at week 1 and continued to be inhibited up to
week 4. On the other hand, I-kappa-B protein levels increased
significantly after troglitazone treatment at week 1, and this increase
persisted throughout the study. The authors concluded that troglitazone
has profound antiinflammatory effects in addition to antioxidant effects
in obese type II diabetics, and that these effects may be relevant to
the beneficial antiatherosclerotic effects of troglitazone at the
vascular level.

In a multicenter, double-blind trial, Garber et al. (2003) enrolled
patients with type II diabetes who had inadequate glycemic control
(glycosylated hemoglobin A1C greater than 7% and less than 12%) with
diet and exercise alone to compare the benefits of initial therapy with
glyburide/metformin tablets versus metformin or glyburide monotherapy.
They randomized 486 patients to receive glyburide/metformin tablets,
metformin, or glyburide. Changes in A1C, fasting plasma glucose,
fructosamine, serum lipids, body weight, and 2-hour postprandial glucose
after a standardized meal were assessed after 16 weeks of treatment.
Glyburide/metformin tablets caused a superior mean reduction in A1C from
baseline versus metformin and glyburide monotherapy. Glyburide/metformin
also significantly reduced fasting plasma glucose and 2-hour
postprandial glucose values compared with either monotherapy. The final
mean doses of glyburide/metformin were lower than those of metformin and
glyburide. The authors concluded that first-line treatment with
glyburide/metformin tablets provided superior glycemic control over
component monotherapy, allowing more patients to achieve American
Diabetes Association treatment goals with lower component doses in
drug-naive patients with type II diabetes.

The GoDARTs and UKPDS Diabetes Pharmacogenetics Study Group and Wellcome
Trust Case Control Consortium 2 (2011) performed a genomewide
association study for glycemic response to metformin in 1,024 Scottish
individuals with type 2 diabetes with replication in 2 cohorts including
1,783 Scottish individuals and 1,113 individuals in the UK Prospective
Diabetes Study. In a combined metaanalysis, the consortia identified a
SNP, dbSNP rs11212617, associated with treatment success (n = 3,920, P =
2.9 x 10(-9), OR = 1.35, 95% CI 1.22-1.49) at a locus containing the ATM
gene (607585). In a rat hepatoma cell line, inhibition of ATM with
KU-55933, a selective ATM inhibitor, attenuated the phosphorylation and
activation of AMP-activated protein kinase (see 602739) in response to
metformin. The consortia concluded that ATM, a gene known to be involved
in DNA repair and cell cycle control, plays a role in the effect of
metformin upstream of AMP-activated protein kinase, and variation in
this gene alters glycemic response to metformin.

Yee et al. (2012) commented on the GoDARTS and UKPDS paper and examined
the inhibitory effect of KU-55933 on metformin in H4IIE cells and in
HEK293 cells stably expressing OCT1. They demonstrated in both cases
that KU-55933 inhibits metformin uptake via inhibition of OCT1 and that
the attenuation of metformin-induced AMPK phosphorylation is a result of
its inhibition of metformin uptake into the cells. This effect is
independent of ATM. Yee et al. (2012) demonstrated that ATM does not
have a detectable effect on OCT1 activity. Woods et al. (2012) also
found that in hepatocytes lacking AMPK activity (see Woods et al.,
2011), metformin still has the ability to reduce hepatic glucose output.
Woods et al. (2012) argued that the SNP dbSNP rs11212617 maps to a locus
on chromosome 11q22 that encodes a number of genes and that no direct
evidence had been found that ATM acts upstream of AMPK; Woods et al.
(2012) concluded that other genes within this locus should be considered
as candidates responsible for the reduced therapeutic effect of
metformin action. Zhou et al. (2012) concurred with the comments of Yee
et al. (2012) and Woods et al. (2012) that all genes surrounding dbSNP
rs11212617 should be examined.

PATHOGENESIS

Piatti et al. (2000) compared resistance to insulin-mediated glucose
disposal and plasma concentrations of nitric oxide (NO) and cGMP in 35
healthy volunteers with, or 27 without, at least 1 sib and 1 parent with
type II diabetes. The mean insulin sensitivity index (ISI) was
significantly greater in those without a family history as compared with
nondiabetic volunteers with a family history of type II diabetes,
whether they had normal glucose tolerance or impaired glucose tolerance.
In addition, basal NO levels, evaluated by the measurement of its stable
end products (i.e., nitrite and nitrate levels, NO2-/NO3-) were
significantly higher, and levels of cGMP, its effector messenger, were
significantly lower in those with a family history, irrespective of
their degree of glucose tolerance, when compared with healthy volunteers
without a family history of type II diabetes. Furthermore, when the 62
volunteers were analyzed as 1 group, there was a negative correlation
between ISI and NO2-/NO3- levels and a positive correlation between ISI
and cGMP levels. The authors concluded that alterations of the NO/cGMP
pathway seem to be an early event in nondiabetic individuals with a
family history of type II diabetes, and that these changes are
correlated with the degree of insulin resistance. To investigate how
insulin resistance arises, Petersen et al. (2003) studied 16 healthy,
lean elderly aged 61 to 84 and 13 young participants aged 18 to 39
matched for lean body mass (BMI less than 25) and fat mass assessed by
DEXA (dual energy X-ray absorptiometry) scanning, and activity level.
Elderly study participants were markedly insulin-resistant as compared
with young controls, and this resistance was attributable to reduced
insulin-stimulated muscle glucose metabolism. These changes were
associated with increased fat accumulation in muscle and liver tissue,
assessed by NMR spectroscopy, and with an approximately 40% reduction in
mitochondrial oxidative and phosphorylation activity, as assessed by in
vivo NMR spectroscopy. Petersen et al. (2003) concluded that their data
support the hypothesis that an age-associated decline in mitochondrial
function contributes to insulin resistance in the elderly.

Petersen et al. (2004) performed glucose clamp studies in healthy,
young, lean, insulin-resistant offspring of patients with type II
diabetes and insulin-sensitive subjects matched for age, height, weight,
and physical activity. The insulin-stimulated rate of glucose uptake by
muscle was approximately 60% lower in insulin-resistant subjects than in
controls (p less than 0.001) and was associated with an increase of
approximately 80% in intramyocellular lipid content (p less than 0.005).
The authors attributed the latter increase to mitochondrial dysfunction,
noting a reduction of approximately 30% in mitochondrial phosphorylation
(p = 0.01 compared to controls). Petersen et al. (2004) concluded that
insulin resistance in the skeletal muscle of insulin-resistant offspring
of patients with type II diabetes is associated with dysregulation of
intramyocellular fatty acid metabolism, possibly because of an inherited
defect in mitochondrial oxidative phosphorylation.

Do et al. (2005) assessed the correlation between persistent diabetic
macular edema and hemoglobin A1c (HbA1C). Patients with type II diabetes
and persistent clinically significant macular edema had higher HbA1C at
the time of their disease than patients with resolved macular edema.
Patients with bilateral disease had more elevated HbA1C than those with
unilateral disease.

Foti et al. (2005) reported 4 patients with insulin resistance and type
II diabetes in whom cell-surface insulin receptors were decreased and
INSR (147670) gene transcription was impaired, although the INSR genes
were normal. In these individuals, expression of HMGA1 (600701) was
markedly reduced; restoration of HMGA1 protein expression in their cells
enhanced INSR gene transcription and restored cell-surface insulin
receptor protein expression and insulin-binding capacity. Foti et al.
(2005) concluded that defects in HMGA1 may cause decreased insulin
receptor expression and induce insulin resistance.

Increases in the concentration of circulating glucose activate the
hexosamine biosynthetic pathway and promote the O-glycosylation of
proteins by O-glycosyl transferase (OGT; 300255). Dentin et al. (2008)
showed that OGT triggered hepatic gluconeogenesis through the
O-glycosylation of the transducer of regulated cAMP response
element-binding protein (CREB) 2 (TORC2 or CRTC2; 608972). CRTC2 was
O-glycosylated at sites that normally sequester CRTC2 in the cytoplasm
through a phosphorylation-dependent mechanism. Decreasing amounts of
O-glycosylated CRTC2 by expression of the deglycosylating enzyme
O-GlcNAcase (604039) blocked effects of glucose on gluconeogenesis,
demonstrating the importance of the hexosamine biosynthetic pathway in
the development of glucose intolerance.

MAPPING

In an autosomal genome screen in 363 nondiabetic Pima Indians at 516
polymorphic microsatellite markers, Pratley et al. (1998) found a
suggestion of linkage at several chromosomal regions with particular
characteristics known to be predictive of NIDDM: 3q21-q24, linked to
fasting plasma insulin concentration and in vivo insulin action;
4p15-q12, linked to fasting plasma insulin concentration; 9q21, linked
to 2-hour insulin concentration during oral glucose tolerance testing;
and 22q12-q13, linked to fasting plasma glucose concentration. None of
the linkages exceeded a lod score of 3.6 (a 5% probability of occurring
in a genomewide screen).

In 719 Finnish sib pairs with type II diabetes, Ghosh et al. (2000)
performed a genome scan at an average resolution of 8 cM. The strongest
results were for chromosome 20, where they observed a weighted maximum
lod score of 2.15 at map position 69.5 cM from pter, and secondary
weighted lod score peaks of 2.04 at 56.5 cM and 1.99 at 17.5 cM. The
next largest maximum lod score was for chromosome 11 (maximum lod score
= 1.75 at 84.0 cM), followed by chromosomes 2, 10, and 6. When they
conditioned on chromosome 2 at 8.5 cM, the maximum lod score for
chromosome 20 increased to 5.50 at 69.0 cM.

Watanabe et al. (2000) reported results from an autosomal genome scan
for type II diabetes-related quantitative traits in 580 Finnish families
ascertained for an affected sib pair and analyzed by the variance
components-based quantitative-trait locus linkage approach. In diabetic
individuals, the strongest results were observed on chromosomes 3 and
13. Integrating genome scan results of Ghosh et al. (2000), they
identified several regions that may harbor susceptibility genes for type
II diabetes in the Finnish population.

In a genomewide scan of 359 Japanese individuals with type II diabetes
from 159 families, including 224 affected sib pairs, Mori et al. (2002)
found suggestive linkage at chromosome 11p13-p12, with a maximum lod
score of 3.08. Analysis of sib pairs who had a BMI of less than 30
revealed suggestive linkage at chromosomes 7p22-p21 and 11p13-p12 (lod
scores of 3.51 and 3.00, respectively). Analysis of sib pairs who were
diagnosed before the age of 45 revealed suggestive linkage at chromosome
15q13-q21, with a maximum lod score of 3.91.

Demenais et al. (2003) applied the genome search metaanalysis (GSMA)
method to genomewide scans conducted with 4 European type II diabetes
mellitus cohorts comprising a total of 3,947 individuals, 2,843 of whom
were affected. The analysis provided evidence for linkage of type II
diabetes to 6 regions, with the strongest evidence on chromosome
17p11.2-q22 (p = 0.0016), followed by 2p22.1-p13.2 (p = 0.027),
1p13.1-q22 (p = 0.028), 12q21.1-q24.12 (p = 0.029), 6q21-q24.1 (p =
0.033), and 16p12.3-q11.2 (p = 0.033). Linkage analysis of the pooled
raw genotype data generated maximum lod scores in the same regions as
identified by GSMA; the maximum lod score for the 17p11.2-q22 region was
1.54.

Using nonparametric linkage analyses, Van Tilburg et al. (2003)
performed a genomewide scan to find susceptibility loci for type II
diabetes mellitus in the Dutch population. They studied 178 families
from the Netherlands, who constituted 312 affected sib pairs. Because
obesity and type II diabetes mellitus are interrelated, the dataset was
stratified for the subphenotype BMI, corrected for age and gender. This
resulted in a suggestive maximum multipoint lod score of 2.3
(single-point P value, 9.7 x 10(-4); genomewide P value, 0.028) for the
most obese 20% pedigrees of the dataset, between marker loci D18S471 and
D18S843. In the lowest 80% obese pedigrees, 2 interesting loci on
chromosome 2 and 19 were found, with lod scores of 1.5 and 1.3.

Shtir et al. (2007) performed ordered subset analysis on affected
individuals from 2 sets of families ascertained on affected sib pairs
with type 2 diabetes mellitus and found that 33 families with the lowest
average fasting insulin (606035) showed evidence for linkage to a locus
on chromosome 6q (maximum lod score of 3.45 at 128 cM near D6S1569,
uncorrected p = 0.017) that was coincident with QTL linkage results for
fasting and 2-hour insulin levels in family members without type 2
diabetes mellitus.

The Wellcome Trust Case Control Consortium (2007) described a joint
genomewide association study using the Affymetrix GeneChip 500K Mapping
Array Set, undertaken in the British population, which examined
approximately 2,000 individuals and a shared set of approximately 3,000
controls for each of 7 major diseases. Case-control comparisons
identified 3 significant independent association signals for type 2
diabetes, at dbSNP rs9465871 on chromosome 6p22, dbSNP rs4506565 on
chromosome 10q25, and dbSNP rs9939609 on chromosome 16q12.

In a genomewide association study of 1,363 French type 2 diabetes cases
and controls, Sladek et al. (2007) confirmed the known association with
dbSNP rs7903146 of the TCF7L2 gene (602228.0001) on chromosome 10q25.2
(p = 3.2 x 10(-17)). They also found significant association between T2D
and 2 SNPs on chromosome 10q23.33 (dbSNP rs1111875 and dbSNP rs7923837),
located near the telomeric end of a 270-kb linkage disequilibrium block
containing the IDE (146680), HHEX (604420), KIF11 (148760) genes. Sladek
et al. (2007) stated that fine mapping of the HHEX locus and biologic
studies would be required to identify the causative variant.

The Diabetes Genetics Initiative of Broad Institute of Harvard and MIT,
Lund University, and Novartis Institutes for BioMedical Research (2007)
analyzed 386,731 common SNPs in 1,464 patients with type 2 diabetes and
1,467 matched controls, each characterized for measures of glucose
metabolism, lipids, obesity, and blood pressure. With collaborators
Finland-United States Investigation of NIDDM Genetics (FUSION) and
Wellcome Trust Case Control Consortium/United Kingdom Type 2 Diabetes
Genetics Consortium (WTCCC/UKT2D), this group identified and confirmed 3
loci associated with type 2 diabetes--in a noncoding region near CDKN2A
(600160) and CDKN2B (600431), in an intron of IGF2BP2 (608289), and in
an intron of CDKAL1 (611259)--and replicated associations near HHEX and
SLC30A8 (611145) by recent whole-genome association study. The Diabetes
Genetics Initiative of Broad Institute of Harvard and MIT, Lund
University, and Novartis Institutes for BioMedical Research (2007)
identified and confirmed association of a SNP in an intron of
glucokinase regulatory protein (GCKR; 600842) with serum triglycerides
(see 613463). The authors concluded that the discovery of associated
variants in unsuspected genes and outside coding regions illustrates the
ability of genomewide association studies to provide potentially
important clues to the pathogenesis of common diseases.

Onuma et al. (2010) analyzed the GCKR SNP dbSNP rs780094 in 488 Japanese
patients with type 2 diabetes and 398 controls and found association
between a reduced risk of T2DM and the A allele (odds ratio, 0.711; p =
4.2 x 10(-4)). A metaanalysis with 2 previous association studies
(Sparso et al., 2008 and Horikawa et al., 2008) confirmed the
association of dbSNP rs780094 with T2D susceptibility. In the general
Japanese population, individuals with the A/A genotype had lower levels
of fasting plasma glucose (see 613463), fasting plasma insulin, and
HOMA-IR than those with the G/G genotype (p = 0.008, 0.008, and 0.002,
respectively); conversely, those with the A/A genotype had higher
triglyceride levels than those with the G/G genotype (p = 0.028).

Adopting a genomewide association strategy, Scott et al. (2007)
genotyped 1,161 Finnish type 2 diabetes cases and 1,174 Finnish normal
glucose tolerant controls with greater than 315,000 SNPs and imputed
genotypes for an additional greater than 2 million autosomal SNPs. Scott
et al. (2007) carried out association analysis with these SNPs to
identify genetic variants that predispose to type 2 diabetes, compared
to their type 2 diabetes association results with the results of 2
similar studies, and genotyped 80 SNPs in an additional 1,215 Finnish
type 2 diabetes cases and 1,258 Finnish normal glucose tolerant
controls. Scott et al. (2007) identified type 2 diabetes-associated
variants in an intergenic region of chromosome 11p12, contributed to the
identification of type 2 diabetes-associated variants near the genes
IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirmed
that variants near TCF7L2, SLC30A8, HHEX, FTO (610966), PPARG (601487),
and KCNJ11 (600937) are associated with type 2 diabetes risk. Scott et
al. (2007) concluded that this brings the number of type 2 diabetes loci
now confidently identified to at least 10.

Starting from genomewide genotype data for 1,924 diabetic cases and
2,938 population controls generated by the Wellcome Trust Case Control
Consortium, Zeggini et al. (2007) set out to detect replicated diabetes
association signals through analysis of 3,757 additional cases and 5,346
controls and by integration of their findings with equivalent data from
other international consortia. Zeggini et al. (2007) detected diabetes
susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and
IGF2BP2 and confirmed associations at HHEX/IDE and at SLC30A8. Zeggini
et al. (2007) concluded that their findings provided insight into the
genetic architecture of type 2 diabetes, emphasizing the contribution of
multiple variants of modest effect. The regions identified underscore
the importance of pathways influencing pancreatic beta cell development
and function in the etiology of type 2 diabetes.

Van Vliet-Ostaptchouk et al. (2008) genotyped 501 unrelated Dutch
patients with type 2 diabetes and 920 healthy controls for 2 SNPs in
strong linkage disequilibrium near the HHEX gene, dbSNP rs7923837 and
dbSNP rs1111875, and found that for both SNPs, the risk for T2D was
significantly increased in carriers of the major alleles (OR of 1.57 and
p = 0.017; OR of 1.68 and p = 0.003, respectively). Assuming a dominant
genetic model, the population-attributable risks for diabetes due to the
at-risk alleles of dbSNP rs7923837 and dbSNP rs1111875 were estimated to
be 33% and 36%, respectively.

Gudmundsson et al. (2007) found that the A allele of dbSNP rs4430796 in
the HNF1B gene (189907) was associated with a protective effect against
type 2 diabetes in a study of 1,380 Icelandic patients and 9,940
controls, and in 7 additional type 2 diabetes case-control groups of
European, African, and Asian ancestry (p = 2.7 x 10(-7) and odds ratio
of 0.91, for the combined results). This SNP is also associated with
prostate cancer risk (see HPC11, 611955).

Prokopenko et al. (2008) reviewed advances in identifying common genetic
variants that contribute to complex multifactorial phenotypes such as
type 2 diabetes (T2D), particularly the ability to perform genomewide
association studies in large samples. They noted that the 2 most robust
T2D candidate-gene associations previously reported, for common
polymorphisms in PPARG and KCNJ11, have only modest effect sizes, with
each copy of the susceptibility allele increasing the risk of disease by
15 to 20%. In contrast, microsatellite mapping detected an association
with variation in the TCF7L2 gene that has a substantially stronger
effect, with the 10% of Europeans who are homozygous for the risk allele
having approximately twice the odds of developing T2D compared to those
carrying no copies of the risk allele. Prokopenko et al. (2008) stated
that about 20 common variants had been robustly implicated in T2D
susceptibility to date, but noted that for most of the loci, causal
variants had yet to be identified with any certainty.

The Wellcome Trust Case Control Consortium (2010) undertook a large
direct genomewide study of association between copy number variants
(CNVs) and 8 common human diseases involving approximately 19,000
individuals. Association testing and follow-up replication analyses
confirmed association of CNV at the TSPAN8 (600769) locus with type 2
diabetes.

- Association with Variation in KCNQ1

Yasuda et al. (2008) carried out a multistage genomewide association
study of type 2 diabetes mellitus in Japanese individuals, with a total
of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant
association was obtained with SNPs in KCNQ1 (607542), and dense mapping
within the gene revealed that dbSNP rs2237892 in intron 15 showed the
lowest P value (6.7 x 10(-13), odds ratio = 1.49). The association of
KCNQ1 with type 2 diabetes was replicated in populations of Korean,
Chinese, and European ancestry as well as in 2 independent Japanese
populations, and metaanalysis with a total of 19,930 individuals (9,569
cases and 10,361 controls) yielded a P value of 1.7 x 10(-42) (odds
ratio = 1.40; 95% confidence interval = 1.34-1.47) for dbSNP rs2237892.
Among control subjects, the risk allele of this polymorphism was
associated with impairment of insulin secretion according to the
homeostasis model assessment of beta-cell function or the corrected
insulin response.

Unoki et al. (2008) conducted a genomewide association study using
207,097 SNP markers in Japanese individuals with type 2 diabetes and
unrelated controls, and identified KCNQ1 to be a strong candidate for
conferring susceptibility to type 2 diabetes. Unoki et al. (2008)
detected consistent association of a SNP in KCNQ1 (dbSNP rs2283228) with
the disease in several independent case-control studies (additive model
P = 3.1 x 10(-12); odds ratio = 1.26, 95% confidence interval =
1.18-1.34). Several other SNPs in the same linkage disequilibrium block
were strongly associated with type 2 diabetes. The association of these
SNPs with type 2 diabetes was replicated in samples from Singaporean and
Danish populations.

- Association with Variation in SHBG

Ding et al. (2009) analyzed levels of sex hormone-binding globulin (see
SHBG; 182205) in 359 women newly diagnosed with type 2 diabetes and 359
female controls and found that higher plasma levels of SHBG were
prospectively associated with a lower risk of type 2 diabetes, with
multivariable odds ratios ranging from 1.00 for the lowest quartile of
plasma levels to 0.09 for the highest quartile; the results were
replicated in an independent cohort of men (p less than 0.001 for
results in both women and men). Ding et al. (2009) identified an SHBG
SNP, dbSNP rs6259, that was associated with a 10% higher plasma level of
SHBG, and another SNP, dbSNP rs6257, that was associated with a 10%
lower plasma level of SHBG; variants of both SNPs were also associated
with a risk of type 2 diabetes in directions corresponding to their
associated SHBG levels. In mendelian randomization analyses, the
predicted odds ratio of type 2 diabetes per standard deviation increase
in plasma level of SHBG was 0.28 among women and 0.29 among men. Ding et
al. (2009) suggested that variation in the SHBG gene on chromosome
17p13-p12 may have a causal role in the risk of type 2 diabetes.

Kong et al. (2009) identified a differentially methylated CTCF binding
site at 11p15 and demonstrated correlation of dbSNP rs2334499 with
decreased methylation of that site. The CTCF-binding site is OREG0020670
and its 2-kb region located 17 kb centromeric to the type 2 diabetes
marker dbSNP rs2334499.

Perry et al. (2010) genotyped 27,657 type 2 diabetes patients and 58,481
controls from 15 studies at the SHBG promoter SNP dbSNP rs1799941 that
is strongly associated with serum levels of SHBG. The authors used data
from additional studies to estimate the difference in SHBG levels
between type 2 diabetes patients and controls. The dbSNP rs1799941
variant was associated with type 2 diabetes (OR, 0.94; 95% CI,
0.91-0.97; p = 2 x 10(-5)), with the SHBG-raising A allele associated
with reduced risk of type 2 diabetes, the results were very similar in
men and women. There was no evidence that dbSNP rs1799941 was associated
with diabetes-related intermediate traits, including several measures of
insulin secretion and resistance.

- Association with Variation in RBP4

Serum levels of RBP4 (180250), a protein secreted by adipocytes, are
increased in insulin-resistant states. Experiments in mice suggested
that elevated RBP4 levels cause insulin resistance (Yang et al., 2005).
Graham et al. (2006) found that serum RBP4 levels correlated with the
magnitude of insulin resistance in human subjects with obesity (601665),
impaired glucose tolerance, or type 2 diabetes and in nonobese,
nondiabetic subjects with a strong family history of type 2 diabetes.
Elevated serum RBP4 was associated with components of the metabolic
syndrome, including increased body mass index (BMI), waist-to-hip ratio,
serum triglyceride levels, and systolic blood pressure and decreased
high-density lipoprotein cholesterol levels. Exercise training was
associated with a reduction in serum RBP4 levels only in subjects in
whom insulin resistance improved. Adipocyte GLUT4 protein (138190) and
serum RBP4 levels were inversely correlated. Graham et al. (2006)
concluded that RBP4 is elevated in serum before the development of frank
diabetes and appears to identify insulin resistance and associated
cardiovascular risk factors in subjects with varied clinical
presentations. They suggested that these findings provide a rationale
for antidiabetic therapies aimed at lowering serum RBP4 levels.

Aeberli et al. (2007) studied serum RBP4, serum retinol (SR), the
RBP4-to-SR molar ratio, and dietary vitamin A intakes in seventy-nine 6-
to 14-year-old normal-weight and overweight children and investigated
the relationship of these variables to insulin resistance, subclinical
inflammation, and the metabolic syndrome. Only 3% of children had low
vitamin A status. Independent of age, vitamin A intakes, and C-reactive
protein (see 123260), BMI, body fat percentage, and waist-to-hip ratio
were significant predictors of RBP4, serum retinol, and RBP4/SR. Aeberli
et al. (2007) concluded that independent of subclinical inflammation and
vitamin A intakes, serum RBP4 and the RBP4-to-SR ratio are correlated
with obesity, central obesity, and components of the metabolic syndrome
in prepubertal and early pubertal children.

MOLECULAR GENETICS

- Mutation in PPAR-Gamma

Altshuler et al. (2000) confirmed an association of the common
pro12-to-ala polymorphism in PPAR-gamma (601487.0002) with type II
diabetes. They found a modest but significant increase in diabetes risk
associated with the more common proline allele (approximately 85%
frequency). Because the risk allele occurs at such high frequency, its
modest effect translates into a large population-attributable
risk--influencing as much as 25% of type II diabetes in the general
population.

Savage et al. (2002) described a family, which they referred to as a
'Europid pedigree,' in which several members had severe insulin
resistance. The grandparents had typical late-onset type II diabetes
with no clinical features of severe insulin resistance. Three of their 6
children and 2 of their grandchildren had acanthosis nigricans, elevated
fasting plasma insulin levels. Hypertension was also a feature. By
mutation screening, Savage et al. (2002) identified a heterozygous
frameshift resulting in a premature stop mutation of the PPARG
(601487.0011) gene which was present in the grandfather, all 5 relatives
with severe insulin resistance, and 1 other relative with normal insulin
levels. Further candidate gene studies revealed a heterozygous
frameshift/premature stop mutation in PPP1R3A (600917.0003) which was
present in the grandmother, in all 5 individuals with severe insulin
resistance, and in 1 other relative. Thus, all 5 family members with
severe insulin resistance, and no other family members, were double
heterozygotes with respect to frameshift mutations. (Although the
article by Savage et al. (2002) originally stated that the affected
individuals were compound heterozygotes, they were actually double
heterozygotes. Compound heterozygosity is heterozygosity at the same
locus for each of 2 different mutant alleles; double heterozygosity is
heterozygosity at each of 2 separate loci. The use of an incorrect term
in the original publication was the result of a 'copy-editing error that
was implemented after the authors returned corrected proofs' (Savage et
al., 2002).)

- Association with Insulin Receptor Substrate-2

Mammarella et al. (2000) genotyped 193 Italian patients with type II
diabetes and 206 control subjects for the insulin receptor substrate-2
G1057D polymorphism (600797.0001). They found evidence for a strong
association between type II diabetes and the polymorphism, which appears
to be protective against type II diabetes in a codominant fashion.

- Association with Adiponectin

For a discussion of an association between variation in the ADIPOQ gene
(605441) on chromosome 3q27 and type 2 diabetes, see ADIPQTL1 (612556).

- Association with Mitochondrial DNA Variation

A common mtDNA variant (T16189C) in a noncoding region of mtDNA was
positively correlated with blood fasting insulin by Poulton et al.
(1998). Poulton et al. (2002) demonstrated a significant association
between the 16189 variant and type II diabetes in a population-based
case-control study in Cambridgeshire, UK (n = 932, odds ratio = 1.61;
1.0-2.7, P = 0.048), which was greatly magnified in individuals with a
family history of diabetes from the father's side (odds ratio =
infinity; P less than 0.001). Poulton et al. (2002) demonstrated that
the 16189 variant had arisen independently many times and on multiple
mitochondrial haplotypes. They speculated that the 16189 variant may
alter mtDNA bending and hence could influence interactions with
regulatory proteins which control replication or transcription.

Mohlke et al. (2005) presented data supporting previous evidence for
association of 16189T-C with reduced ponderal index at birth and also
showed evidence for association with reduced birth weight but not with
diabetes status. This study suggested that mitochondrial genome variants
may play at most a modest role in glucose metabolism in the Finnish
population studied. Furthermore, the data did not support a reported
maternal inheritance pattern of type II diabetes mellitus but instead
showed a strong effect of recall bias.

Because mitochondria play pivotal roles in both insulin secretion from
the pancreatic beta cells and insulin resistance of skeletal muscles,
Fuku et al. (2007) performed a large-scale association study to identify
mitochondrial haplogroups that may confer resistance against or
susceptibility to type II diabetes mellitus. The study population
comprised 2,906 unrelated Japanese individuals, including 1,289 patients
with type II diabetes mellitus and 1,617 controls, and 1,365 unrelated
Korean individuals, including 732 patients with type II diabetes and 633
controls. The genotypes for 25 polymorphisms in the coding region of the
mitochondrial genome were determined, and the haplotypes were classified
into 10 major haplogroups. Multivariate logistic regression analysis
with adjustment for age and sex revealed that the mitochondrial group
N9a was significantly associated with resistance against type II
diabetes mellitus (P = 0.0002) with an odds ratio of 0.55 (95%
confidence interval 0.40-0.75). Even in the modern environment, which is
often characterized by satiety and physical inactivity, this haplotype
might confer resistance against type II diabetes mellitus. The N9a
haplogroup found to be associated with reduced susceptibility to type II
diabetes mellitus by Fuku et al. (2007) consisted of a synonymous SNP in
ND2 (516001), 5231G-A; a missense change in ND5 (516005), thr8 to ala;
and a synonymous change also in ND5, 12372G-A.

- Mutation in PAX4

Shimajiri et al. (2001) scanned the PAX4 gene (167413) in 200 unrelated
Japanese probands with type 2 diabetes and identified an arg121-to-tyr
mutation (R121W; 167413.0001) in 6 heterozygous patients and 1
homozygous patient (mutant allele frequency 2.0%). The mutation was not
found in 161 nondiabetic subjects (p = 0.01). Six of 7 patients had a
family history of diabetes or impaired glucose tolerance, and 4 of 7 had
transient insulin therapy at the onset. One of them, a homozygous
carrier, had relatively early-onset diabetes and slowly fell into an
insulin-dependent state without an autoimmune-mediated process.

- Association with TFAP2B

Maeda et al. (2005) performed a genomewide, case-control association
study using gene-based SNPs in Japanese patients with type II diabetes
and controls and identified several variations within the TFAP2B gene
(601601) that were significantly associated with type II diabetes: an
intron 1 VNTR (p = 0.0009), intron 1 +774G-T (p = 0.0006), and intron 1
+2093A-C (p = 0.0004). The association of TFAP2B with type II diabetes
was also observed in a U.K. population. Maeda et al. (2005) suggested
that the TFAP2B gene may confer susceptibility to type II diabetes.

- Mutation in ABCC8

Babenko et al. (2006) screened the ABCC8 gene (600509) in 34 patients
with permanent neonatal diabetes (606176) or transient neonatal diabetes
(see 601410) and identified heterozygosity for 7 missense mutations in 9
patients (see, e.g., 600509.0017-600509.0020). The mutation-positive
fathers of 5 of the probands with transient neonatal diabetes developed
type II diabetes mellitus in adulthood; Babenko et al. (2006) proposed
that mutations of the ABCC8 gene may give rise to a monogenic form of
type II diabetes with variable expression and age at onset.

- Association with WFS1

Sandhu et al. (2007) conducted a gene-centric association study for type
2 diabetes in multiple large cohorts and identified 2 SNPs located in
the WFS1 gene, dbSNP rs10010131 (606201.0021) and dbSNP rs6446482
(602201.0022), that were strongly associated with diabetes risk (P = 1.4
x 10(-7) and P = 3.4 x 10(-7), respectively, in the pooled study set).
The risk allele was the major allele for both SNPs, with a frequency of
60% for both. The authors noted that both are intronic, with no obvious
evidence for biologic function.

- Association with IL6

Mohlig et al. (2004) investigated the IL6 -174C-G SNP (147620.0001) and
development of NIDDM. They found that this SNP modified the correlation
between BMI and IL6 by showing a much stronger increase of IL6 at
increased BMI for CC genotypes compared with GG genotypes. The -174C-G
polymorphism was found to be an effect modifier for the impact of BMI
regarding NIDDM. The authors concluded that obese individuals with BMI
greater than or equal to 28 kg/m2 carrying the CC genotype showed a more
than 5-fold increased risk of developing NIDDM compared with the
remaining genotypes and, hence, might profit most from weight reduction.

Illig et al. (2004) investigated the association of the IL6 SNPs -174C-G
and -598A-G on parameters of type 2 diabetes and the metabolic syndrome
in 704 elderly participants of the Kooperative Gesundheitsforschung im
Raum Augsburg/Cooperative Research in the Region of Augsburg (KORA)
Survey 2000. They found no significant associations, although both SNPs
exhibited a positive trend towards association with type 2 diabetes.
Illig et al. (2004) also found that circulating IL6 levels were not
associated with the IL6 polymorphisms; however, significantly elevated
levels of the chemokine monocyte chemoattractant protein-1 (MCP1;
158105)/CC chemokine ligand-2 (CKR2; 601267) in carriers of the
protective genotypes suggested an indirect effect of these SNPs on the
innate immune system.

- Association with KCNJ15

Okamoto et al. (2010) identified a synonymous SNP (dbSNP rs3746876,
C566T) in exon 4 of the KCNJ15 (602106) that showed significant
association with type 2 diabetes mellitus affecting lean individuals in
3 independent Japanese sample sets (p = 2.5 x 10(-7); odds ratio, 2.54)
and with unstratified T2DM (p = 6.7 x 10(-6); OR, 1.76). The diabetes
risk allele frequency was, however, very low among Europeans and no
association between the variant and T2DM could be shown in a Danish
case-control study. Functional analysis in HEK293 cells demonstrated
that the risk T allele increased KCNJ15 expression via increased mRNA
stability, which resulted in higher expression of protein compared to
the C allele.

- Mutation in MTNR1B

Bonnefond et al. (2012) performed large-scale exon resequencing of the
MTNR1B gene (600804) in 7,632 Europeans, including 2,186 individuals
with type 2 diabetes mellitus, and identified 36 very rare variants
associated with T2D. Among the very rare variants, partial or total
loss-of-function variants but not neutral ones contributed to T2D (odds
ratio, 5.67; p = 4.09 x 10(-4)). Genotyping 4 variants with complete
loss of melatonin-binding and signaling capabilities (A42P, 600804.0001;
L60R, 600804.0002; P95L, 600804.0003; and Y308S, 600804.0004) as a pool
in 11,854 additional French individuals, including 5,967 with T2D,
demonstrated their association with T2D (odds ratio, 3.88; p = 5.37 x
10(-3)). Bonnefond et al. (2012) concluded that their study established
a firm functional link between MTNR1B and T2D risk.

OTHER FEATURES

Diabetes mellitus is a recognized consequence of hereditary
hemochromatosis (HFE; 235200). To test whether common mutations in the
HFE gene (613609) that associate with this condition and predispose to
increases in serum iron indices are overrepresented in diabetic
populations, Halsall et al. (2003) determined the allele frequencies of
the C282Y (613609.0001) and H63D (613609.0002) HFE mutations among a
cohort of 552 patients with typical type II diabetes mellitus. There was
no evidence for overrepresentation of iron-loading HFE alleles in type
II diabetes mellitus, suggesting that screening for HFE mutations in
this population is of no value.

Meigs et al. (2008) genotyped SNPs at 18 loci associated with diabetes
in 2,377 participants of the Framingham Offspring Study. They created a
genotype score from the number of risk alleles and used logistic
regression to generate C statistics indicating the extent to which the
genotype score can discriminate the risk of diabetes when used alone and
in addition to clinical risk factors. There were 255 new cases of
diabetes during 28 years of follow-up. The mean (+/- standard deviation)
genotype score was 17.7 +/- 2.7 among subjects in whom diabetes
developed and 17.1 +/- 2.6 among those in whom diabetes did not develop
(P = less than 0.001). The sex-associated odds ratio for diabetes was
1.12 per risk allele (95% confidence interval, 1.07 to 1.17). The C
statistic was 0.534 without the genotype score and 0.581 with the score
(P = 0.01). In a model adjusted for age, sex, family history, body mass
index, fasting glucose level, systolic blood pressure, high-density
lipoprotein cholesterol level, and triglyceride level, the C statistic
was 0.900 without the genotype score and 0.901 with the score, not
significantly different. The genotype score resulted in the appropriate
risk reclassification of, at most, 4% of the subjects. Meigs et al.
(2008) concluded that a genotype score based on 18 risk alleles
predicted new cases of diabetes in the community but provided only a
slightly better prediction of risk than knowledge of common risk factors
alone.

Lyssenko et al. (2008) genotyped 16 SNPs and examined clinical factors
in 16,061 Swedish and 2,770 Finnish subjects. Type 2 diabetes developed
in 2,201 (11.7%) of these subjects during a median follow-up period of
23.5 years. Strong predictors of diabetes were a family history of the
disease, increased body mass index, elevated liver enzyme levels,
current smoking status, and reduced measures of insulin secretion
action. Variants in 11 genes were significantly associated with the risk
of type 2 diabetes independently of clinical risk factors; variants in 8
of these genes were associated with impaired beta cell function. The
addition of specific genetic information to clinical factors slightly
improved the prediction of future diabetes, with a slight increase in
the area under the receiver-operating-characteristic (also known as C
statistics) curve from 0.74 to 0.75; however, the magnitude of the
increase was significant (P = 1.0 x 10(-4)). Lyssenko et al. (2008)
concluded that as compared with clinical risk factors alone, common
genetic variants associated with the risk of diabetes had a small effect
on the ability to predict the future development of type 2 diabetes. The
value of genetic factors increased with an increasing duration of
follow-up.

ANIMAL MODEL

The most widely used animal model of nonobese NIDDM is the Goto-Kakizaki
(GK) rat. Galli et al. (1996) mapped 3 independent loci involved in the
disease. Thus, NIDDM in the rat is polygenic. The 3 NIDDM loci were
found to have distinct physiologic effects. One affected postprandial
but not fasting hyperglycemia, whereas the other 2 affected both.
Gauguier et al. (1996) mapped up to 6 independently segregating loci
predisposing to hyperglycemia, glucose intolerance, or altered insulin
secretion in the GK rat. Both Galli et al. (1996) and Gauguier et al.
(1996) identified a locus implicated in body weight. The close
similarity between diabetes-related phenotypes in the GK rat and human
NIDDM suggested to the authors that similar patterns of genetic
heterogeneity may underlie the disease in humans and that the results in
rats may be useful in understanding the human disease.

Fakhrai-Rad et al. (2000) mapped the NIDDM1B locus in the GK rat to a
1-cM region by genetic and pathophysiologic characterization of new
congenic substrains for the locus. The gene encoding insulin-degrading
enzyme (IDE; 146680) was also mapped to this 1-cM region, and 2 amino
acid substitutions (H18R and A890V) were identified in the GK allele
which reduced insulin-degrading activity by 31% in transfected cells.
However, when the H18R and A890V variants were studied separately, no
effects were observed, suggesting a synergistic effect of the 2 variants
on insulin degradation. No effect on insulin degradation was observed in
cell lysates, suggesting that the effect may be coupled to
receptor-mediated internalization of insulin. Congenic rats with the IDE
GK allele displayed postprandial hyperglycemia, reduced lipogenesis in
fat cells, blunted insulin-stimulated glucose transmembrane uptake, and
reduced insulin degradation in isolated muscle. Analysis of additional
rat strains demonstrated that the dysfunctional IDE allele was unique to
GK rats. The authors concluded that IDE plays an important role in the
diabetic phenotype in GK rats.

Bruning et al. (1997) created a polygenic (or at least digenic) model of
NIDDM in mice. The model reproduced the characteristics of the human
disease, namely insulin resistance in muscle, fat, and liver, followed
by failure of pancreatic beta-cells to compensate adequately for this
resistance despite increased insulin secretion. Mice doubly heterozygous
for null alleles in the insulin receptor (147670) and insulin receptor
substrate-1 (IRS1; 147545) genes exhibited the expected reduction by
approximately 50% in expression of these 2 proteins, but a synergism at
the level of insulin resistance with 5- to 50-fold elevated plasma
insulin levels and comparable levels of beta-cell hyperplasia. At 4 to 6
months of age, 40% of these doubly heterozygote mice became overtly
diabetic. Thus, diabetes arose in an age-dependent manner from an
interaction between 2 genetically determined, subclinical defects in the
insulin signaling cascade, demonstrating the role of epistatic
interactions in the pathogenesis of common diseases with nonmendelian
genetics.

Terauchi et al. (1997) likewise created a polygenic model of NIDDM by
heterozygous knockout of the IRS1 gene with heterozygous knockout of the
beta-cell GCK gene. They found that the genetic abnormalities, each of
which was nondiabetogenic by itself, caused overt diabetes if they
coexisted.

The Zucker diabetic fatty (ZDF) rat is another animal model of human
adipogenic NIDDM. Shimabukuro et al. (1998) demonstrated in islets of
obese ZDF rats a pathway of lipotoxicity leading to diabetes. Elevated
levels of circulating free fatty acids (Lee et al., 1994) and
lipoproteins transport to islets of obese ZDF rats far more free fatty
acids than can be oxidized. Because fa/fa islets exhibit a markedly
increased lipogenic capacity and a decreased oxidative capacity, unused
free fatty acids in islets are esterified and over time an excessive
quantity is deposited (Lee et al., 1997). This is associated with an
increase in ceramide, inducible NOS expression, and NO production, which
causes apoptosis. That troglitazone, an agent that reduces islet fat in
ZDF rats (Shimabukuro et al., 1997) and prevents their diabetes (Sreenan
et al., 1996), is equally efficacious in human NIDDM suggests a
comparable pathway of lipotoxicity to diabetes in humans.

Hart et al. (2000) showed that FGF receptors 1 and 2 (136350, 176943),
together with ligands FGF1 (131220), FGF2 (134920), FGF4 (164980), FGF5
(165190), FGF7 (148180), and FGF10 (602115), are expressed in adult
mouse beta cells, indicating that FGF signaling may have a role in
differentiated beta cells. When Hart et al. (2000) perturbed signaling
by expressing dominant-negative forms of the receptors, FGFR1C and
FGFR2B, in the pancreas, they found that mice with attenuated FGFR1C
signaling, but not those with reduced FGFR2B signaling, developed
diabetes with age and exhibited a decreased number of beta cells,
impaired expression of glucose transporter 2 (138160), and increased
proinsulin content in beta cells owing to impaired expression of
prohormone convertases 1/3 and 2. These defects are all characteristic
of patients with type II diabetes. Mutations in the homeobox gene
IPF1/PDX1 (600733) are linked to diabetes in both mouse and human. Hart
et al. (2000) showed that IPF1/PDX1 is required for the expression of
FGFR1 signaling components in beta cells, indicating that IPF1/PDX1 acts
upstream of FGFR1 signaling in beta cells to maintain proper glucose
sensing, insulin processing, and glucose homeostasis.

Yuan et al. (2001) demonstrated that high doses of salicylates reverse
hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by
sensitizing insulin signaling. Activation or overexpression of IKBKB
(603258) attenuated insulin signaling in cultured cells, whereas IKKB
inhibition reversed insulin resistance. Thus, Yuan et al. (2001)
concluded that IKKB, rather than the cyclooxygenases (see 600262),
appears to be the relevant molecular target. Heterozygous deletion (IKKB
+/-) protected against the development of insulin resistance during high
fat feeding and in obese Lep (ob/ob) (see 164160) mice. Yuan et al.
(2001) concluded that their findings implicate an inflammatory process
in the pathogenesis of insulin resistance in obesity and type II
diabetes mellitus and identified the IKKB pathway as a target for
insulin sensitization.

Scheuner et al. (2005) studied glucose homeostasis in mice with a
ser51-to-ala substitution at the phosphorylation site of the translation
initiation factor eIF2-alpha (see 603907) and observed that heterozygous
mutant mice became obese and diabetic on a high-fat diet. Profound
glucose intolerance resulted from reduced insulin secretion accompanied
by abnormal distention of the ER lumen, defective trafficking of
proinsulin, and a reduced number of insulin granules in beta cells.
Scheuner et al. (2005) proposed that translational control couples
insulin synthesis with folding capacity to maintain ER integrity and
that this signal is essential to prevent diet-induced type II diabetes.

In Hmga1 (600701)-deficient mice, Foti et al. (2005) observed decreased
insulin receptor expression in muscle, fat, and liver, largely impaired
insulin signaling, and severely reduced insulin secretion, causing a
phenotype characteristic of human type II diabetes.

Matsuzaka et al. (2007) reported that Elovl6 (611546) -/- mice developed
obesity and hepatosteatosis when fed a high-fat diet or when mated to
leptin-deficient (ob/ob) mice, but showed marked protection from
hyperinsulinemia, hyperglycemia, and hyperleptinemia. Amelioration of
insulin resistance was associated with restoration of hepatic insulin
receptor substrate-2 (IRS2; 600797) and suppression of hepatic protein
kinase C-epsilon (PRKCE; 176975), resulting in restoration of Akt (see
164730) phosphorylation. Matsuzaka et al. (2007) noted that the Elovl6
-/- mice were unique in that their insulin resistance was reduced
without the amelioration of obesity or hepatosteatosis, and concluded
that hepatic fatty acid composition is a new determinant for insulin
sensitivity that acts independently of cellular energy balance and
stress.

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C.; Donnelly, P.; Pearson, E.: Response to Yee et al. (Letter) Nature
Genet. 44: 361-362, 2012.

*FIELD* CS

Endo:
Noninsulin-dependent diabetes mellitus

Misc:
Late onset

Lab:
Insulin resistance;
Decreased glucose disposal

Inheritance:
Autosomal dominant

*FIELD* CN
Ada Hamosh - updated: 7/24/2012
Marla J. F. O'Neill - updated: 7/6/2012
Marla J. F. O'Neill - updated: 3/16/2012
Marla J. F. O'Neill - updated: 10/19/2011
Ada Hamosh - updated: 5/23/2011
Ada Hamosh - updated: 5/3/2011
Marla J. F. O'Neill - updated: 4/15/2011
George E. Tiller - updated: 1/5/2011
Ada Hamosh - updated: 4/28/2010
Marla J. F. O'Neill - updated: 2/26/2010
Ada Hamosh - updated: 1/6/2010
Marla J. F. O'Neill - updated: 10/5/2009
Marla J. F. O'Neill - updated: 9/16/2009
Marla J. F. O'Neill - updated: 2/12/2009
Marla J. F. O'Neill - updated: 1/29/2009
Ada Hamosh - updated: 11/21/2008
Ada Hamosh - updated: 10/22/2008
Marla J. F. O'Neill - updated: 8/4/2008
Ada Hamosh - updated: 4/16/2008
Victor A. McKusick - updated: 4/4/2008
Ada Hamosh - updated: 4/4/2008
Marla J. F. O'Neill - updated: 12/5/2007
Marla J. F. O'Neill - updated: 8/16/2007
George E. Tiller - updated: 5/21/2007
Victor A. McKusick - updated: 2/19/2007
Marla J. F. O'Neill - updated: 12/12/2006
Marla J. F. O'Neill - updated: 9/8/2006
Marla J. F. O'Neill - updated: 8/30/2006
Marla J. F. O'Neill - updated: 8/11/2006
Victor A. McKusick - updated: 6/6/2006
Marla J. F. O'Neill - updated: 4/4/2006
Victor A. McKusick - updated: 2/14/2006
Marla J. F. O'Neill - updated: 11/17/2005
Marla J. F. O'Neill - updated: 7/27/2005
Jane Kelly - updated: 7/19/2005
George E. Tiller - updated: 5/4/2005
George E. Tiller - updated: 3/21/2005
Marla J. F. O'Neill - updated: 3/1/2005
John A. Phillips, III - updated: 10/15/2004
Ada Hamosh - updated: 6/8/2004
George E. Tiller - updated: 2/4/2004
John A. Phillips, III - updated: 8/20/2003
Victor A. McKusick - updated: 8/11/2003
George E. Tiller - updated: 7/14/2003
Ada Hamosh - updated: 6/10/2003
John A. Phillips, III - updated: 2/26/2002
Ada Hamosh - updated: 10/18/2001
Ada Hamosh - updated: 9/12/2001
John A. Phillips, III - updated: 7/27/2001
John A. Phillips, III - updated: 3/5/2001
John A. Phillips, III - updated: 2/12/2001
George E. Tiller - updated: 2/5/2001
Ada Hamosh - updated: 12/21/2000
Victor A. McKusick - updated: 12/13/2000
Victor A. McKusick - updated: 11/21/2000
George E. Tiller - updated: 11/17/2000
Victor A. McKusick - updated: 9/22/2000
Victor A. McKusick - updated: 8/29/2000
John A. Phillips, III - updated: 10/7/1999
Wilson H. Y. Lo - updated: 8/24/1999
Wilson H. Y. Lo - updated: 7/26/1999
Victor A. McKusick - updated: 4/5/1999
John A. Phillips, III - updated: 3/2/1999
Victor A. McKusick - updated: 5/18/1998
Victor A. McKusick - updated: 3/25/1998
Victor A. McKusick - updated: 5/9/1997
Victor A. McKusick - updated: 4/7/1997
Mark H. Paalman - updated: 9/10/1996

*FIELD* CD
Victor A. McKusick: 5/14/1993

*FIELD* ED
tpirozzi: 07/12/2013
terry: 4/4/2013
carol: 4/4/2013
carol: 3/29/2013
terry: 11/13/2012
alopez: 7/31/2012
terry: 7/27/2012
terry: 7/24/2012
carol: 7/6/2012
carol: 3/16/2012
terry: 3/16/2012
carol: 10/19/2011
terry: 5/27/2011
alopez: 5/25/2011
terry: 5/23/2011
alopez: 5/9/2011
terry: 5/3/2011
wwang: 4/19/2011
terry: 4/15/2011
wwang: 1/19/2011
terry: 1/5/2011
alopez: 11/10/2010
carol: 10/21/2010
alopez: 7/21/2010
terry: 7/7/2010
alopez: 5/25/2010
alopez: 4/29/2010
terry: 4/28/2010
wwang: 4/1/2010
terry: 3/30/2010
carol: 3/9/2010
carol: 2/26/2010
wwang: 2/25/2010
alopez: 1/15/2010
terry: 1/6/2010
terry: 12/16/2009
wwang: 10/22/2009
terry: 10/5/2009
carol: 9/16/2009
wwang: 3/6/2009
carol: 2/12/2009
wwang: 2/5/2009
wwang: 2/2/2009
terry: 1/29/2009
alopez: 1/21/2009
wwang: 12/30/2008
terry: 12/19/2008
alopez: 12/16/2008
terry: 11/21/2008
alopez: 10/31/2008
terry: 10/22/2008
alopez: 8/28/2008
carol: 8/6/2008
terry: 8/4/2008
mgross: 7/25/2008
alopez: 6/27/2008
alopez: 5/13/2008
terry: 4/16/2008
alopez: 4/4/2008
alopez: 3/13/2008
alopez: 12/7/2007
wwang: 12/5/2007
wwang: 8/16/2007
terry: 5/21/2007
carol: 4/13/2007
alopez: 2/27/2007
terry: 2/19/2007
wwang: 12/14/2006
terry: 12/12/2006
alopez: 11/21/2006
wwang: 9/22/2006
wwang: 9/12/2006
terry: 9/8/2006
wwang: 9/6/2006
carol: 9/5/2006
terry: 8/30/2006
wwang: 8/16/2006
terry: 8/11/2006
alopez: 6/12/2006
terry: 6/6/2006
wwang: 5/17/2006
carol: 4/4/2006
terry: 2/14/2006
wwang: 1/13/2006
wwang: 11/21/2005
terry: 11/17/2005
terry: 10/4/2005
alopez: 8/22/2005
wwang: 8/3/2005
terry: 7/27/2005
alopez: 7/27/2005
alopez: 7/19/2005
tkritzer: 5/4/2005
alopez: 4/1/2005
alopez: 3/30/2005
alopez: 3/21/2005
wwang: 3/1/2005
alopez: 10/15/2004
alopez: 8/19/2004
alopez: 6/9/2004
terry: 6/8/2004
terry: 6/2/2004
carol: 5/4/2004
ckniffin: 4/27/2004
terry: 3/18/2004
cwells: 2/4/2004
alopez: 9/30/2003
alopez: 8/21/2003
alopez: 8/20/2003
carol: 8/13/2003
mgross: 8/13/2003
terry: 8/11/2003
cwells: 7/14/2003
alopez: 6/11/2003
terry: 6/10/2003
alopez: 1/21/2003
alopez: 9/25/2002
carol: 3/1/2002
alopez: 2/26/2002
carol: 10/18/2001
carol: 10/17/2001
alopez: 9/17/2001
terry: 9/12/2001
mgross: 7/27/2001
alopez: 6/4/2001
alopez: 3/6/2001
alopez: 3/5/2001
terry: 2/12/2001
carol: 2/5/2001
carol: 12/23/2000
terry: 12/21/2000
terry: 12/13/2000
mcapotos: 12/11/2000
mcapotos: 11/30/2000
mcapotos: 11/27/2000
terry: 11/21/2000
mcapotos: 11/21/2000
terry: 11/17/2000
alopez: 9/25/2000
terry: 9/22/2000
alopez: 8/29/2000
alopez: 3/1/2000
alopez: 2/17/2000
alopez: 2/4/2000
alopez: 12/6/1999
alopez: 11/5/1999
alopez: 11/4/1999
mgross: 10/7/1999
carol: 8/24/1999
carol: 7/26/1999
mgross: 4/5/1999
mgross: 3/11/1999
mgross: 3/2/1999
carol: 6/9/1998
terry: 5/18/1998
alopez: 3/25/1998
terry: 3/20/1998
alopez: 5/9/1997
alopez: 5/7/1997
mark: 4/7/1997
terry: 4/2/1997
mark: 9/10/1996
terry: 9/5/1996
mark: 5/30/1996
terry: 5/28/1996
mark: 1/4/1996
terry: 12/29/1995
jason: 7/14/1994
mimadm: 6/25/1994
carol: 5/10/1994
carol: 12/22/1993
carol: 7/13/1993
carol: 5/14/1993

MIM 600281
*RECORD*
*FIELD* NO
600281
*FIELD* TI
*600281 HEPATOCYTE NUCLEAR FACTOR 4-ALPHA; HNF4A
;;HNF4-ALPHA;;
HEPATOCYTE NUCLEAR FACTOR 4; HNF4;;
read moreTRANSCRIPTION FACTOR 14, HEPATIC NUCLEAR FACTOR; TCF14
*FIELD* TX

DESCRIPTION

The hepatocyte nuclear factor-4-alpha (HNF4A) is a member of the nuclear
receptor family of transcription factors and is the most abundant
DNA-binding protein in the liver, where it regulates genes largely
involved in the hepatic gluconeogenic program and lipid metabolism
(summary by Chandra et al., 2013).

CLONING

Cell specificity is based on differential gene expression, which is in
turn determined, at least in part, by a particular set of transcription
factors present and active in a given cell at a certain time. Isoforms
of a transcription factor can be expressed at different stages of cell
differentiation. Many transcription factors have been identified and
characterized, particularly in the liver where there is a wide range of
transcriptionally controlled genes. The extinction of many hepatic
functions and their reexpression are correlated with the extinction and
expression of hepatocyte nuclear factor-4 (HNF4). Moreover, HNF4 has a
key role in a transcriptional hierarchy since it also controls the
expression of the transcription factor HNF1 (TCF1; 142410), which is
important in the expression of several hepatic genes. Chartier et al.
(1994) demonstrated that there are 2 isoforms of HNF4 in human liver, a
situation comparable to that in the rat. The 2 isoforms differ by an
extra peptide of 10 amino acids located in the C-terminal part of the
protein. The gene is also symbolized TCF14.

GENE STRUCTURE

Furuta et al. (1997) reported the exon/intron organization and partial
sequence of the HNF4A gene. In addition, they screened 12 exons,
flanking introns and minimal promoter regions for mutations in a group
of 57 unrelated Japanese subjects with early-onset NIDDM/MODY of unknown
cause. They identified an arg127-to-trp mutation (R127W; 600281.0003) in
3 of 5 diabetic members of one family.

Thomas et al. (2001) identified an alternative promoter of the HNF4A
gene, P2, which is 46 kb 5-prime to the previously identified P1
promoter of the human gene. Based on RT-PCR, this distant upstream P2
promoter represents the major transcription site in pancreatic
beta-cells, and is also used in hepatic cells. Transfection assays with
various deletions and mutants of the P2 promoter revealed functional
binding sites for HNF1A, HNF1B (189907), and IPF1 (600733), the other
transcription factors known to encode MODY genes. In a large MODY
family, a mutated IPF1 binding site in the P2 promoter of the HNF4A gene
cosegregated with diabetes (lod score 3.25). The authors proposed a
regulatory network of the 4 MODY transcription factors interconnected at
the distant upstream P2 promoter of the HNF4A gene.

BIOCHEMICAL FEATURES

- Crystal Structure

Chandra et al. (2013) described the 2.9-angstrom crystal structure of
the multidomain human HNF4-alpha homodimer bound to its DNA response
element and coactivator-derived peptides. A convergence zone connects
multiple receptor domains in an asymmetric fashion, joining distinct
elements from each monomer. An arginine target of PRMT1 (602950)
methylation protrudes directly into this convergence zone and sustains
its integrity. A serine target of protein kinase C (see 176960) is also
responsible for maintaining domain-domain interactions. These
posttranslational modifications lead to changes in DNA binding by
communicating through the tightly connected surfaces of the quaternary
fold. Chandra et al. (2013) found that some mutations resulting in MODY1
(125850), positioned on the ligand-binding domain and hinge regions of
the receptor, compromise DNA binding at a distance by communicating
through the interjunctional surfaces of the complex. The overall domain
representation of the HNF4-alpha homodimer is different from that of the
PPAR-gamma (601487)-RXR-alpha (180245) heterodimer, even when both
nuclear receptor complexes are assembled on the same DNA element.

GENE FUNCTION

Tirona et al. (2003) showed that HNF4A is critically involved in the PXR
(603065)- and CAR (603881)-mediated transcriptional activation of CYP3A4
(124010). They identified a specific cis-acting element in the CYP3A4
gene enhancer that confers HNF4-alpha binding and thereby permits PXR-
and CAR-mediated gene activation. Fetal mice with conditional deletion
of Hnf4-alpha had reduced or absent expression of CYP3A. Furthermore,
adult mice with conditional hepatic deletion of the gene had reduced
basal and inducible expression of CYP3A. These data identified
HNF4-alpha as an important regulator of coordinate nuclear
receptor-mediated response to xenobiotics. To elucidate how
differentiated cells form tissues and organs, Parviz et al. (2003)
studied liver organogenesis because the cell and tissue architecture of
this organ is well defined. Approximately 60% of the adult liver
consists of hepatocytes that are arranged as single-cell anastomosing
plates extending from the portal region of the liver lobule toward the
central vein. The basal surface of the hepatocytes is separated from
adjacent sinusoidal endothelial cells by the space of Disse, where the
exchange of substances between serum and hepatocytes takes place. The
apical surface of the hepatocytes forms bile canaliculi that transport
bile to the hepatic ducts. Parviz et al. (2003) reported that hepatocyte
nuclear factor 4-alpha is essential for morphologic and functional
differentiation of hepatocytes, accumulation of hepatic glycogen stores,
and generation of a hepatic epithelium. They showed that HNF4A is a
dominant regulator of the epithelial phenotype because its ectopic
expression in fibroblasts induces a mesenchymal-to-epithelial
transition. The morphogenetic parameters controlled by HNF4A in
hepatocytes are essential for normal liver architecture, including the
organization of the sinusoidal endothelium.

By cotransfection in COS-1 cells, Ribeiro et al. (1999) showed that
mammalian HNF4 synergized with USF2a (600390) in the transactivation of
the APOA2 (107670) promoter. HNF4 and USF2a bound to the enhancer
cooperatively, which Ribeiro et al. (1999) suggested may account for the
transcriptional synergism observed.

To gain insight into the transcriptional regulatory networks that
specify and maintain human tissue diversity, Odom et al. (2004) used
chromatin immunoprecipitation combined with promoter microarrays to
identify systematically the genes occupied by the transcriptional
regulators HNF1-alpha (142410), HNF4-alpha, and HNF6 (604164), together
with RNA polymerase II (see 180660), in human liver and pancreatic
islets. Odom et al. (2004) identified tissue-specific regulatory
circuits formed by HNF1-alpha, HNF4-alpha, and HNF6 with other
transcription factors, revealing how these factors function as master
regulators of hepatocyte and islet transcription. Odom et al. (2004)
concluded that their results suggested how misregulation of HNF4-alpha
can contribute to type 2 diabetes (125853). Odom et al. (2004) found
that HNF4-alpha bound to the promoters of about 12% of hepatocyte islet
genes represented on the microarray. HNF4-alpha acted in a much larger
number of hepatocyte and beta-cell genes than did HNF1-alpha, suggesting
that HNF4-alpha has broad activities in these 2 tissues.

By microarray and molecular analyses, Battle et al. (2006) found that
Hnf4a regulated developmental expression of a myriad of genes encoding
proteins required for cell junction assembly and adhesion in developing
mouse liver.

Odom et al. (2007) analyzed the binding of HNF3B (600288), HNF1A, HNF4A,
and HNF6 to 4,000 orthologous gene pairs in hepatocytes purified from
human and mouse livers. Despite the conserved function of these factors,
41 to 89% of the binding events seemed to be species-specific.
Importantly, the binding sites varied widely between species in ways
that could not be predicted from human-mouse sequence alignments alone.

MAPPING

Argyrokastritis et al. (1997) used genetic linkage analysis and
fluorescence in situ hybridization to map HNF4 to chromosome 20, in a
region syntenic with mouse chromosome 2, where the hnf4 homolog had been
assigned by Avraham et al. (1992).

MOLECULAR GENETICS

Yamagata et al. (1996) demonstrated a gln268-to-ter mutation (Q268X;
600281.0001) in the gene encoding hepatocyte nuclear factor-4-alpha in a
multigeneration family referred to as R-W, in which type I
maturity-onset diabetes of the young (MODY1; 125850) was first defined.
A member of the steroid/thyroid hormone receptor superfamily,
HNF-4-alpha is most highly expressed in liver, kidney, and intestine. It
is also expressed in pancreatic islets and insulinoma cells. It is a key
regulator of hepatic gene expression and is a major activator of
HNF-1-alpha (TCF1), which in turn activates the expression of a large
number of liver-specific genes, including those involved in glucose,
cholesterol, and fatty acid metabolism. TCF1 is the site of mutations
causing type 3 MODY (MODY3; 600496).

Stoffel and Duncan (1997) investigated the molecular mechanism by which
the Q268X mutation, which deletes 187 C-terminal amino acids of the
HNF4-alpha protein, causes diabetes. They showed that the mutant gene
product had lost its transcriptional transactivation activity and failed
to dimerize and bind DNA, implying that the MODY1 phenotype is due to a
loss of HNF4-alpha function. The effect of loss of function on
expression of HNF4-alpha target genes was investigated further in
embryonic stem cells, which are amenable to genetic manipulation and can
be induced to form visceral endoderm. Because the visceral endoderm
shares many properties with the liver and pancreatic beta-cells,
including expression of genes for glucose transport and metabolism, it
offers an ideal system to investigate HNF4-dependent gene regulation in
glucose homeostasis. With this approach, Stoffel and Duncan (1997)
identified several genes encoding components of the glucose-dependent
insulin secretion pathway whose expression is dependent upon HNF4-alpha.
These included glucose transporter-2 (SLC2A2; 138160), and the
glycolytic enzymes aldolase B (ALDOB; 612724) and
glyceraldehyde-3-phosphate dehydrogenase (GAPDH; 138400), and liver
pyruvate kinase (PKLR; 609712). In addition, they found that expression
of the fatty acid binding proteins and cellular retinol binding protein
also are downregulated in the absence of HNF4-alpha. These data provided
direct evidence that HNF4-alpha is critical for regulating glucose
transport and glycolysis and in doing so is critical for maintaining
glucose homeostasis.

During the course of a search for susceptibility genes contributing to
late-onset noninsulin-dependent diabetes mellitus (NIDDM), Zouali et al.
(1997) found a suggestion for linkage with markers in the region of the
HNF4A/MODY1 gene in a subset of French families with age at onset less
than 45 years. This prompted Hani et al. (1998) to screen the HNF4A gene
for mutations in 19 French NIDDM families diagnosed before 45 years of
age. In 1 family they found a val393-to-ile substitution (600281.0004).
This mutation cosegregated with diabetes and impaired insulin secretion.
Expression studies showed that the substitution was associated with a
marked reduction of transactivation activity, a result consistent with
this mutation contributing to the insulin secretory defect observed in
the family.

Aguilar-Salinas et al. (2001) investigated possible defects in the
insulin sensitivity and the acute insulin response in a group of Mexican
patients displaying early-onset NIDDM and evaluated the contribution of
mutations in 3 of the genes linked to MODY. They studied 40 Mexican
patients diagnosed between 20 and 40 years of age in which the insulin
sensitivity as well as the insulin secretory response were measured
using the minimal model approach. A partial screening for possible
mutations in 3 of the 5 genes linked to MODY was carried out by
PCR-SSCP. Among this group they found 2 individuals carrying missense
mutations in exon 4 of the HNF4A gene and 1 carrying a nonsense mutation
in exon 7 of the HNF1A gene; 7.5% had positive titers for glutamic acid
decarboxylase antibodies. Thirty-five percent of cases had insulin
resistance; these subjects had the lipid abnormalities seen in the
metabolic syndrome. The authors concluded that a defect in insulin
secretion is the hallmark in Mexican diabetic patients diagnosed between
20 and 40 years of age. Mutations in either the HNF1A or the HNF4A genes
were present among the individuals who developed early-onset diabetes in
their population.

To investigate the properties of naturally occurring HNF4A mutations,
Lausen et al. (2000) analyzed 5 MODY1 mutations, including Q268X, R154X
(600281.0002), and R127W. Activation of reporter genes in transfection
assays and DNA-binding studies showed that the MODY1-associated
mutations resulted in a variable reduction in function. None of the
MODY1 mutants acted in a dominant-negative manner, thus excluding
inactivation of the wildtype factor as a critical event in MODY1
development. A MODY3-associated mutation in the HNF1A gene, a well-known
target gene of HNF4A, resulted in dramatic loss of the HNF4-binding site
in the promoter, indicating that mutations in the HNF4A gene might cause
MODY through impaired HNF1A gene function. Based on these data, Lausen
et al. (2000) proposed a 2-hit model for MODY development. Because MODY1
patients are not born with diabetes and initially have no measurable
abnormal function in the beta cells of the pancreas, it seemed unlikely
that the mutated HNF4A is deficient in a specific function such as
interaction with COUP-TF (TFCOUP1; 132890). It seemed more probable that
additional events occur with time. Therefore, Lausen et al. (2000)
speculated that the function of the wildtype allele was occasionally
lost in beta cells, involving either a somatic mutation or some
epigenetic event. They imagined that this loss of function of the
wildtype allele led to some selective advantage, thus allowing
overgrowth of the original beta-cell population.

Fajans et al. (2001) reported that mutation in the HNF4A gene is a
relatively uncommon cause of MODY. They stated that only 13 families had
been identified as having this form of MODY.

Barrio et al. (2002) estimated the prevalence of major MODY subtypes in
Spanish MODY families and analyzed genotype-phenotype correlations.
Twenty-two unrelated pediatric MODY patients and 97 relatives were
screened for mutations in the coding region of the GCK (138079), HNF1A
(142410), and HNF4A genes using PCR-SSCP and/or direct sequencing.
Mutations in MODY genes were identified in 64% of the families. One
family (4%) carried a novel mutation in the HNF4A gene (IVS5-2delA;
600281.0006), representing the first report of a MODY1 pedigree in the
Spanish population. Clinical expression of MODY3 and MODY1 mutations,
the second and third groups of defects found, was more severe, including
the frequent development of chronic complications.

Johansen et al. (2005) examined the prevalence and nature of mutations
in the 3 common MODY genes HNF4A, GCK, and TCF1 (HNF1A) in Danish
patients with a clinical diagnosis of MODY and determined metabolic
differences in probands with and without mutations in HNF4A, GCK, and
TCF1. They identified 29 different mutations in 38 MODY families.
Fifteen of the mutations were novel. The variants segregated with
diabetes within the families, and none of the variants were found in 100
normal Danish chromosomes. Their findings suggested a relative
prevalence of 3% of MODY1 (2 different mutations in 2 families), 10% of
MODY2 (7 in 8), and 36% of MODY3 (21 in 28) among Danish kindred
clinically diagnosed as MODY. No significant differences in biochemical
and anthropometric measurements were observed at baseline examinations.
Forty-nine percent of the families carried mutations in the 3 examined
MODY genes.

Pearson et al. (2007) studied 108 members of 15 families with MODY due
to a mutation in the HNF4A gene and found that birth weights were
significantly higher in mutation carriers (p less than 0.001), with 30
(56%) of 54 mutation-positive infants being macrosomic compared to 7
(13%) of 54 mutation-negative infants (p less than 0.001). In addition,
8 of 54 mutation-positive infants had transient hypoglycemia versus none
of the 54 mutation-negative infants (p = 0.003), and inappropriate
hyperinsulinemia was documented in all 3 hypoglycemic cases tested (see,
e.g., 600281.0007). The authors concluded that mutations in HNF4A are
associated with increased birth weight and macrosomia, and that the
natural history of MODY1 includes hyperinsulinemia at birth that evolves
to decreased insulin secretion and diabetes later in life.

ANIMAL MODEL

To study the contribution of HNF4A to hepatic development and
differentiation, Li et al. (2000) used a technique in which Hnf4a -/-
mouse embryos were complemented with wildtype visceral endoderm to
counteract early embryonic lethality. By histologic analyses, the
authors found that specification and early development of the liver and
liver morphology did not require Hnf4a. In addition, the expression of
many liver genes was unaffected in these mice. However, RT-PCR analysis
showed that Hnf4a -/- fetal livers failed to express a large array of
genes whose expression in differentiated hepatocytes is essential for a
functional hepatic parenchyma, including apolipoproteins (e.g., APOA1,
107680), metabolic proteins (e.g., aldolase B, 612724), transferrin
(190000), retinol-binding protein (e.g., RBP4, 180250), and
erythropoietin (133170). The lack of Hnf4a did not affect the expression
of most transcription factors but did significantly reduce the levels of
Hnf1a (TCF1; 142410) and the pregnane X receptor (NR1I2; 603065),
suggesting that HNF4A acts upstream of at least these 2 transcription
factors, which are also important in hepatocyte gene expression.

In mice with a conditional deletion of Hnf4a in pancreatic beta cells,
Gupta et al. (2005) observed hyperinsulinemia in fasted and fed animals
but also impaired glucose tolerance. Islet perifusion and
calcium-imaging studies showed abnormal beta cell responses to
stimulation by glucose and sulfonylureas, explainable in part by a 60%
reduction in expression of the potassium channel subunit Kir6.2 (KCNJ11;
600937). Cotransfection assays revealed that the Kir6.2 gene is a
transcriptional target of HNF4A. Gupta et al. (2005) concluded that
HNF4A is required in the pancreatic beta cell for regulation of the
pathway of insulin secretion dependent on the ATP-dependent potassium
channel.

Pearson et al. (2007) generated mice with pancreatic beta-cell deletion
of Hnf4a and observed hyperinsulinemia in utero and hyperinsulinemic
hypoglycemia at birth.

Sekiya and Suzuki (2011) screened the effects of 12 candidate factors to
identify 3 specific combinations of 2 transcription factors, comprising
Hnf4-alpha plus Foxa1 (602294), Foxa2 (600288), or Foxa3 (602295), that
can convert mouse embryonic and adult fibroblasts into cells that
closely resemble hepatocytes in vitro. The induced hepatocyte-like
(iHep) cells had multiple hepatocyte-specific features and reconstituted
damaged hepatic tissues after transplantation.

EVOLUTION

To explore the evolution of gene regulation, Schmidt et al. (2010) used
chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq)
to determine experimentally the genomewide occupancy of 2 transcription
factors, CEBPA (116897) and HNF4A, in the livers of 5 vertebrates, Homo
sapiens, Mus musculus, Canis familiaris, Monodelphis domesticus
(short-tailed opossum), and Gallus gallus. Although each transcription
factor displayed highly conserved DNA binding preferences, most binding
was species-specific, and aligned binding events present in all 5
species were rare. Regions near genes with expression levels that are
dependent on a transcription factor were often bound by the
transcription factor in multiple species yet showed no enhanced DNA
sequence constraint. Binding divergence between species can be largely
explained by sequence changes to the bound motifs. Among the binding
events lost in one lineage, only half are recovered by another binding
event within 10 kb. Schmidt et al. (2010) concluded that their results
revealed large interspecies differences in transcriptional regulation
and provided insight into regulatory evolution.

*FIELD* AV
.0001
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 1
HNF4A, GLN268TER

In the historic R-W pedigree in which Fajans (1989) defined type 1
maturity-onset diabetes of the young (125850), Yamagata et al. (1996)
found a C-to-T substitution in codon 268 of the TCF14 gene that
generated a CAG-to-TAG (Q268X) nonsense mutation. Some subjects in the
R-W pedigree had inherited the Q268X mutation but were not yet diabetic;
in addition, there were subjects in the pedigree who had
noninsulin-dependent diabetes mellitus but did not inherit the Q268X
mutation or at-risk haplotype. In one case, NIDDM had been diagnosed at
the age of 48 years, and the patient was hyperinsulinemic, indicating
that this was probably late-onset NIDDM rather than MODY. The patient
had 6 children, 1 of whom also had NIDDM; another child had impaired
glucose tolerance, and all had only normal alleles at the TCF14 locus.

.0002
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 1
HNF4A, ARG154TER

Lindner et al. (1997) reported a second nonsense mutation in the
HNF4-alpha gene in a 3-generation MODY1 (125850) pedigree, Dresden-11. A
C-to-T transition resulted in an arg-to-ter mutation at codon 154
(R154X). Extensive clinical studies of 6 affected members of this family
showed severe diabetes requiring insulin or oral hypoglycemic agents,
but no liver or renal abnormalities. These results suggested to Lindner
et al. (1997) that despite expression of HNF4-alpha in liver, kidney,
intestine, and pancreas, nonsense mutations in HNF4-alpha appear to
affect only pancreatic beta-cell function.

Eeckhoute et al. (2001) reported that loss of HNF4-alpha function by
R154X is increased through impaired physical interaction and functional
cooperation between HNF4-alpha and p300 (602700).

.0003
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 1
HNF4A, ARG127TRP

In 3 of 5 members with MODY (125850) in 1 family, Furuta et al. (1997)
identified an arg127-to-trp (R127W) mutation resulting from a transition
from CGG to TGG. The mutation was located in the T-box, a region of the
protein that may play a role in HNF-4-alpha dimerization and DNA
binding. The findings in the family suggested that the R172W mutation
was not the only cause of diabetes. The overall results suggested that
mutations in the HNF4A gene may cause early onset NIDDM/MODY in Japanese
but such mutations are less common than mutations in the HNF1A/MODY3
gene (142410).

.0004
NONINSULIN-DEPENDENT DIABETES MELLITUS
HNF4A, VAL393ILE

In a single French family with NIDDM (125853) diagnosed before the age
of 45 years, Hani et al. (1998) found a val393-to-ile amino acid
substitution in the TCF14 gene. Expression studies showed a marked
reduction of transactivation activity, a result consistent with this
mutation contributing to the insulin secretory defect observed in the
family.

.0005
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 1
HNF4A, 1-BP DEL, PHE75T

To determine the prevalence of MODY caused by HNF4-alpha mutations
(MODY1; 125850), Moller et al. (1999) screened 10 Danish non-MODY3
probands for mutations in the minimal promoter and the 12 exons of the
HNF4-alpha gene. One proband had a frameshift mutation (Phe75fsdelT) in
exon 2 resulting in a premature termination after 117 amino acids. The
authors concluded that defects in the HNF4-alpha gene are a rare cause
of MODY in Denmark.

.0006
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 1
HNF4A, IVS5, DEL A, -2

In a Spanish family with MODY (125850), Barrio et al. (2002) found a
deletion of an A nucleotide at the canonic acceptor splice site of exon
6. The pedigree exhibited a severe form of diabetes with a high
incidence of chronic complications. The proband was diagnosed at 15
years of age. This represented the first report of a MODY1 pedigree in
the Spanish population.

.0007
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 1
HNF4A, MET364ARG

In affected members of a 3-generation family with MODY (125850), Pearson
et al. (2007) identified heterozygosity for a 1091T-G transversion in
the HNF4A gene, resulting in a met364-to-arg (M364R) substitution. A
16-year-old girl and her 15-year-old brother were macrosomic at birth
and hypoglycemic in the first 24 hours of life, and the sister also had
documented inappropriate hyperinsulinemia in the presence of
hypoglycemia; both later developed diabetes, at 12 and 14 years of age,
respectively. Their mother, maternal aunt, and maternal grandmother had
developed diabetes at ages 31, 18, and 40 years, respectively.

*FIELD* RF
1. Aguilar-Salinas, C. A.; Reyes-Rodriguez, E.; Ordonez-Sanchez, M.
L.; Torres, M. A.; Ramirez-Jimenez, S.; Dominguez-Lopez, A.; Martinez-Francois,
J. R.; Velasco-Perez, M. L.; Alpizar, M.; Garcia-Garcia, E.; Gomez-Perez,
F.; Rull, J.; Tusie-Luna, M. T.: Early-onset type 2 diabetes: metabolic
and genetic characterization in the Mexican population. J. Clin.
Endocr. Metab. 86: 220-226, 2001.

2. Argyrokastritis, A.; Kamakari, S.; Kapsetaki, M.; Kritis, A.; Talianidis,
I.; Moschonas, N. K.: Human hepatocyte nuclear factor-4 (hHNF-4)
gene maps to 20q12-q13.1 between PLCG1 and D20S17. Hum. Genet. 99:
233-236, 1997.

3. Avraham, K. B.; Prezioso, V. R.; Chen, W. S.; Lai, E.; Sladek,
F. M.; Zhong, W.; Darnell, J. E., Jr.; Jenkins, N. A.; Copeland, N.
G.: Murine chromosomal location of four hepatocyte-enriched transcription
factors: HNF-3-alpha, HNF3-beta, HNF-3-gamma, and HNF-4. Genomics 13:
264-268, 1992.

4. Barrio, R.; Bellanne-Chantelot, C.; Moreno, J. C.; Morel, V.; Calle,
H.; Alonso, M.; Mustieles, C.: Nine novel mutations in maturity-onset
diabetes of the young (MODY) candidate genes in 22 Spanish families. J.
Clin. Endocr. Metab. 87: 2532-2539, 2002.

5. Battle, M. A.; Konopka, G.; Parviz, F.; Gaggl, A. L.; Yang, C.;
Sladek, F. M.; Duncan, S. A.: Hepatocyte nuclear factor 4-alpha orchestrates
expression of cell adhesion proteins during the epithelial transformation
of the developing liver. Proc. Nat. Acad. Sci. 103: 8419-8424, 2006.

6. Chandra, V.; Huang, P.; Potluri, N.; Wu, D.; Kim, Y.; Rastinejad,
F.: Multidomain integration in the structure of the HNF-4-alpha nuclear
receptor complex. Nature 495: 394-398, 2013.

7. Chartier, F. L.; Bossu, J.-P.; Laudet, V.; Fruchart, J.-C.: Cloning
and sequencing of cDNAs encoding the human hepatocyte nuclear factor
4 indicate the presence of two isoforms in human liver. Gene 147:
269-272, 1994.

8. Eeckhoute, J.; Formstecher, P.; Laine, B.: Maturity-onset diabetes
of the young type 1 (MODY1)-associated mutations R154X and E276Q in
hepatocyte nuclear factor 4-alpha (HNF4-alpha) gene impair recruitment
of p300, a key transcriptional coactivator. Molec. Endocr. 15: 1200-1210,
2001.

9. Fajans, S. S.: Maturity-onset diabetes of the young (MODY). Diabetes
Metab. Rev. 5: 579-606, 1989.

10. Fajans, S. S.; Bell, G. I.; Polonsky, K. S.: Molecular mechanisms
and clinical pathophysiology of maturity-onset diabetes of the young. New
Eng. J. Med. 345: 971-980, 2001.

11. Furuta, H.; Iwasaki, N.; Oda, N.; Hinokio, Y.; Horikawa, Y.; Yamagata,
K.; Yano, N.; Sugahiro, J.; Ogata, M.; Ohgawara, H.; Omori, Y.; Iwamoto,
Y.; Bell, G. I.: Organization and partial sequence of the hepatocyte
nuclear factor-4-alpha/MODY1 gene and identification of a missense
mutation, R127W, in a Japanese family with MODY. Diabetes 46: 1652-1657,
1997.

12. Gupta, R. K.; Vatamaniuk, M. Z.; Lee, C. S.; Flaschen, R. C.;
Fulmer, J. T.; Matschinsky, F. M.; Duncan, S. A.; Kaestner, K. H.
: The MODY1 gene HNF-4-alpha regulates selected genes involved in
insulin secretion. J. Clin. Invest. 115: 1006-1015, 2005.

13. Hani, E. H.; Suaud, L.; Boutin, P.; Chevre, J.-C.; Durand, E.;
Philippi, A.; Demenais, F.; Vionnet, N.; Furuta, H.; Velho, G.; Bell,
G. I.; Laine, B.; Froguel, P.: A missense mutation in hepatocyte
nuclear factor-4-alpha, resulting in a reduced transactivation activity,
in human late-onset non-insulin-dependent diabetes mellitus. J. Clin.
Invest. 101: 521-526, 1998.

14. Johansen, A.; Ek, J.; Mortensen, H. B.; Pedersen, O.; Hansen,
T.: Half of clinically defined maturity-onset diabetes of the young
patients in Denmark do not have mutations in HNF4A, GCK, and TCF1. J.
Clin. Endocr. Metab. 90: 4607-4614, 2005.

15. Lausen, J.; Thomas, H.; Lemm, I.; Bulman, M.; Borgschulze, M.;
Lingott, A.; Hattersley, A. T.; Ryffel, G. U.: Naturally occurring
mutations in the human HNF4-alpha gene impair the function of the
transcription factor to a varying degree. Nucleic Acids Res. 28:
430-437, 2000.

16. Li, J.; Ning, G.; Duncan, S. A.: Mammalian hepatocyte differentiation
requires the transcription factor HNF-4-alpha. Genes Dev. 14: 464-474,
2000.

17. Lindner, T.; Gragnoli, C.; Furuta, H.; Cockburn, B. N.; Petzold,
C.; Rietzsch, H.; Weiss, U.; Schulze, J.; Bell, G. I.: Hepatic function
in a family with a nonsense mutation (R154X) in the hepatocyte nuclear
factor-4-alpha/MODY1 gene. J. Clin. Invest. 100: 1400-1405, 1997.

18. Moller, A. M.; Dalgaard, L. T.; Ambye, L.; Hansen, L.; Schmitz,
O.; Hansen, T.; Pedersen, O.: A novel Phe75fsdelT mutation in the
hepatocyte nuclear factor-4-alpha gene in a Danish pedigree with maturity-onset
diabetes of the young. J. Clin. Endocr. Metab. 84: 367-369, 1999.

19. Odom, D. T.; Dowell, R. D.; Jacobsen, E. S.; Gordon, W.; Danford,
T. W.; MacIsaac, K. D.; Rolfe, P. A.; Conboy, C. M.; Gifford, D. K.;
Fraenkel, E.: Tissue-specific transcriptional regulation has diverged
significantly between human and mouse. Nature Genet. 39: 730-732,
2007.

20. Odom, D. T.; Zizlsperger, N.; Gordon, D. B.; Bell, G. W.; Rinaldi,
N. J.; Murray, H. L.; Volkert, T. L.; Schreiber, J.; Rolfe, P. A.;
Gifford, D. K.; Fraenkel, E.; Bell, G. I.; Young, R. A.: Control
of pancreas and liver gene expression by HNF transcription factors. Science 303:
1378-1381, 2004.

21. Parviz, F.; Matullo, C.; Garrison, W. D.; Savatski, L.; Adamson,
J. W.; Ning, G.; Kaestner, K. H.; Rossi, J. M.; Zaret, K. S.; Duncan,
S. A.: Hepatocyte nuclear factor 4-alpha controls the development
of a hepatic epithelium and liver morphogenesis. Nature Genet. 34:
292-296, 2003.

22. Pearson, E. R.; Boj, S. F.; Steele, A. M.; Barrett, T.; Stals,
K.; Shield, J. P.; Ellard, S.; Ferrer, J.; Hattersley, A. T.: Macrosomia
and hyperinsulinaemic hypoglycaemia in patients with heterozygous
mutations in the HNF4A gene. PLoS Med. 4: e118, 2007. Note: Electronic
Article.

23. Ribeiro, A.; Pastier, D.; Kardassis, D.; Chambaz, J.; Cardot,
P.: Cooperative binding of upstream stimulatory factor and hepatic
nuclear factor 4 drives the transcription of the human apolipoprotein
A-II gene. J. Biol. Chem. 274: 1216-1225, 1999.

24. Schmidt, D.; Wilson, M. D.; Ballester, B.; Schwalie, P. C.; Brown,
G. D.; Marshall, A.; Kutter, C.; Watt, S.; Martinez-Jimenez, C. P.;
Mackay, S.; Talianidis, I.; Flicek, P.; Odom, D. T.: Five-vertebrate
ChIP-seq reveals the evolutionary dynamics of transcription factor
binding. Science 328: 1036-1040, 2010.

25. Sekiya, S.; Suzuki, A.: Direct conversion of mouse fibroblasts
to hepatocyte-like cells by defined factors. Nature 475: 390-393,
2011.

26. Stoffel, M.; Duncan, S. A.: The maturity-onset diabetes of the
young (MODY1) transcription factor HNF4-alpha regulates expression
of genes required for glucose transport and metabolism. Proc. Nat.
Acad. Sci. 94: 13209-13214, 1997.

27. Thomas, H.; Jaschkowitz, K.; Bulman, M.; Frayling, T. M.; Mitchell,
S. M. S.; Roosen, S.; Lingott-Frieg, A.; Tack, C. J.; Ellard, S.;
Ryffel, G. U.; Hattersley, A. T.: A distant upstream promoter of
the HNF-4-alpha gene connects the transcription factors involved in
maturity-onset diabetes of the young. Hum. Molec. Genet. 10: 2089-2097,
2001.

28. Tirona, R. G.; Lee, W.; Leake, B. F.; Lan, L.-B.; Cline, C. B.;
Lamba, V.; Parviz, F.; Duncan, S. A.; Inoue, Y.; Gonzalez, F. J.;
Schuetz, E. G.; Kim, R. B.: The orphan nuclear receptor HNF4-alpha
determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nature
Med. 9: 220-224, 2003.

29. Yamagata, K.; Furuta, H.; Oda, N.; Kaisaki, P. J.; Menzel, S.;
Cox, N. J.; Fajans, S. S.; Signorini, S.; Stoffel, M.; Bell, G. I.
: Mutations in the hepatocyte nuclear factor-4-alpha gene in maturity-onset
diabetes of the young (MODY1). Nature 384: 458-460, 1996.

30. Zouali, H.; Hani, E. H.; Philippi, A.; Vionnet, N.; Beckmann,
J. S.; Demenais, F.; Froguel, P.: A susceptibility locus for early-onset
non-insulin dependent (type 2) diabetes mellitus maps to chromosome
20q, proximal to the phosphoenolpyruvate carboxykinase gene. Hum.
Molec. Genet. 6: 1401-1408, 1997.

*FIELD* CN
Ada Hamosh - updated: 07/16/2013
Ada Hamosh - updated: 8/4/2011
Ada Hamosh - updated: 6/30/2010
Marla J. F. O'Neill - updated: 5/6/2008
Patricia A. Hartz - updated: 8/3/2007
John A. Phillips, III - updated: 10/19/2006
Patricia A. Hartz - updated: 7/11/2006
Marla J. F. O'Neill - updated: 7/8/2005
Ada Hamosh - updated: 6/10/2004
Patricia A. Hartz - updated: 5/7/2004
Victor A. McKusick - updated: 6/16/2003
Victor A. McKusick - updated: 1/15/2003
John A. Phillips, III - updated: 1/9/2003
John A. Phillips, III - updated: 7/12/2002
George E. Tiller - updated: 2/8/2002
Ada Hamosh - updated: 10/18/2001
John A. Phillips, III - updated: 9/25/2001
Paul J. Converse - updated: 9/5/2000
Victor A. McKusick - updated: 2/4/2000
John A. Phillips, III - updated: 11/17/1999
Victor A. McKusick - updated: 3/20/1998
Victor A. McKusick - updated: 2/24/1998
Victor A. McKusick - updated: 2/13/1998
Ada Hamosh - updated: 10/20/1997
Victor A. McKusick - updated: 2/11/1997

*FIELD* CD
Victor A. McKusick: 1/5/1995

*FIELD* ED
alopez: 07/16/2013
tpirozzi: 7/12/2013
alopez: 8/15/2011
terry: 8/4/2011
alopez: 7/1/2010
terry: 6/30/2010
carol: 4/14/2009
terry: 2/19/2009
carol: 5/8/2008
terry: 5/6/2008
alopez: 8/3/2007
alopez: 10/19/2006
mgross: 7/11/2006
terry: 7/11/2006
carol: 11/18/2005
terry: 7/8/2005
alopez: 6/15/2004
terry: 6/10/2004
mgross: 5/7/2004
alopez: 7/28/2003
alopez: 6/16/2003
terry: 6/16/2003
carol: 5/28/2003
alopez: 2/28/2003
alopez: 1/15/2003
alopez: 1/9/2003
tkritzer: 12/10/2002
alopez: 7/12/2002
cwells: 2/19/2002
cwells: 2/8/2002
carol: 10/18/2001
cwells: 9/28/2001
cwells: 9/25/2001
mgross: 9/5/2000
mcapotos: 2/29/2000
mcapotos: 2/15/2000
terry: 2/4/2000
alopez: 11/17/1999
carol: 8/26/1998
alopez: 8/25/1998
dkim: 7/21/1998
dholmes: 4/17/1998
alopez: 3/25/1998
terry: 3/20/1998
alopez: 2/25/1998
terry: 2/24/1998
mark: 2/22/1998
terry: 2/13/1998
alopez: 12/8/1997
alopez: 11/19/1997
jamie: 5/7/1997
jenny: 3/31/1997
terry: 2/11/1997
mark: 12/4/1996
terry: 12/3/1996
mark: 12/7/1995
carol: 1/5/1995

MIM 606391
*RECORD*
*FIELD* NO
606391
*FIELD* TI
#606391 MATURITY-ONSET DIABETES OF THE YOUNG; MODY
;;MASON-TYPE DIABETES
*FIELD* TX
read moreA number sign (#) is used with this entry because maturity-onset
diabetes of the young (MODY) can be caused by mutation in several
different genes.

DESCRIPTION

Maturity-onset diabetes of the young is an autosomal dominant form of
diabetes typically occurring before 25 years of age and caused by
primary insulin secretion defects. Despite its low prevalence, MODY is
not a single entity but represents genetic, metabolic, and clinical
heterogeneity (Vaxillaire and Froguel, 2008).

- Genetic Heterogeneity of MODY

MODY1 (125850) is determined by heterozygous mutation in the hepatocyte
nuclear factor-4-alpha gene (HNF4A; 600281) on chromosome 20.

MODY2 (125851) is caused by heterozygous mutation in the glucokinase
gene (GCK; 138079) on chromosome 7.

MODY3 (600496) is caused by heterozygous mutation in the hepatocyte
nuclear factor-1alpha gene (HNF1A; 142410) on chromosome 12q24.2.

MODY4 (606392) is caused by heterozygous mutation in the
pancreas/duodenum homeobox protein-1 gene (PDX1; 600733) on chromosome
13q12.1.

MODY5 (137920) is caused by heterozygous mutation in the gene encoding
hepatic transcription factor-2 (TCF2; 189907) on chromosome 17cen-q21.3.

MODY6 (606394) is caused by heterozygous mutation in the NEUROD1 gene
(601724) on chromosome 2q32.

MODY7 (610508) is caused by heterozygous mutation in the KLF11 gene
(603301) on chromosome 2p25.

MODY8 (609812), or diabetes-pancreatic exocrine dysfunction syndrome, is
caused by heterozygous mutation in the CEL gene (114840) on chromosome
9q34.

MODY9 (612225) is caused by heterozygous mutation in the PAX4 gene
(167413) on chromosome 7q32.

MODY10 (613370) is caused by heterozygous mutation in the insulin gene
(INS; 176730) on chromosome 11p15.5.

MODY11 (613375) is caused by heterozygous mutation in the BLK gene
(191305) on chromosome 8p23.

NOMENCLATURE

The term 'maturity-onset diabetes of the young,' or MODY relies on the
old classification of diabetes into juvenile-onset and maturity-onset
diabetes. A revised, etiology-based classification for diabetes was
introduced by both the American Diabetes Association and the World
Health Organization, and MODY is now included in the group of 'genetic
defect in beta-cell function' with a subclassification according to the
gene involved (Vaxillaire and Froguel, 2008).

Glaser (2003) stated that although MODY is typically used to indicate
autosomal dominant noninsulin-dependent diabetes diagnosed before the
age of 25 years, there is an increasing incidence of polygenic type 2
diabetes (125853) in childhood and adolescence, and patients with gene
mutations characteristic of MODY often present with clinical diabetes
later in life. He therefore suggested abandoning the term MODY and
substituting the term autosomal dominant type 2 diabetes, just as the
terms maturity-onset diabetes and noninsulin-dependent diabetes have
been abandoned for describing polygenic type 2 diabetes. He cited the
case described by Huopio et al. (2003) with a dominant mutation in the
sulfonylurea receptor-1 gene (ABCC8; 600509.0011) that caused congenital
hyperinsulinism in infancy, loss of insulin secretory capacity in early
adulthood, and diabetes mellitus in middle age. Huopio et al. (2003)
noted that, except for age at presentation, the mutation in the ABCC8
gene causes a disorder that fulfills the criteria for a form of MODY.
They suggested that the ABCC8 gene qualified as the seventh gene
associated with autosomal dominant type 2 diabetes.

CLINICAL FEATURES

Tattersall (1974) described 3 families with an autosomal dominant form
of diabetes. This form had early onset, but mild and relatively
uncomplicated course. For example, 7 out of 12 diabetics diagnosed under
the age of 30 years had no retinopathy after an average duration of 37
years. In 2 of the families diabetes was associated with a low renal
threshold for glucose. They noted transmission over at least 3
generations with 50% of affected children of an affected parent, and an
affected parent of almost all affected persons. Further evidence for a
separate autosomal dominant form was provided by Tattersall and Fajans
(1975) and by Johansen and Gregersen (1977). Nelson and Pyke (1976)
referred to this as maturity-onset diabetes of the young. It has also
been called the Mason type, after the family in which it was first
observed. Despite the early onset, the natural history is that of the
late-onset type.

Irvine et al. (1977) concluded from a family study that insulin
dependence or independence is a better means of separating distinct
forms of diabetes mellitus than is age of onset.

See 118430 for a discussion of chlorpropamide-alcohol flushing, which
may be a marker for this form of diabetes.

DIAGNOSIS

Vaxillaire and Froguel (2008) noted that 5 major diagnosis criteria for
MODY are usually accepted: (1) hyperglycemia usually diagnosed before
age 25 years in at least 1 and ideally 2 family members; (2) autosomal
dominant inheritance, with a vertical transmission of diabetes through
at least 3 generations, and a similar phenotype shared by diabetic
family members; (3) absence of insulin therapy at least 5 years after
diagnosis or significant C-peptide levels even in a patient on insulin
treatment; (4) insulin levels that are often in the normal range,
although inappropriately low for the degree of hyperglycemia, suggesting
a primary defect in beta-cell function; and (5) overweight or obesity is
rarely associated (and is not required for the development of diabetes).

POPULATION GENETICS

Rimoin (1979) sated that MODY has an unusually high prevalence in
Romania.

Winter et al. (1987) found that MODY is unusually frequent in black
Americans. This atypical form was found in 12 of 129 black patients with
youth-onset diabetes and in at least 2 generations in 9 of the 12
families of the probands. Fourteen of the diabetic relatives as well as
the 12 probands were studied. Islet cell autoantibodies were not found
in any, and thyroid microsomal autoantibodies were found in only one.
The frequencies of the insulin-dependent-diabetes-associated antigens
HLA-DR3 and -DR4 were not increased among the probands, and diabetes did
not cosegregate with HLA haplotypes in the informative families.

Ledermann (1995) stated that the prevalence of MODY is about 5% of type
2 diabetes patients in most populations.

Fajans et al. (2001) stated that families whose members have a clinical
history compatible with the diagnosis of MODY but who do not have
mutations in any of the 6 known MODY-related genes account for an
estimated 15 to 20% of Europeans with clinical MODY and as many as 80%
of Japanese persons with clinical MODY.

MODY3 and MODY2 are the 2 most prevalent forms of MODY, accounting for
more than 80% of MODY patients in Caucasians (Frayling et al., 2001).
Mutations in the HNF4A gene are less common and are found in 1 of 57
Japanese patients with MODY (Furuta et al., 1997). Other subtypes are
rare disorders reported in only a few families. Yamada et al. (2000)
suggested that about 80% of Japanese MODY patients cannot be explained
by known MODY genes.

Xu et al. (2005) studied 146 Chinese families fulfilling the minimum
criteria for MODY: 2 consecutive generations of type 2 diabetes with at
least 1 member diagnosed under the age of 25 years. Thirteen families
had MODY3 mutations and 2 had MODY2 mutations. No MODY1 mutation was
found. Four of the 12 different MODY3 mutations were novel. The authors
referred to the untyped cases as MODYX. MODY3 and MODY2 accounted for
only 9 and 1%, respectively, of Chinese MODY. Xu et al. (2005) concluded
that the majority of Chinese MODY patients are due to defects in unknown
genes and appear to be characterized by insulin resistance.

CYTOGENETICS

Kayashima et al. (2002) described a 20-year-old man with maternal
uniparental disomy for chromosome 14 and maturity-onset diabetes
mellitus. He had pre- and postnatal growth retardation, developed
diabetes mellitus at age 20 years without any autoimmune antibodies, and
had a mosaic karyotype interpreted as representing segmental maternal
isodisomy for 14q21-q24 and maternal heterodisomy of the remaining
regions of the chromosome. Kayashima et al. (2002) speculated that the
segmental isodisomy led to reduction to homozygosity for a mutant gene
and thus caused the patient's diabetes mellitus. FISH analysis using BAC
clones revealed that the isodisomic segment did not overlap any known
IDDM or NIDDM susceptibility loci on chromosome 14, suggesting a novel
locus for a subset of diabetes mellitus located at the isodisomic
segment.

HISTORY

In a case resembling MODY, Haneda et al. (1983) found that one insulin
gene (INS; 176730) had a point mutation at position 24 of the beta
chain, resulting in substitution of serine for phenylalanine
(176730.0002). The proband had fasting hyperglycemia without resistance
to exogenously administered insulin. Five additional family members of
both sexes in 3 generations were affected. Johnston et al. (1984) could
demonstrate no linkage (or association) with a particular polymorphism
of the sequences flanking the insulin gene, and Bell et al. (1983) found
no linkage to the insulin gene. In 3 families with MODY and 7 with
'common' type II diabetes mellitus, O'Rahilly et al. (1992) excluded
linkage to the INS locus.

*FIELD* RF
1. Bell, J. I.; Wainscoat, J. S.; Old, J. M.; Chlouverakis, C.; Keen,
H.; Turner, R. C.; Weatherall, D. J.: Maturity onset diabetes of
the young is not linked to the insulin gene. Brit. Med. J. 286:
590-593, 1983.

2. Fajans, S. S.; Bell, G. I.; Polonsky, K. S.: Molecular mechanisms
and clinical pathophysiology of maturity-onset diabetes of the young. New
Eng. J. Med. 345: 971-980, 2001.

3. Frayling, T. M.; Evans, J. C.; Bulman, M. P.; Pearson, E.; Allen,
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*FIELD* CN
Marla J. F. O'Neill - updated: 4/21/2010
Marla J. F. O'Neill - updated: 4/19/2010
Carol A. Bocchini - updated: 2/16/2009
Marla J. F. O'Neill - updated: 10/17/2006
Victor A. McKusick - updated: 12/27/2005
Victor A. McKusick - updated: 4/26/2005
Victor A. McKusick - updated: 3/10/2003
Victor A. McKusick - updated: 8/8/2002

*FIELD* CD
Ada Hamosh: 10/16/2001

*FIELD* ED
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