RBCC Red Blood Cell Collection

SH2B3 (LNK) [Confidence: low (only semi-automatic identification from reviews)]
SH2B adapter protein 3 (Lymphocyte adapter protein; Lymphocyte-specific adapter protein Lnk; Signal transduction protein Lnk)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q9UQQ2
ID SH2B3_HUMAN Reviewed; 575 AA.
AC Q9UQQ2; B9EGG5; O95184;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 27-APR-2001, sequence version 2.
DT 22-JAN-2014, entry version 101.
DE RecName: Full=SH2B adapter protein 3;
DE AltName: Full=Lymphocyte adapter protein;
DE AltName: Full=Lymphocyte-specific adapter protein Lnk;
DE AltName: Full=Signal transduction protein Lnk;
GN Name=SH2B3; Synonyms=LNK;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10799879;
RA Li Y., He X., Schembri-King J., Jakes S., Hayashi J.;
RT "Cloning and characterization of human Lnk, an adaptor protein with
RT pleckstrin homology and Src homology 2 domains that can inhibit T cell
RT activation.";
RL J. Immunol. 164:5199-5206(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Bartholomew M.A., Morse M.A., Vivier R.G., Blanchard A.D., Boyhan A.,
RA Tite J.P., Fuller K.J., Lewis A.P., Sims M.J.;
RT "Characterisation of human Lnk a lymphocyte adaptor protein with a
RT multiple domain structure.";
RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP INVOLVEMENT IN SUSCEPTIBILITY TO IDDM, AND VARIANT ARG-262.
RX PubMed=17554260; DOI=10.1038/ng2068;
RG Genetics of type 1 diabetes in Finland;
RG The Wellcome Trust case control consortium;
RA Todd J.A., Walker N.M., Cooper J.D., Smyth D.J., Downes K.,
RA Plagnol V., Bailey R., Nejentsev S., Field S.F., Payne F., Lowe C.E.,
RA Szeszko J.S., Hafler J.P., Zeitels L., Yang J.H.M., Vella A.,
RA Nutland S., Stevens H.E., Schuilenburg H., Coleman G., Maisuria M.,
RA Meadows W., Smink L.J., Healy B., Burren O.S., Lam A.A.C.,
RA Ovington N.R., Allen J., Adlem E., Leung H.-T., Wallace C.,
RA Howson J.M.M., Guja C., Ionescu-Tirgoviste C., Simmonds M.J.,
RA Heward J.M., Gough S.C.L., Dunger D.B., Wicker L.S., Clayton D.G.;
RT "Robust associations of four new chromosome regions from genome-wide
RT analyses of type 1 diabetes.";
RL Nat. Genet. 39:857-864(2007).
RN [6]
RP INVOLVEMENT IN SUSCEPTIBILITY TO CELIAC13, AND VARIANT ARG-262.
RX PubMed=18311140; DOI=10.1038/ng.102;
RA Hunt K.A., Zhernakova A., Turner G., Heap G.A.R., Franke L.,
RA Bruinenberg M., Romanos J., Dinesen L.C., Ryan A.W., Panesar D.,
RA Gwilliam R., Takeuchi F., McLaren W.M., Holmes G.K.T., Howdle P.D.,
RA Walters J.R.F., Sanders D.S., Playford R.J., Trynka G., Mulder C.J.,
RA Mearin M.L., Verbeek W.H.M., Trimble V., Stevens F.M., O'Morain C.,
RA Kennedy N.P., Kelleher D., Pennington D.J., Strachan D.P.,
RA McArdle W.L., Mein C.A., Wapenaar M.C., Deloukas P., McGinnis R.,
RA McManus R., Wijmenga C., van Heel D.A.;
RT "Newly identified genetic risk variants for celiac disease related to
RT the immune response.";
RL Nat. Genet. 40:395-402(2008).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-150, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
CC -!- FUNCTION: Links T-cell receptor activation signal to phospholipase
CC C-gamma-1, GRB2 and phosphatidylinositol 3-kinase (By similarity).
CC -!- SUBUNIT: Binds to the tyrosine-phosphorylated TCR zeta chain via
CC its SH2 domain.
CC -!- INTERACTION:
CC P00533:EGFR; NbExp=2; IntAct=EBI-7879749, EBI-297353;
CC P21860:ERBB3; NbExp=2; IntAct=EBI-7879749, EBI-720706;
CC -!- TISSUE SPECIFICITY: Preferentially expressed by lymphoid cell
CC lines.
CC -!- PTM: Tyrosine phosphorylated by LCK.
CC -!- DISEASE: Celiac disease 13 (CELIAC13) [MIM:612011]: A
CC multifactorial, chronic disorder of the small intestine caused by
CC intolerance to gluten. It is characterized by immune-mediated
CC enteropathy associated with failed intestinal absorption, and
CC malnutrition. In predisposed individuals, the ingestion of gluten-
CC containing food such as wheat and rye induces a flat jejunal
CC mucosa with infiltration of lymphocytes. Note=Disease
CC susceptibility is associated with variations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Diabetes mellitus, insulin-dependent (IDDM) [MIM:222100]:
CC A multifactorial disorder of glucose homeostasis that is
CC characterized by susceptibility to ketoacidosis in the absence of
CC insulin therapy. Clinical features are polydipsia, polyphagia and
CC polyuria which result from hyperglycemia-induced osmotic diuresis
CC and secondary thirst. These derangements result in long-term
CC complications that affect the eyes, kidneys, nerves, and blood
CC vessels. Note=Disease susceptibility is associated with variations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the SH2B adapter family.
CC -!- SIMILARITY: Contains 1 PH domain.
CC -!- SIMILARITY: Contains 1 SH2 domain.
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DR EMBL; AF055581; AAC71695.1; -; mRNA.
DR EMBL; AJ012793; CAB42642.1; -; mRNA.
DR EMBL; CH471054; EAW97955.1; -; Genomic_DNA.
DR EMBL; BC136451; AAI36452.1; -; mRNA.
DR RefSeq; NP_005466.1; NM_005475.2.
DR UniGene; Hs.506784; -.
DR ProteinModelPortal; Q9UQQ2; -.
DR SMR; Q9UQQ2; 197-312, 359-441.
DR IntAct; Q9UQQ2; 3.
DR MINT; MINT-1494618; -.
DR STRING; 9606.ENSP00000345492; -.
DR PhosphoSite; Q9UQQ2; -.
DR DMDM; 13628527; -.
DR PaxDb; Q9UQQ2; -.
DR PRIDE; Q9UQQ2; -.
DR Ensembl; ENST00000341259; ENSP00000345492; ENSG00000111252.
DR GeneID; 10019; -.
DR KEGG; hsa:10019; -.
DR UCSC; uc001tse.3; human.
DR CTD; 10019; -.
DR GeneCards; GC12P111843; -.
DR HGNC; HGNC:29605; SH2B3.
DR HPA; HPA005483; -.
DR MIM; 222100; phenotype.
DR MIM; 605093; gene.
DR MIM; 612011; phenotype.
DR neXtProt; NX_Q9UQQ2; -.
DR PharmGKB; PA145148124; -.
DR eggNOG; NOG77816; -.
DR HOGENOM; HOG000047355; -.
DR HOVERGEN; HBG093951; -.
DR InParanoid; Q9UQQ2; -.
DR KO; K12459; -.
DR OMA; PWSLARE; -.
DR OrthoDB; EOG70CR6F; -.
DR PhylomeDB; Q9UQQ2; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_604; Hemostasis.
DR SignaLink; Q9UQQ2; -.
DR ChiTaRS; SH2B3; human.
DR GeneWiki; SH2B3; -.
DR GenomeRNAi; 10019; -.
DR NextBio; 37857; -.
DR PRO; PR:Q9UQQ2; -.
DR ArrayExpress; Q9UQQ2; -.
DR Bgee; Q9UQQ2; -.
DR CleanEx; HS_SH2B3; -.
DR Genevestigator; Q9UQQ2; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0042301; F:phosphate ion binding; IEA:Ensembl.
DR GO; GO:0005543; F:phospholipid binding; IEA:InterPro.
DR GO; GO:0004871; F:signal transducer activity; IEA:InterPro.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0030154; P:cell differentiation; IEA:Ensembl.
DR GO; GO:0035162; P:embryonic hemopoiesis; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; IEA:Ensembl.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR015012; Phe_ZIP.
DR InterPro; IPR001849; Pleckstrin_homology.
DR InterPro; IPR000980; SH2.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF08916; Phe_ZIP; 1.
DR Pfam; PF00017; SH2; 1.
DR PRINTS; PR00401; SH2DOMAIN.
DR SMART; SM00233; PH; 1.
DR SMART; SM00252; SH2; 1.
DR SUPFAM; SSF109805; SSF109805; 1.
DR PROSITE; PS50003; PH_DOMAIN; FALSE_NEG.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW Complete proteome; Diabetes mellitus; Phosphoprotein; Polymorphism;
KW Reference proteome; SH2 domain.
FT CHAIN 1 575 SH2B adapter protein 3.
FT /FTId=PRO_0000084454.
FT DOMAIN 194 307 PH.
FT DOMAIN 364 462 SH2.
FT MOD_RES 150 150 Phosphoserine.
FT VARIANT 182 182 F -> L (in dbSNP:rs7972796).
FT /FTId=VAR_046210.
FT VARIANT 262 262 W -> R (associated with susceptibility to
FT CELIAC13 and IDDM; dbSNP:rs3184504).
FT /FTId=VAR_024168.
FT CONFLICT 309 309 G -> GR (in Ref. 2; CAB42642).
FT CONFLICT 491 491 H -> P (in Ref. 2; CAB42642).
SQ SEQUENCE 575 AA; 63225 MW; EE30B9E21E0009E5 CRC64;
MNGPALQPSS PSSAPSASPA AAPRGWSEFC ELHAVAAARE LARQYWLFAR EHPQHAPLRA
ELVSLQFTDL FQRYFCREVR DGRAPGRDYR DTGRGPPAKA EASPEPGPGP AAPGLPKARS
SEELAPPRPP GPCSFQHFRR SLRHIFRRRS AGELPAAHTA AAPGTPGEAA ETPARPGLAK
KFLPWSLARE PPPEALKEAV LRYSLADEAS MDSGARWQRG RLALRRAPGP DGPDRVLELF
DPPKSSRPKL QAACSSIQEV RWCTRLEMPD NLYTFVLKVK DRTDIIFEVG DEQQLNSWMA
ELSECTGRGL ESTEAEMHIP SALEPSTSSS PRGSTDSLNQ GASPGGLLDP ACQKTDHFLS
CYPWFHGPIS RVKAAQLVQL QGPDAHGVFL VRQSETRRGE YVLTFNFQGI AKHLRLSLTE
RGQCRVQHLH FPSVVDMLHH FQRSPIPLEC GAACDVRLSS YVVVVSQPPG SCNTVLFPFS
LPHWDSESLP HWGSELGLPH LSSSGCPRGL SPEGLPGRSS PPEQIFHLVP SPEELANSLQ
HLEHEPVNRA RDSDYEMDSS SRSHLRAIDN QYTPL
//

MIM 222100
*RECORD*
*FIELD* NO
222100
*FIELD* TI
%222100 DIABETES MELLITUS, INSULIN-DEPENDENT; IDDM
;;DIABETES MELLITUS, TYPE I;;
JUVENILE-ONSET DIABETES; JOD
read moreDIABETES MELLITUS, INSULIN-DEPENDENT, 1, INCLUDED; IDDM1, INCLUDED;;
INSULIN-DEPENDENT DIABETES MELLITUS 1, INCLUDED
*FIELD* TX

DESCRIPTION

The type of diabetes mellitus called IDDM is a disorder of glucose
homeostasis that is characterized by susceptibility to ketoacidosis in
the absence of insulin therapy. It is a genetically heterogeneous
autoimmune disease affecting about 0.3% of Caucasian populations (Todd,
1990). Genetic studies of IDDM have focused on the identification of
loci associated with increased susceptibility to this multifactorial
phenotype.

The classical phenotype of diabetes mellitus is polydipsia, polyphagia,
and polyuria which result from hyperglycemia-induced osmotic diuresis
and secondary thirst. These derangements result in long-term
complications that affect the eyes, kidneys, nerves, and blood vessels.

CLINICAL FEATURES

The term diabetes mellitus is not precisely defined and the lack of a
consensus on diagnostic criteria has made its genetic analysis
difficult. Diabetes mellitus is classified clinically into 2 major forms
of the primary illness, insulin-dependent diabetes mellitus (IDDM) and
noninsulin-dependent diabetes mellitus (NIDDM; 125853), and secondary
forms related to gestation or medical disorders.

Appearance of the IDDM phenotype is thought to require a predisposing
genetic background and interaction with other environmental factors.
Rotter and Rimoin (1978) hypothesized that there are at least 2 forms of
IDDM: a B8 (DR3)-associated form characterized by pancreatic
autoimmunity, and a B15-associated form characterized by antibody
response to exogenous insulin. Interestingly, the DR3 and DR4 alleles
seem to have a synergistic effect on the predisposition to IDDM based on
the greatly increased risk observed in persons having both the B8 and
B15 antigens (Svejgaard and Ryder, 1977). Rotter and Rimoin (1979)
hypothesized a combined form. Tolins and Raij (1988) cited clinical and
experimental evidence to support the idea that those IDDM patients in
whom diabetic nephropathy (see 603933) eventually develops may have a
genetic predisposition to essential hypertension.

Gambelunghe et al. (2001) noted heterogeneity of the clinical and
immunologic features of IDDM in relation to age at clinical onset.
Childhood IDDM is characterized by an abrupt onset and ketosis and is
associated with HLA-DRB1*04-DQA1*0301-DQB1*0302 and a high frequency of
insulin and IA-2 autoantibodies. On the other hand, the so-called latent
autoimmune diabetes of the adult (LADA) is a slowly progressive form of
adult-onset autoimmune diabetes that is noninsulin-dependent at the time
of clinical diagnosis and is characterized by the presence of glutamic
acid decarboxylase-65 (GAD65: 138275) autoantibodies and/or islet cell
antibodies.

BIOCHEMICAL FEATURES

Nepom et al. (1987) studied the mechanism of the exaggerated
susceptibility to IDDM in DR3/DR4 heterozygotes, and concluded that its
basis is the formation of hybrid molecules of the closely linked
DQ-alpha (HLA-DQA1; 146880) and -beta (HLA-DQB1; 604305) chains. The
DR-alpha molecules are not polymorphic, and mixed DR alpha-beta dimers
would not result in novel HLA molecules. On the other hand, both the
alpha and beta chains of DQ are polymorphic, and a DQ alpha-beta dimer
composed of transcomplementing chains would be unique to a heterozygous
individual and not expressed in either parent. In the mouse, such
transcomplementation has been demonstrated structurally, and epitopes
newly formed in the resulting hybrid molecules allow for an altered
functional immune response different from that of either parent.

The human MHC class II molecule encoded by DQA1*0102/DQB1*0602 (termed
DQ0602) confers strong susceptibility to narcolepsy (161400) but
dominant protection against type I diabetes. To elucidate the molecular
features underlying these contrasting genetic properties, Siebold et al.
(2004) determined the crystal structure of the DQ0602 molecule at
1.8-angstrom resolution. Structural comparisons to homologous DQ
molecules with differential disease associations highlighted a
previously unrecognized interplay between the volume of the P6 pocket
and the specificity of the P9 pocket, which implies that presentation of
the expanded peptide repertoire is critical for dominant protection
against type I diabetes. In narcolepsy, the volume of the P4 pocket
appears central to the susceptibility, suggesting that the presentation
of a specific peptide population plays a major role.

OTHER FEATURES

Hyperglycemia, the basic metabolic abnormality in IDDM, is caused by
abnormally increased gluconeogenesis and insufficient glucose disposal.
Ketosis results from the accumulation of free fatty acids and their
oxidation.

McCorry et al. (2006) found an association between IDDM and idiopathic
generalized epilepsy (EIG; 600669) in a population-based survey in the
U.K. Among 518 EIG patients aged 15 to 30 years, 7 also had IDDM. In
contrast, there were 465 IDDM patients among an age-matched cohort of
150,000 individuals. The findings suggested that the prevalence of IDDM
is increased in patients with EIG (odds ratio of 4.4).

PATHOGENESIS

Type 1 diabetic patients have diminished responses following T-cell
activation. By immunoblot analysis, Nervi et al. (2000) found reduced
levels of phosphorylated CD3Z (186780) in IDDM1 patients after T-cell
stimulation. Immunoblot, immunoprecipitation, and densitometric analyses
revealed significantly reduced LCK expression in unstimulated peripheral
blood cells of IDDM1 patients compared to controls. The reduced LCK
expression correlated with a lower proliferative response. Very low LCK
expression may also correlate with the HLA-DQB1*0201/0302 (see 604305)
genotype. Confocal microscopy demonstrated normal plasma membrane
expression of LCK in patients and controls. Downstream signal
transducing molecules were not affected in these patients.

Kent et al. (2005) examined T cells from pancreatic draining lymph
nodes, the site of islet cell-specific self-antigen presentation. They
cloned single T cells in a nonbiased manner from pancreatic draining
lymph nodes of patients with type I diabetes and from nondiabetic
controls. A high degree of T-cell clonal expansion was observed in
pancreatic lymph nodes from long-term diabetic patients but not from
controls. The oligoclonally expanded T cells from diabetic patients with
DR4, a susceptibility allele for type I diabetes, recognized the insulin
A 1-15 epitope restricted by DR4. Kent et al. (2005) concluded that
their results identified insulin-reactive, clonally expanded T cells
from the site of autoinflammatory drainage in long-term type I
diabetics, indicating that insulin may indeed be the target antigen
causing autoimmune diabetes.

Porter and Barrett (2005) reviewed monogenic syndromes of abnormal
glucose homeostasis, focusing on 3 mechanisms: insulin resistance,
insulin secretion defects, and beta-cell apoptosis.

Stechova et al. (2012) reported a family with naturally conceived
monozygotic female quadruplets, in which type 1 diabetes was diagnosed
in 2 of the quadruplets simultaneously and a third quadruplet was
diagnosed as pre-diabetic. All 4 quadruplets were positive for
anti-islet cell autoantibodies to GAD65 (138275) and to IA-2 (601773),
indicating an ongoing anti-islet autoimmunity in the nondiabetic
quadruplets. Serologic examination confirmed that all the quadruplets
and their father had recently undergone an enteroviral infection of the
EV68-81 serotype. Immunocompetent cells from all family members were
characterized by gene expression arrays, immune-cell enumerations, and
cytokine-production assays. The microarray data provided evidence that
the viral infection and IL27 (608273) and IL9 (146931) cytokine
signaling contributed to the onset of T1D in 2 of the quadruplets.
Stechova et al. (2012) stated that the propensity of stimulated
immunocompetent cells from nondiabetic members of the family to secrete
high levels of IFN-alpha (IFNA1; 147660) further corroborated their
conclusion. They observed that the number of T-regulatory cells as well
as plasmacytoid and/or myeloid dendritic cells was diminished in all
family members. Stechova et al. (2012) concluded that this family
supported the so-called 'fertile-field' hypothesis proposing that
genetic predisposition to anti-islet autoimmunity, if 'fertilized' and
precipitated by a viral infection, results in full-blown type 1
diabetes.

INHERITANCE

IDDM exhibits 30 to 50% concordance in monozygotic twins, suggesting
that the disorder is dependent on environmental factors as well as
genes. The average risk to sibs is 6% (Todd, 1990). Recessive, dominant,
and multifactorial hypotheses have been advanced, as well as
'susceptibility' hypotheses (Rotter, 1981). Genetic and environmental
influences in IDDM were reviewed by Craighead (1978). Usually in genetic
disease the most severe form of a disorder shows the clearest genetic
basis. It is therefore surprising to find that the genetics of IDDM is
less clear than that of NIDDM. Concordance in NIDDM was 100% for
identical twins in which the index case had onset of diabetes after age
45 years, and nearly half had a diabetic parent, while discordance was
found in half the pairs with earlier onset, few of whom had a family
history of diabetes (Tattersall and Pyke, 1972).

Nilsson (1964) commented on the difficulties of distinguishing dominant
and recessive inheritance when gene frequency is high. He considered
autosomal recessive inheritance to be most likely, with a gene frequency
of about 0.30 and a lifetime penetrance of about 70% for males and 90%
for females. A gene frequency of about 0.05 and a penetrance of 25 to
30% would be required to account for the findings on a dominant
hypothesis. Hodge et al. (1980) proposed a 3-allele model based on a
susceptibility locus (S) tightly linked to the HLA complex. Thomson
(1980) espoused a 2-locus model. See 125850 for a clear example of an
autosomal dominant type of diabetes mellitus: maturity-onset diabetes of
the young (MODY).

Cudworth and Woodrow (1975) found that the relative risk of IDDM was
2.12 for HLA-A 8 and 2.60 for W15. Rubinstein et al. (1977) found that
diabetic sibs shared their HLA genes with a significantly increased
frequency, leading them to postulate a recessive gene linked to HLA (and
specifically to HLA-D as indicated by 3 informative cases with
recombination within the HLA). They estimated the penetrance at 50%
because half the HLA-identical sibs of index cases were diabetic. This
conclusion fits with published observations of 6-10% risk to sibs of
patients when both parents are normal. As an appendix to their paper,
they presented a table of risk to relatives on the basis of the above
hypotheses. Barbosa et al. (1978) also concluded that IDDM is a
recessive with 50% penetrance and with linkage to HLA (theta = 0.13, lod
= 3.98) on the basis of the study of 21 families with 2 or more affected
sibs and normal parents.

Vadheim et al. (1986) pointed out that several studies suggested a
higher incidence of IDDM among the offspring of affected males than
among those of affected females. To test the hypothesis that
differential transmission by the father of genes predisposed to diabetes
may explain this phenomenon, Vadheim et al. (1986) examined
parent-to-offspring transmission of HLA haplotypes and DR alleles in 107
nuclear families in which a child had IDDM. They found that fathers with
a DR4 allele were significantly more likely to transmit this allele to
their diabetic or nondiabetic children than were mothers with a DR4
allele. No difference between parents was observed for HLA-DR3; however,
DR3 was transmitted significantly more than 50% of the time from either
parent. Field et al. (1986) reconfirmed the fact that sharing of 2 HLA
haplotypes by sibs with diabetes mellitus was increased in comparison to
mendelian expectations. Whereas sharing of GM-region genes was not
different from mendelian expectations in the total sampled, affected
pairs who shared 2 HLA haplotypes did show significantly increased
sharing of GM-region genes.

MacDonald et al. (1986) studied families with IDDM in parent and child.
The proportion of diabetic parents who transmitted DR4 to diabetic
offspring (78%) was significantly higher (P less than 0.001) than the
gene frequency of DR4 in the overall diabetic population (43%). The
proportion of nondiabetic parents who transmitted DR4 to diabetic
offspring (22%) was not significantly different from the gene frequency
in the nondiabetic population but significantly lower (P less than 0.05)
than the gene frequency in the overall IDDM population. This was taken
to indicate a strong dominant effect of DR4. The proportion of
nondiabetic parents who transmitted DR3 was similar to the gene
frequency of DR3 in the overall diabetic population, but it was
significantly higher than the gene frequency of DR 3 in the nondiabetic
population (15%; P less than 0.005). The percentage of diabetic
offspring who were DR3/DR4 (35%) was identical to that in the overall
IDDM population (35%). MacDonald et al. (1986) interpreted this to mean
that DR3 plays an enhancing role, with DR4 playing the main role.

Thomson et al. (1988) analyzed the results from 11 studies involving
1,792 Caucasian probands with IDDM. Antigen genotype frequencies in
patients, transmission from affected parents to affected children, and
the relative frequencies of HLA-DR3 and -DR4 homozygous patients all
indicated that DR3 predisposes in a 'recessive'-like and DR4 in a
'dominant'-like or 'intermediate' fashion, after allowing for the
synergistic effect of the 2 HLA types. DR2 showed a protective effect,
DR1 and DRw8 showed predisposing effects, and DR5 showed a slight
protective effect. They found evidence that only subsets of DR3 and DR4
are predisposing. The presence or absence of asp at position 57 of the
DQ-beta gene was shown to be insufficient of itself in explaining the
inheritance of IDDM. They suggested that the distinguishing features of
the DR3-associated and DR4-associated predisposition remain to be
identified at the molecular level.

Using an overall sib risk of 6%, Thomson et al. (1988) estimated that
the risks for those sharing 2, 1, or 0 haplotypes are 12.9%, 4.5%, and
1.8%, respectively. The highest sib risk was 19.2% for sibs sharing 2
haplotypes with a DR3/DR4 proband. Field (1988) put this study in
perspective with a discussion of other factors, including nongenetic
factors. Sheehy et al. (1989) likewise concluded that susceptibility to
diabetes is best defined by a combination of HLA-DR and HLA-DQ alleles.

In a study of 266 unrelated white patients with IDDM, Baisch et al.
(1990) extended the assessment of the role of HLA-DQ alleles in
susceptibility to the disease. They used allele-specific oligonucleotide
probes and PCR to study HLA-DQ beta-chain alleles. Two major findings
emerged. First, HLA-DQw1.2 was protective; it was found in only 2.3% of
IDDM patients and in 36.4% of controls. This was 'dominant protection,'
i.e., it did not matter what other allele was present. Second, HLA-DQw8
increased the risk of IDDM and the effect was one of 'dominant
susceptibility' except that persons who were HLA-DQw1.2/DQw8 had a
relative risk of 0.37, demonstrating that the protective effect of
HLA-DQw1.2 predominated over the effect of HLA-DQw8. Segall and Bach
(1990) reviewed the significance of these findings. See also review by
Todd (1990).

The Eurodiab Ace Study Group and the Eurodiab Ace Substudy 2 Study Group
(1998) studied the characteristics of familial type I diabetes mellitus,
i.e., cases in which more than one affected first-degree relative was
diagnosed before the age of 15 years. They used data from an
international network of population-based registries and from a
case-control study conducted in 8 of the network's centers. They found a
positive association between the population incidence rate of type I
diabetes and the prevalence of type I diabetes in fathers of affected
children. A similar association was observed with the prevalence in
sibs, but the association with prevalence in mothers was weaker and not
significant. Pooling results from all centers showed that a greater
proportion of fathers (3.4%) of affected children had type I diabetes
than mothers (1.8%) giving a risk ratio of 1.8. Affected girls were more
likely to have a father with type I diabetes than affected boys, but
there was no evidence of a similar finding for mothers or sibs. Familial
type I diabetes patients had a younger age at onset than nonfamilial
patients.

Krischer et al. (2003) determined the extent to which different
screening strategies could identify a population of nondiabetic
relatives of a proband with type 1 diabetes who had 2 or more
immunologic markers from the group consisting of islet cell antibodies
(ICA), microinsulin autoantibodies (MIAA), GAD65 (138275) autoantibodies
(GAA), and ICA512 (601773) autoantibodies (ICA512AA). Screening for any
3 antibodies guaranteed that all multiple antibody-positive subjects
were detected. Screening for 2 antibodies at once and testing for the
remaining antibodies among those who were positive for 1 resulted in a
sensitivity of 99% for GAA and ICA, 97% for GAA and MIAA or GAA and
ICA512AA, 93% for ICA512AA and ICA, 92% for MIAA and ICA, and 73% for
ICA512AA and MIAA. From a laboratory perspective, screenings for GAA,
ICA512AA, and MIAA are semiautomated tests with high throughput that, if
used as initial screen, would identify at first testing 67% of the 2.3%
of multiple antibody-positive relatives (100% if antibody-positive
subjects are subsequently tested for ICA) as well as 4.7% of relatives
with a single biochemical autoantibody, some of whom may convert to
multiple autoantibody positivity on follow-up. Testing for ICA among
relatives with 1 biochemical antibody would identify the remaining 33%
of multiple antibody-positive relatives. They concluded that further
follow-up and analysis of actual progression to diabetes will be
essential to define actual diabetes risk in this large cohort.

MAPPING

- General

Clerget-Darpoux et al. (1981) concluded that the data in 30 multiplex
families best fitted a model with a susceptibility gene which was not
linked to but interacted with the HLA system. Under 3 different genetic
models for IDDM, Hodge et al. (1981) found evidence for linkage with 2
different sets of marker loci: HLA, properdin factor B, and glyoxalase-1
on chromosome 6, and Kidd blood group (then thought to be on chromosome
2, but later shown to be on chromosome 18). Thus, 2 distinct
disease-susceptibility loci may be involved in IDDM, a situation also
postulated for Graves disease (275000).

Bell et al. (1984) described an association between IDDM and a
polymorphic region in the 5-prime flanking region of the insulin gene
(INS; 176730). This polymorphism (Bell et al., 1981) arises from a
variable number of tandemly repeated (VNTR) 14-bp oligonucleotides. When
divided into 3 size classes, a significant association was seen between
the short-length (class I) alleles and IDDM. Several studies were unable
to demonstrate linkage of these VNTR alleles to IDDM in families, but
this may in part be attributable to the fact that the disease-associated
allele is present at high frequency in the general population. Several
disease-associated polymorphisms were identified and the boundaries of
association were mapped to a region of 19 kb on 11p15.5. Ferns et al.
(1986) studied 14 families in which 13 had 2 cases of IDDM and found no
linkage to polymorphic loci 5-prime to the insulin gene or to those
3-prime to the HRAS gene. Association with HLA was again found; persons
who were HLA identical to the diabetic proband were more likely to be
diabetic than those who were nonidentical. From studies of allele
sharing in affected sib pairs, Cox et al. (1988) found evidence of
HLA-linked susceptibility to IDDM but no evidence of a contribution of
similar magnitude by the insulin-gene region. This failure of family
studies to demonstrate linkage is difficult to reconcile with the
association demonstrated between alleles at the VNTR locus in the
5-prime region of the insulin gene on 11p (Bell et al., 1984; Bell et
al., 1985). Donald et al. (1989) used DR and DQ RFLPs for linkage
analysis and demonstrated very close linkage of an IDDM-susceptibility
locus. No evidence was found of any effect of the insulin gene.

Raum et al. (1979) found a rare genetic type of properdin factor B (F1)
in 22.6% of patients with IDDM but in only 1.9% of the general
population. If, as the authors suggested, this is an indication of
linkage disequilibrium, not association, some populations should not
show the relationship.

Based on a study in mice (Prochazka et al., 1987) it may be that
corresponding recessive genes are located on chromosomes 6 and 11 in
man; the THY1 (188230) and the APOA1 (107680) genes are on human 11q. By
use of an affected sib pair method, Hyer et al. (1991) excluded the
possibility of an IDDM susceptibility gene on 11q.

Lucassen et al. (1993) presented a detailed sequence comparison of the
predominant haplotypes found in the region of 19 kb on 11p15.5 in a
population of French-Canadian IDDM patients and controls. Identification
of polymorphisms, both associated and unassociated with IDDM, permitted
a further definition of the region of association to 4.1 kb. Ten
polymorphisms within this region were found to be in strong linkage
disequilibrium with each other and extended across the insulin gene
locus and the VNTR situated immediately 5-prime to the insulin gene.
These represent a set of candidate disease polymorphisms, one or more of
which may account for the susceptibility to IDDM.

Using 96 affected sib pairs and a fluorescence-based linkage map of 290
marker loci (average spacing 11 cM), Davies et al. (1994) searched the
human genome for genes that predispose to type I (insulin-dependent)
diabetes mellitus. A total of 18 different chromosomal regions showed
some positive evidence of linkage to the disease, strongly suggesting
that IDDM is inherited in a polygenic fashion. Although the authors
determined that no genes are likely to have as large effects as IDDM1
(in the major histocompatibility complex on 6p21), significant linkage
was confirmed in the insulin gene region on 11p15 (IDDM2; 125852) and
established to 11q (IDDM4; 600319), 6q (600320), and possibly to
chromosome 18. Possible candidate genes within regions of linkage
include GAD1 (605363) and GAD2 (138275), which encode the enzyme
glutamic acid decarboxylase; SOD2 (147460), which encodes superoxide
dismutase; and the Kidd blood group locus. Linkage of IDDM
susceptibility to the region of the FGF gene on chromosome 11q13 was
also reported by Hashimoto et al. (1994).

Genetic analysis of a mouse model of major histocompatibility
complex-associated autoimmune type I (insulin-dependent) diabetes
mellitus showed that the disease is caused by a combination of a major
effect at the MHC and at least 10 other susceptibility loci elsewhere in
the genome (Risch et al., 1993).

In a genomewide scan of 93 affected sib pair families from the UK,
Davies et al. (1994) found a similar genetic basis for human type I
diabetes, with a major component at the MHC locus (IDDM1) explaining 34%
of the familial clustering of the disease. Mein et al. (1998) analyzed a
further 263 multiplex families from the same population to provide a
total UK dataset of 356 affected sib pair families. Only 4 regions of
the genome outside IDDM1/MHC, which was still the only major locus
detected, were not excluded, and 2 of these showed evidence of linkage:
10p13-p11 (maximum lod score = 4.7) and 16q22-q24 (maximum lod score =
3.4). They stated that these and other novel regions, including
14q12-q21 and 19p13-q13, could potentially harbor disease loci.

Concannon et al. (1998) reported the results of a genome screen for
linkage with IDDM and analyzed the data by multipoint linkage methods.
An initial panel of 212 affected sib pairs were genotyped for 438
markers spanning all autosomes, and an additional 467 affected sib pairs
were used for follow-up genotyping. Other than the well-established
linkage with the HLA region at 6p21.3, they found only 1 region, located
on 1q and not previously reported, where the lod score exceeded 3.0.
Lods between 1.0 and 1.8 were found in 6 other regions, 3 of which had
been reported in other studies.

Cox et al. (2001) reported a genome scan using a new collection of 225
multiplex families with type I diabetes and combining the data with
those from previous genome scans (Davies et al., 1994; Concannon et al.,
1998; Mein et al., 1998). The combined sample of 831 affected sib pairs,
all with both parents genotyped, provided 90% power to detect linkage.
Three chromosome regions were identified that showed significant
evidence of linkage with lod scores greater than 4: 6p21 (IDDM1); 11p15
(IDDM2); and 16q22-q24; 4 other regions showed suggestive evidence of
linkage with lod scores of 2.2 or greater: 10p11 (IDDM10, 601942); 2q31
(IDDM7, 600321; IDDM12, 601388; IDDM13, 601318); 6q21 (IDDM15, 601666);
and 1q42. Exploratory analyses, taking into account the presence of
specific high-risk HLA genotypes or affected sibs' ages at disease
onset, provided evidence of linkage at several additional sites,
including the putative IDDM8 (600883) locus on 6q27. The results
indicated that much of the difficulty in mapping type I diabetes
susceptibility genes results from inadequate sample sizes, and pointed
to the value of international collaborations to assemble and analyze
much larger datasets for linkage in complex diseases.

Paterson and Petronis (2000) used data from a genomewide linkage study
of 356 affected sib pairs with type I diabetes to perform linkage
analyses using parental origin of shared alleles in subgroups based on
sex of affected sibs and age of diagnosis. They found that evidence for
linkage to IDDM4 occurred predominantly from opposite sex sib pairs and
that for linkage to a locus on chromosome 4q occurred in sibs where one
was diagnosed before age 10 years and one after age 10. Paterson and
Petronis (2000) concluded that these methods might help reduce locus
heterogeneity in type I diabetes.

Using DNA from 253 Danish IDDM families, Bergholdt et al. (2005)
analyzed the chromosomal region 21q21.3-qter, which had been previously
linked to IDDM by the European Consortium for IDDM Genome Studies
(2001). Multipoint nonparametric linkage analysis showed a peak score of
3.61 at marker D21S1920 (p = 0.0002), and a '1-lod drop' interval of 6.3
Mb was identified between markers D21S261 and D21S270. No association
was found with 74 coding SNPs from 32 candidate genes within the '1-lod
drop' interval.

Using 2,360 SNP markers in the 4.4-Mb human major histocompatibility
complex (MHC) locus and the adjacent 493 kb centromeric to the MHC,
Roach et al. (2006) mapped the genetic influences for type 1 diabetes in
2 Swedish samples. They confirmed previous studies showing association
with T1D in the MHC, most significantly near HLA-DR/DQ. In the region
centromeric to the MHC, they identified a peak of association within the
inositol 1,4,5-triphosphate receptor 3 gene (ITPR3; 147267). The most
significant single SNP in this region was at the center of the ITPR3
peak of association. The estimated population-attributable risk of 21.6%
suggested that variation within ITPR3 reflects an important contribution
to T1D in Sweden. Two-locus regression analysis supported an influence
of ITPR3 variation on T1D that is distinct from that of any MHC class II
gene.

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 7 independent association signals in type 1 diabetes at p
values of less than 5.0 x 10(-7).

In a study of 4,000 individuals with type 1 diabetes, 5,000 controls,
and 2,997 family trios independent of the Wellcome Trust Case Control
Consortium (2007) study, Todd et al. (2007) confirmed the previously
reported associations of dbSNP rs2542151 in the PTPN2 gene (176887) on
chromosome 18p11, dbSNP rs17696736 in the C12ORF30 gene on chromosome
12q24, dbSNP rs2292239 in the ERBB3 gene (190151) on chromosome 12q13,
and dbSNP rs12708716 in the KIAA0350 gene (CLEC16A; 611303) on
chromosome 16p13 (p less than or equal to 10(-9); combined with WTCCC p
less than or equal to 1.15 x 10(-14)), leaving 8 regions with small
effects or false-positive associations. The association with dbSNP
rs17696736 led to the identification of a nonsynonymous SNP (dbSNP
rs3184504) in the SH2B3 gene (605093) that was sufficient to model the
association of the entire region (p = 1.73 x 10(-21); see IDDM20,
612520).

To identify genetic factors that increase the risk of type 1 diabetes,
Hakonarson et al. (2007) performed a genomewide association study in a
large pediatric cohort of European descent. In addition to confirming
previously identified loci, they found that type 1 diabetes was
significantly associated with variation within a 233-kb linkage
disequilibrium block on chromosome 16p13 that contains the KIAA0350
gene, which is predicted to encode a sugar-binding, C-type lectin. Three
common noncoding variants of this gene (dbSNP rs2903692, dbSNP rs725613,
and dbSNP rs17673553) in strong linkage disequilibrium reached
genomewide significance for association with type 1 diabetes. A
subsequent transmission disequilibrium test replication study in an
independent cohort confirmed the association. The combined P values for
these SNPs ranged from 2.74 x 10(-5) to 6.7 x 10(-7). Hakonarson et al.
(2007) noted that the Wellcome Trust Case Control Consortium (2007) had
identified the KIAA0350 gene as a type 1 diabetes locus in a genomewide
association study.

Smyth et al. (2008) evaluated the association between type 1 diabetes
and 8 loci related to the risk of celiac disease in 8,064 patients with
type 1 diabetes, 2,828 families providing 3,064 parent-child trios, and
9,339 controls. The authors found significant association between type 1
diabetes and dbSNP rs1738074 in the TAGAP gene on chromosome 6q25 (see
IDDM21, 612521) and confirmed association with dbSNP rs3184504 in the
SH2B3 gene (605093) on chromosome 12q24 (see IDDM20, 612520).

Cooper et al. (2008) performed a metaanalysis of 3 genomewide
association studies, combining British type 1 diabetes (T1D)
case-control data (Wellcome Trust Case Control Consortium, 2007) with
T1D cases from the Genetics of Kidneys in Diabetes study (Mueller et
al., 2006) for a total of 3,561 cases and 4,646 controls. Cooper et al.
(2008) found support for a previously detected locus on chromosome 4q27
at dbSNP rs17388568 (p = 1.87 x 10(-8); see IDDM23, 612622). After
genotyping an additional 6,225 cases, 6,946 controls, and 2,828
families, they also found evidence for 4 previously unknown and distinct
risk loci: at dbSNP rs11755527 in intron 3 of the BACH2 gene (605394) on
chromosome 6q15 (p = 4.7 x 10(-12)); at dbSNP rs947474, near the PRKCQ
gene (600448) on chromosome 10p15 (p = 3.7 x 10(-9)); at dbSNP rs3825932
in intron 1 of the CTSH gene (116820) on chromosome 15q24 (p = 3.2 x
10(-15)); and at dbSNP rs229541, located between the C1QTNF6 and SSTR3
(182453) genes on chromosome 22q13 (p = 2.0 x 10(-8)).

Barrett et al. (2009) reported the findings of a genomewide association
study of type 1 diabetes, combined in a metaanalysis with 2 previously
published studies (Wellcome Trust Case Control Consortium, 2007; Cooper
et al., 2008). The total sample set included 7,514 cases and 9,045
reference samples. Forty-one distinct genomic locations provided
evidence for association with type 1 diabetes in the metaanalysis (P
less than 10(-6)). Using an analysis that combined comparisons over the
3 studies, they confirmed several previously reported associations,
including dbSNP rs2476601 at chromosome 1p13.2 (P = 8.5 x 10(-85)),
dbSNP rs7111341 at 11p15.5 (P = 4.4 x 10(-48)), dbSNP rs2292239 at
12q13.2 (P = 2.2 x 10(-25)), and dbSNP rs3184504 at 12q24.12 (P = 2.8 x
10(-27)). Barrett et al. (2009) further tested 27 novel regions in an
independent set of 4,267 cases and 4,463 controls, and 2,319 affected
sib pair families. Of these, 18 regions were replicated (P less than
0.01; overall P less than 5 x 10(-8)) and 4 additional regions provided
nominal evidence of replication. A region on 1q32.1 represented by SNP
dbSNP rs3024505 (combined P = 1.9 x 10(-9)) contains the
immunoregulatory cytokine genes IL10 (124092), IL19 (605687), and IL20
(605619). The strongest evidence of association among these 27 novel
regions was achieved at dbSNP rs10509540 on chromosome 10q23.31; see
IDDM24, 613006.

Wallace et al. (2010) used imputation to assess association with T1D
across 2.6 million SNPs in a total of 7,514 cases and 9,405 controls
from 3 existing GWA studies (Wellcome Trust Case Control Consortium,
2007; Cooper et al., 2008; Barrett et al., 2009). They obtained evidence
of an association at dbSNP rs941576, a marker in the imprinted region of
chromosome 14q32.2, for paternally inherited risk of T1D (p = 1.62 x
10(-10); ratio of allelic affects for paternal versus maternal
transmissions = 0.75). Wallace et al. (2010) suggested that dbSNP
rs941576, which is located within intron 6 of the maternally expressed
noncoding RNA gene MEG3 (605636), or another nearby variant alters the
regulation of the neighboring functional candidate gene DLK1 (176290).

Inflammatory bowel disease (see 266600), including Crohn disease (CD)
and ulcerative colitis (UC), and T1D are autoimmune diseases that may
share common susceptibility pathways. Wang et al. (2010) examined known
susceptibility loci for these diseases in a cohort of 1,689 CD cases,
777 UC cases, 989 T1D cases, and 6,197 shared control subjects of
European ancestry. Multiple previously unreported or unconfirmed
disease-loci associations were identified, including CD loci (ICOSLG,
605717; TNFSF15, 604052) and T1D loci (TNFAIP3; 191163) that conferred
UC risk; UC loci (HERC2, 605837; IL26, 605679) that conferred T1D risk;
and UC loci (IL10, 124092; CCNY, 612786) that conferred CD risk. T1D
risk alleles residing at the PTPN22 (600716), IL27 (608273), IL18RAP
(604509), and IL10 loci protected against CD. The strongest risk alleles
for T1D within the major histocompatibility complex (MHC) conferred
strong protection against CD and UC. The authors suggested that many
loci involved in autoimmunity may be under a balancing selection due to
antagonistic pleiotropic effects, and variants with opposite effects on
different diseases may facilitate the maintenance of common
susceptibility alleles in human populations.

- HLA Associations

IDDM, although called the juvenile-onset type of diabetes, has its onset
after the age of 20 years in 50% of cases. Caillat-Zucman et al. (1992)
investigated whether the association of IDDM with certain HLA alleles,
well documented in pediatric patients, also holds for adults.
Interestingly, they found quite different HLA class II gene profiles,
with a significantly higher percentage of non-DR3/non-DR4 genotypes and
a lower percentage of DR3/4 genotypes in older patients. Although the
non-DR3/non-DR4 patients presented clinically as IDDM, they showed a
lower frequency of islet cell antibodies (ICA) at diagnosis and a
significantly milder insulin deficiency. These data (1) suggest these
subjects probably represent a particular subset of IDDM patients in whom
frequency increases with age; (2) confirm the genetic heterogeneity of
IDDM; and (3) prompt caution in extrapolating the genetic concepts
derived from childhood IDDM to adult patients.

Nerup et al. (1974) found that IDDM (but not NIDDM) is associated with 2
particular HLA-A types (142800)--HLA-A8 and W15. Woodrow and Cudworth
(1975) interpreted the association of HLA-A8 and W15 with IDDM as
resulting from linkage disequilibrium between genes for these antigens
and a gene determining susceptibility of diabetes.

To test for linkage between HLA and a locus for susceptibility to this
disease, Clerget-Darpoux et al. (1980) studied 28 informative families
with at least 1 child suffering from juvenile-onset IDDM. The 28
families were pooled with 21 from the literature and autosomal recessive
inheritance was assumed. Maximum lod scores (6.00 to 7.36) were obtained
for recombination fractions from 4% to 16%, according to the level of
assumed penetrance (from 90% down to 10%). These high estimates of the
recombination fraction are not consistent with the hypothesis that the
association between IDDM and specific HLA haplotypes is a consequence of
simple linkage disequilibrium between HLA and a susceptibility locus.

Spielman et al. (1980) did HLA-typing on all members of 33 families in
which 2 or more sibs had IDDM. They interpreted the results as
supporting the hypothesis that, closely linked to the HLA region, there
is a locus (symbolized S by them) for susceptibility to
insulin-dependent diabetes. (S(d) was their symbol for the
susceptibility allele and S(a) for all other alleles.) They estimated
penetrance for the homozygote for S(d) to be 71% and for the
heterozygote 6.5%. The recombination fraction between S and HLA was
estimated to be under 3%.

Rubinstein et al. (1981) analyzed 3 sets of published data on HLA-typed
families with IDDM in which no significant heterogeneity was detected.
Autosomal recessive inheritance and incomplete penetrance were assumed.
A maximum lod score of 7.40 at theta = 0.05 was found. The segregation
of HLA and GLO in 5 affected sib pairs (4 of the 5 pairs were
HLA-identical and GLO-different), in which one of the sibs carried an
HLA-GLO recombinant, placed the IDDM locus closer to HLA than to GLO.

Dunsworth et al. (1982) performed complex segregation and linkage
analysis in 182 families with at least 1 IDDM proband. All families were
typed for HLA-B antigens and 118 for HLA-DR. The recessive model best
fitted the data, with the maximum likelihood estimate of recombination
between HLA-DR and the diabetes susceptibility factor being 0.019.
Substantial heterogeneity was suggested; the smallest recombination was
for families whose probands had 2 high-risk D alleles. Using RFLPs of
the HLA-DR-alpha gene, Stetler et al. (1985) could show a higher
association than is found with serologic markers.

Rich et al. (1987) studied linkage of IDDM with HLA and factor B
(138470) in combination with segregation analysis. They found evidence
of strong linkage disequilibrium with the B-BF-D haplotype, with IDDM
probably tightly linked to HLA-DR. The recombination fraction between
the postulated major locus for IDDM and HLA was 0 in all models. They
concluded that the best fitting genetic model of diabetic susceptibility
is that of a single major locus with 'near recessivity' on a scale of
standardized genetic liability, with a gene frequency of the IDDM
susceptibility allele of approximately 14%.

Julier et al. (1991) studied polymorphisms of INS and neighboring loci
in random diabetics, IDDM multiplex families, and controls. They found
that HLA-DR4-positive diabetics showed an increased risk associated with
common variants at polymorphic sites in a 19-kb segment spanned by the
5-prime INS VNTR and the third intron of the gene for insulin-like
growth factor II (147470). In multiplex families the IDDM-associated
alleles for polymorphisms in this region were transmitted preferentially
to HLA-DR4-positive diabetic offspring from heterozygous parents. The
effect was strongest in paternal meioses, suggesting a possible role for
maternal imprinting. Julier et al. (1991) suggested that the results
strongly support the existence of a gene or genes affecting HLA-DR4 IDDM
susceptibility in a 19-kb region of INS-IGF2. Their approach may be
useful in mapping susceptibility loci in other common diseases.

The fact that the association between IDDM and certain HLA-DQ alleles is
even stronger than that with certain DR alleles and that there is little
association with HLA-DP provides a boundary of disease association to
the 430 kb between DQ and DP. In further studies of disease association
with TAP (transporter associated with antigen processing) genes
(170260), which map approximately midway between DP and DQ, Jackson and
Capra (1993) found a higher association of a TAP allele with IDDM than
with any single HLA-DP allele but the risk was lower than with
HLA-DQB1*0302. These data provided new limits for IDDM susceptibility to
the 190-kb interval between TAP1 and HLA-DQB1.

In a 2-stage approach to fine mapping, Herr et al. (2000) evaluated
linkage in 385 affected sib-pair families using 13 evenly spaced
polymorphic microsatellite markers spanning 14 Mb. Evidence of disease
association was found for D6S2444, located within the 95% confidence
interval of 1.7 cM obtained by linkage. Analysis of an additional 12
flanking markers revealed a highly specific region of 570 kb associated
with disease that included the HLA class II genes. The peak of
association was as close as 85 kb centromeric of HLA-DQB1. Recombination
within the major histocompatibility complex was rare and nearly absent
in the class III region. The authors concluded that the majority of
disease association in the region can be explained by linkage
disequilibrium with the class II susceptibility genes.

Greenbaum et al. (2000) noted that the presence of HLA haplotype
DQA1*0102-DQB1*0602 is associated with protection from type I diabetes.
The Diabetes Prevention Trial-type I has identified 100 islet cell
antibody (ICA)-positive relatives with this protective haplotype, far
exceeding the number of such subjects reported in other studies
worldwide. Comparisons between ICA+ relatives with and without DQB1*0602
demonstrated no differences in gender or age; however, among racial
groups, African American ICA+ relatives were more likely to carry this
haplotype than others. The ICA+ DQB1*0602 individuals were less likely
to have additional risk factors for diabetes (insulin autoantibody (IAA)
positive or low first phase insulin release (FPIR)) than ICA+ relatives
without DQB1*0602. However, 29% of the ICA+ DQB1*0602 relatives did have
IAA or low FPIR. Hispanic ICA+ individuals with DQB1*0602 were more
likely to be IAA positive or to have low FPIR than other racial groups.
The authors conclude that the presence of ICA found in relatives
suggests that whatever the mechanism that protects DQB1*0602 individuals
from diabetes, it is likely to occur after the diabetes disease process
has begun. In addition, they suggest that there may be different effects
of DQB1*0602 between ethnic groups.

Redondo et al. (2000) used the transmission disequilibrium test to
analyze haplotypes for association and linkage to diabetes within
families from the Human Biological Data Interchange type I diabetes
repository (1,371 subjects) and from the Norwegian Type 1 Diabetes
Simplex Families study (2,441 subjects). DQA1*0102-DQB1*0602 was
transmitted to 2 of 313 (0.6%) affected offspring (P less than 0.001, vs
the expected 50% transmission). Protection was associated with the DQ
alleles rather than DRB1*1501 in linkage disequilibrium with
DQA1*0102-DQB1*0602: rare DRB1*1501 haplotypes without
DQA1*0102-DQB1*0602 were transmitted to 5 of 11 affected offspring,
whereas DQA1*0102-DQB1*0602 was transmitted to 2 of 313 affected
offspring (P less than 0.0001). The authors concluded that both DR and
DQ molecules (the DRB1*1401 and DQA1*0102-DQB1*0602 alleles) can provide
protection from type IA diabetes.

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 I 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.

Linkage data implicating other disease susceptibility loci for type I
diabetes are conflicting. This is likely due to (1) the limited power
for detection of contributions of additional susceptibility loci, given
the limited number of informative families available for study, (2)
factors such as genetic heterogeneity between populations, and (3)
potential gene-gene and gene-environment interactions. To circumvent
some of these problems, the European Consortium for IDDM Genome Studies
(2001) conducted a genomewide linkage analysis for type I diabetes
mellitus-susceptibility loci in 408 multiplex families from Scandinavia,
a population expected to be homogeneous for genetic and environmental
factors. In addition to verifying the HLA and INS susceptibility loci,
the study confirmed the locus of IDDM15 (601666) on chromosome 6q21.
Suggestive evidence of additional susceptibility loci was found on 2p,
5q, and 16p. For some loci, the support for linkage increased
substantially when families were stratified on the basis of HLA or INS
genotypes, with statistically significant heterogeneity between the
stratified subgroups. These data support both the existence of non-HLA
genes of significance for type I diabetes mellitus and the interaction
between HLA and non-HLA loci in the determination of the type I diabetes
mellitus phenotype.

Gambelunghe et al. (2001) estimated the frequency of major
histocompatibility complex class I chain-related A gene (MICA; 600169)
alleles and HLA-DRB1*03-DQA1*0501-DQB1*0201 and
HLA-DRB1*04-DQA1*0301-DQB1*0302 in 195 type I diabetes mellitus
subjects, in 80 latent autoimmune diabetes of the adult subjects, and in
158 healthy subjects from central Italy. The MICA5 allele was
significantly associated with type I diabetes mellitus only in the group
diagnosed before 25 years of age, and the odds ratio of the simultaneous
presence of both the MICA5 allele and HLA-DRB1*03-DQA1*0501-DQB1*0201
and/or HLA-DRB1*04-DQA1*0301-DQB1*0302 was as high as 54 and higher than
388 when compared with double-negative individuals. Adult-onset type I
diabetes mellitus (age at diagnosis greater than 25 years) and latent
autoimmune diabetes of the adult were significantly associated with the
MICA5.1 allele, which was not significantly increased among diabetic
children. Only the combination of MICA5.1 and
HLA-DRB1*03-DQA1*0501-DQB1*0201 and/or HLA-DRB1*04-DQA1*0301-DQB1*0302
conferred increased risk for adult-onset type I diabetes mellitus or for
latent autoimmune diabetes of the adult. The authors concluded the
existence of distinct genetic markers for childhood/young-onset IDDM and
for adult-onset IDDM, namely the MICA5 and MICA5.1 alleles,
respectively.

Qu and Polychronakos (2009) analyzed anti-IA-2 and anti-GAD65
autoantibody data from 2,282 type 1 diabetes patients from 1,117
multiplex families and found no association between anti-GAD65 (138275)
autoantibodies and HLA. However, significant positive association was
detected between anti-IA-2 (601773) autoantibodies and HLA-DRB1*0401,
whereas negative association was detected with the
DRB1*03-DQA1*0501-DQB1*0201 haplotype as well as with HLA-A*24,
independent of the DRB1*03-DQA1*0501-DQB1*0201 haplotype.

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. Using a purpose-designed array, they
typed approximately 19,000 individuals into distinct copy-number classes
at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs
greater than 500 basepairs. The Wellcome Trust Case Control Consortium
(2010) identified several biologic artifacts that led to false-positive
associations, including systematic CNV differences between DNAs derived
from blood and cell lines. Association testing and follow-up replication
analyses confirmed 3 loci where CNVs were associated with disease: HLA
for Crohn disease (266600), rheumatoid arthritis (RA; 180300), and IDDM;
IRGM (608282) for Crohn disease; and TSPAN8 (600769) for type 2 diabetes
(125853). In each case the locus had previously been identified in
SNP-based studies, reflecting the observation of The Wellcome Trust Case
Control Consortium (2010) that most common CNVs that are well-typed on
their array are well-tagged by SNPs and so have been indirectly explored
through SNP studies. The Wellcome Trust Case Control Consortium (2010)
concluded that common CNVs that can be typed on existing platforms are
unlikely to contribute greatly to the genetic basis of common human
diseases.

MOLECULAR GENETICS

Todd et al. (1987) estimated that more than half of the inherited
predisposition to IDDM maps to the region of the HLA class II genes on
chromosome 6. Analysis of the DNA sequences from diabetics indicated
that alleles of HLA-DQ(beta) determined both disease susceptibility and
resistance. A non-asp at residue 57 of the beta-chain in particular
confers susceptibility to IDDM and the autoimmune response against the
insulin-producing islet cells. Morel et al. (1988) found that HLA
haplotypes carrying an asp in position 57 of the DQ-beta chain (146880)
were significantly increased in frequency among nondiabetics, while
non-asp57 haplotypes were significantly increased in frequency among
diabetics. Ninety-six percent of the diabetic probands were homozygous
non-asp/non-asp as compared to 19.5% of healthy, unrelated controls.
This represented a relative risk of 107 for non-asp57 homozygous
individuals. See critique by Klitz (1988).

Khalil et al. (1990) presented evidence suggesting that asp57-negative
DQ-beta as well as arg52-positive DQ-alpha chains are important to
susceptibility to IDDM. Presumably, the modulation of susceptibility
operates via the presentation of viral-antigenic peptide and/or
autoantigen. I-Ag7, the only class II allele expressed by the nonobese
diabetic mouse, lacks asp57. Corper et al. (2000) determined the crystal
structure of the I-Ag7 molecule at 2.6-angstrom resolution as a complex
with a high-affinity peptide from the autoantigen glutamic acid
decarboxylase (GAD) 65 (138275). I-Ag7 has a substantially wider
peptide-binding groove around beta-57, which accounts for distinct
peptide preferences compared with other MHC class II alleles. Loss of
asp-beta-57 leads to an oxyanion hole in I-Ag7 that can be filled by
peptide carboxyl residues or, perhaps, through interaction with the
T-cell receptor (see 186830).

Nakanishi et al. (1999) sought to identify IDDM-susceptible HLA antigens
in IDDM patients who did not have the HLA-DQA1*0301 allele and to
correlate the relationship of these HLA antigens to the degree of
beta-cell destruction. In 139 Japanese IDDM patients and 158 normal
controls, they typed HLA-A, -C, -B, -DR, and -DQ antigens. Serum
C-peptide immunoreactivity response (delta-CPR) to a 100-g oral glucose
load of 0.033 nmol/L or less was regarded as complete beta-cell
destruction. All 14 patients without HLA-DQA1*0301 had HLA-A24, whereas
only 35 of 58 (60.3%) normal controls without HLA-DQA1*0301 and only 72
of 125 (57.6%) IDDM patients with HLA-DQA1*0301 had this antigen (Pc of
0.0256 and 0.0080, respectively). Delta-CPR in IDDM patients with both
HLA-DQA1*0301 and HLA-A24 was lower than in IDDM patients with
HLA-DQA1*0301 only and in IDDM patients with HLA-A24 only. The authors
concluded that both HLA-DQA1*0301 and HLA-A24 contribute susceptibility
to IDDM independently and accelerate beta-cell destruction in an
additive manner.

Donner et al. (1999) analyzed the presence of a solitary human
endogenous retrovirus-K (HERV-K) long terminal repeat (LTR) in the
HLA-DQ region (DQ-LTR3) and its linkage to DRB1, DQA1, and DQB1
haplotypes derived from 246 German and Belgian families with a patient
suffering from IDDM. Segregation analysis of 984 HLA-DQA1/B1 haplotypes
showed that DQ-LTR3 is linked to distinct DQA1 and DQB1 haplotypes but
is absent in others. The presence of DQ-LTR3 on HLA-DQB1*0302 haplotypes
was preferentially transmitted to patients from heterozygous parents
(82%; P less than 10-6), in contrast to only 2 of 7 DQB1*0302 haplotypes
without DQ-LTR3. Also, the extended HLA-DRB1*0401, DQB1*0302
DQ-LTR3-positive haplotypes were preferentially transmitted (84%; P less
than 10-6) compared with 1 of 6 DR-DQ-matched DQ-LTR3-negative
haplotypes. DQ-LTR3 is missing on most DQB1*0201 haplotypes, and those
LTR3-negative haplotypes were also preferentially transmitted to
patients (80%; P less than 10-6), whereas DQB1*0201 DQ-LTR3-positive
haplotypes were less often transmitted to patients (36%). The authors
concluded that the presence of DQ-LTR3 on HLA-DQB1*0302 and its absence
on DQB1*0201 haplotypes are independent genetic risk markers for IDDM.

Pugliese et al. (1999) sequenced the DQB1*0602 and DQA1*0102 alleles in
8 ICA/DQB1*0602-positive relatives and in 6 rare patients with type I
diabetes and DQB1*0602. They found that all relatives and patients carry
the known DQB1*0602 and DQA1*0102 sequences, and none of them had the
mtDNA 3243A-G mutation (590050.0001) associated with late-onset diabetes
in ICA-positive individuals. Because they did not find diabetes in
ICA/DQB1*0602-positive relatives, the authors concluded that the
development of diabetes in individuals with DQB1*0602 remains very
unlikely, even in the presence of ICA.

Cordell et al. (1995) applied to insulin-dependent diabetes mellitus an
extension of the maximum lod score method of Risch (1990), which allowed
the simultaneous detection and modeling of 2 unlinked disease loci. The
method was applied to affected sib pair data, and the joint effects of
IDDM1 (HLA) and IDDM2, the INS VNTR, and IDDM1 and IDDM4 (FGF3-linked)
were assessed. In the presence of genetic heterogeneity, there seemed to
be a significant advantage in analyzing more than 1 locus
simultaneously. Cordell et al. (1995) stated that the effects at IDDM1
and IDDM2 were well described by a multiplicative genetic model, while
those at IDDM1 and IDDM4 followed a heterogeneity model.

Cucca et al. (2001) predicted the protein structure of HLA-DQ by using
the published crystal structures of different allotypes of the murine
ortholog of DQ, IA. There were marked similarities both within and
across species between type 1 diabetes protective class II molecules.
Likewise, the type 1 diabetes predisposing molecules DR and murine IE
showed conserved similarities that contrasted with the shared patterns
observed between the protective molecules. There was also inter-isotypic
conservation between protective DQ, IA allotypes, and protective DR4
subtypes. The authors proposed a model for a joint action of the class
II peptide-binding pockets P1, P4, and P9 in disease susceptibility and
resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE.
They suggested shared epitope(s) in the target autoantigen(s) and common
pathways in human and murine type 1 diabetes.

Kristiansen et al. (2003) demonstrated that the -174C variant of the
-174G/C SNP in the IL6 gene (147620.0001) was significantly associated
with IDDM in Danish females, but not in males, and that the association
was not caused by preferential transmission distortion in females. Using
reporter assay studies, they also demonstrated evidence suggesting that
the repressed PMA-stimulated activity of the -174G variant was reverted
by 17-beta-estradiol (E2), whereas the stimulated activity of the -174C
variant was E2 insensitive and higher than the stimulated activity of
the -174G variant in the absence of E2. Kristiansen et al. (2003)
concluded that higher IL6 promoter activity may confer risk to IDDM in
very young females and that this risk may be negated with increasing
age, possibly by the increasing E2 levels in puberty.

Bottini et al. (2004) demonstrated association of a missense SNP in the
PTPN22 gene (R620W; 600716.0001) with type I diabetes. Kawasaki et al.
(2006) identified a promoter SNP in the PTPN22 gene (600716.0002) that
associated with type 1 diabetes in Japanese and Korean IDDM patients.

Tessier et al. (2006) confirmed association of type 1 diabetes with 2
SNPs in the OAS1 gene (164350.0001, 164350.0002).

Smyth et al. (2008) identified a significant association between an
insertion-deletion variant in the CCR5 gene on chromosome 3p21
(601373.0001) and a reduced risk for type 1 diabetes (IDDM22; 612522).

Concannon et al. (2009) reviewed the genetics of type 1A
(immune-mediated) diabetes, noting that genes within the HLA region,
predominantly those that encode antigen-presenting molecules, confer the
greatest part of the genetic risk for type 1A diabetes. The authors
concluded that the existence of other loci with individual effects on
risk of a similar magnitude is very unlikely, and suggested that the
remaining non-HLA loci will make only modest individual contributions to
risk, with odds ratios of 1.3 or less. Concannon et al. (2009) noted
that a majority of the other loci appear to exert their effects in the
immune system, particularly on T cells.

Zalloua et al. (2008) identified homozygous or compound heterozygous
mutations in the WFS1 gene (see, e.g., 606201.0024) in 22 (5.5%) of 399
Lebanese probands ascertained with juvenile-onset insulin-dependent
diabetes, of whom 17 had Wolfram syndrome (WFS1; 222300) and 5 had
nonsyndromic nonautoimmune diabetes mellitus. There were 2 additional
probands who were given an initial diagnosis of nonsyndromic DM that was
revised to WFS when they developed optic atrophy during the course of
the study, and Zalloua et al. (2008) noted that longer follow-up of the
nonsyndromic DM patients or a specific study of WFS adult patient
populations would be needed to determine whether a subset of the
WFS1-mutated nonsyndromic DM patients are exempted from extrapancreatic
manifestations during their lifetime.

DIAGNOSIS

The diagnosis is made on the basis of hyperglycemia with relative
insulin deficiency with or, in the early stages, without ketosis in the
absence of medications or conditions known to promote hyperglycemia.

In a study of an unselected population of 755 sibs of children with
IDDM, Kulmala et al. (1998) evaluated the predictive value of islet cell
antibodies, antibodies to the IA-2 protein, antibodies to the 65-kD
isoform of GADA, insulin autoantibodies, and combinations of these
markers. Within 7.7 years of the initial sample taken at or close to the
diagnosis in the index case, 32 sibs progressed to IDDM. The positive
predictive values of the 4 antibodies mentioned were 43%, 55%, 42%, and
29%, and their sensitivities 81%, 69%, 69%, and 25%, respectively. The
final conclusion made by Kulmala et al. (1998) was that accurate
assessment of the risk for IDDM in sibs is complicated, as not even all
those with 4 antibody specificities contract the disease, and some with
only 1 or no antibodies initially will progress to IDDM.

Kimpimaki et al. (2000) evaluated the emergence of diabetes-associated
autoantibodies in young children and assessed whether such antibodies
could be used as surrogate markers of type I diabetes in young subjects
at increased genetic risk. They studied 180 initially unaffected sibs
(92 boys and 88 girls) of children with newly diagnosed type I diabetes.
All sibs were younger than 6 years of age at the initial sampling, and
they were monitored for the emergence of islet cell antibodies (ICA),
insulin autoantibodies (IAA), glutamate decarboxylase antibodies (GADA),
and IA-2 antibodies (IA-2A) up to the age of 6 years and for progression
to clinical type I diabetes up to the age of 10 years. Twenty-two sibs
(12.2%) tested positive for ICA in their first antibody-positive sample
before the age of 6 years, 13 (7.2%) tested positive for IAA, 15 (8.3%)
tested positive for GADA, and 14 (7.8%) tested positive for IA-2A. There
were 16 sibs (8.9%) who had 1 detectable autoantibody, 5 (2.8%) who had
2, and 12 (6.7%) who had 3 or more. These observations suggested to
Kimpimaki et al. (2000) that disease-associated autoantibodies could be
used as surrogate markers of clinical type I diabetes in primary
prevention trials targeting young subjects with increased genetic
disease susceptibility.

Wenzlau et al. (2007) identified type 1 diabetes autoantigen candidates
from microarray expression profiling of human and rodent pancreas and
islet cells, then screened the candidates with radioimmunoprecipitation
assays using new-onset type 1 diabetes and prediabetic sera. The zinc
transporter SLC30A8 (611145) was targeted by autoantibodies in 60 to 80%
of new-onset type 1 diabetes compared with less than 2% of controls,
less than 3% of type 2 diabetics, and up to 30% of patients with other
autoimmune disorders with a type 1 diabetes association. SLC30A8
antibodies were found in 26% of type 1 diabetics classified as
autoantibody-negative on the basis of existing markers; the combined
measurement of antibodies to SLC30A8, GADA, IA2, and insulin raised
autoimmunity detection rates to 98% at disease onset. Wenzlau et al.
(2007) concluded that SLC30A8 is a major autoantigen in type 1 diabetes.

CLINICAL MANAGEMENT

Clinical management requires use of dietary alterations and insulin
therapy to maintain blood glucose levels within accepted range.

Lee et al. (2000) reported that a single-chain insulin analog (SIA)
produced from the gene construct recombinant adeno-associated virus
(AAV)-L-type pyruvate kinase (LPK)-SIA caused remission of diabetes in
streptozotocin-induced diabetic rats and autoimmune diabetic mice for up
to 8 months without any apparent side effects. Three of the authors
retracted the paper in 2009 on the grounds that they had not been able
to reproduce the results.

Cheung et al. (2000) found that gut K cells could be induced to produce
human insulin by providing the cells with the human insulin gene linked
to the 5-prime regulatory region of the gene encoding glucose-dependent
insulinotropic polypeptide (GIP; 137240). Mice expressing this transgene
produced human insulin specifically in gut K cells. This insulin
protected the mice from developing diabetes and maintained glucose
tolerance after destruction of the native insulin-producing beta cells.

POPULATION GENETICS

IDDM occurs about 20 times more frequently among children in the United
States than among those in China. Bao et al. (1989) examined the
question of whether this was due to a difference in the frequency of the
allele leading to aspartic acid in position 57 of the HLA-DQ-beta chain.
The presence of asp57 (or A) seems to protect against IDDM, while a
noncharged amino acid in the same position (NA) is associated with
increased susceptibility. Among probands in the IDDM registries in
Allegheny County, Pa., 96% were homozygous NA, 4% were heterozygous, and
none was homozygous A. In studies of 18 Chinese IDDM patients and 25
unrelated healthy Chinese controls, Bao et al. (1989) found that only 1
patient was homozygous NA and 13 were heterozygous, while among the 25
Chinese controls, 23 were homozygous A. The large proportion of
homozygous A persons in the Chinese population is consistent with the
low incidence of IDDM in China. The association between NA and IDDM may
be strong in both populations.

Dorman et al. (1990) hypothesized that the 30-fold difference in IDDM
incidence across racial groups and countries is related to variability
in the frequency of NA alleles. To test the hypothesis, they evaluated
diabetic and nondiabetic persons in 5 populations, with risks that were
low, moderate, and high. NA alleles were significantly associated with
IDDM in all areas, with population-specific odds ratios for NA
homozygotes relative to A homozygotes ranging from 14 to 111. Dorman et
al. (1990) used estimated genotype-specific incidence rates for
Allegheny County, Pa., Caucasians to predict the overall incidence rates
in the remaining populations. These predictions fell within the 95%
confidence limits of the actual rates established from incidence
registries. Results were considered consistent with the hypothesis that
population variation in the distribution of NA alleles explains much of
the geographic variation in IDDM incidence. Concannon et al. (1990)
excluded close linkage of a gene making a major contribution to
susceptibility to IDDM and the genes for 2 T-cell receptors, TCRA (see
186880) and TCRB (see 186930).

In a Japanese study, Imagawa et al. (2000) described what appeared to be
a novel subtype of type I diabetes mellitus characterized by a rapid
onset and an absence of diabetes-related antibodies. Lernmark (2000)
argued that, despite the unusual features, these patients had autoimmune
type I diabetes. Since the patients described by Imagawa et al. (2000)
had features of genetic susceptibility to autoimmune type I diabetes,
Lernmark (2000) found it tempting to speculate that diabetes resulted
from accelerated beta-cell destruction due to some environmental factor
that had such a rapid effect that the autoimmune response characteristic
of autoimmune type I diabetes was precluded. Along the same lines,
Honeyman et al. (2000) suggested that rotavirus, which is not infectious
until it is activated by trypsin (a product of the exocrine pancreas
that can infect islets in tissue culture), may have been a cause of
clinically silent pancreatic infection in the patients reported by
Imagawa et al. (2000) and may have led to T cell-mediated loss of beta
cells before islet-cell antibodies could develop.

The incidence of IDDM in Korea is less than one-tenth of that in the
United States, and it has been suggested that HLA alleles of Asian
patients associated with diabetes differ from those of Caucasians. Park
et al. (2000) analyzed the common susceptibility and transmission
pattern of a series of HLA DRB1-DQB1 haplotypes to Korean and Caucasian
patients with IDDM. They performed HLA DR and DQ typing of 158 IDDM
patients in a case control study, 140 nondiabetic subjects from the same
geographic area, 49 simplex families from Seoul, and 283 families from
the Human Biological Data Interchange. Although the haplotype
frequencies in the 2 populations are quite different, when identical
haplotypes are compared, their odds ratios are nearly the same. For all
parental haplotypes, the transmission to diabetic offspring was similar
for Korean and Caucasian families. The authors concluded that, not only
by case-control comparison but also by transmission analyses of the
haplotypes, that the susceptibility effects of DRB1-DQB1 haplotypes are
consistent in Koreans and Caucasians. Thus, the influence of class II
susceptibility and resistance alleles appears to transcend ethnic and
geographic diversity of IDDM.

ANIMAL MODEL

Onodera et al. (1978) presented evidence that a single locus controls
susceptibility to virus-induced diabetes mellitus in mice. They
speculated that the gene might modulate expression of viral receptors on
the beta cells of islets. DRw3 and DRw4 appear to be associated with
JOD. The disease may be somewhat different depending on which is
associated. The disease is more severe in homozygotes or genetic
compounds (Bodmer, 1978).

Prochazka et al. (1987) established a polygenic basis for susceptibility
to IDDM in nonobese diabetic mice (NOD) by outcross to a related inbred
strain, nonobese normal. Analysis of first and second backcross progeny
showed that at least 3 recessive genes are required for development of
overt diabetes. One of them was tightly linked to the major
histocompatibility complex on chromosome 17 of the mouse; a second was
localized proximal to the Thy-1/Alp-1 cluster on mouse chromosome 9. It
may be that corresponding recessive genes are located on chromosomes 6
and 11 in man; the THY1 (188230) and APOA1 (107680) genes are on human
11q. By use of an affected sib pair method, however, Hyer et al. (1991)
appeared to have excluded the possibility of an IDDM susceptibility gene
on 11q (see 125852).

Several features of the genetics and immunopathology of diabetes in the
NOD mouse are closely similar to those of the human disease. Three
murine diabetes susceptibility genes, Idd-1, Idd-3, and Idd-4, had been
mapped, but only in the case of Idd-1 was there evidence concerning the
identity of the gene product. Allelic variation within the murine immune
response I-A(beta) gene and its human homolog, HLA-DQB1, correlated with
susceptibility. Cornall et al. (1991) mapped Idd-5 to the proximal
region of mouse chromosome 1. This region contains at least 2 candidate
susceptibility genes: the interleukin-1 receptor gene (see 147810) and
the Lsh/Ity/Bcg gene which encodes resistance to bacterial and parasitic
infections and affects the function of macrophages (see 209950).

Garchon et al. (1991) demonstrated close association of periinsulitis in
the NOD mouse with a locus on chromosome 1. In the NOD mouse,
furthermore, insulitis and early-onset diabetes had been linked to
chromosomes 3 and 11, respectively (Todd et al., 1991). Garchon et al.
(1991) suggested that the existence of conserved syntenies between the
human and murine genomes point to possible IDDM genes on human
chromosomes 1, 2, or 18.

Overt type I diabetes is often preceded by the appearance of insulin
autoantibodies. Furthermore, prophylactic administration of insulin to
diabetes-prone rats, NOD mice, and human subjects results in protection
from diabetes. These 2 observations suggest that an immune response to
insulin is involved in the process of beta cell destruction in the
pancreas. Daniel and Wegmann (1996) noted that islet-infiltrating cells
isolated from NOD mice are enriched for insulin-specific T cells,
insulin-specific T cell clones are capable of adoptive transfer of
diabetes, and epitopes present on residues 9-23 of the B chain appear to
be dominant in this spontaneous response. Against this background,
Daniel and Wegmann (1996) tested the effect of either subcutaneous or
intranasal administration of B-(9-23) on the incidence of diabetes in
NOD mice. The results indicated to them that both modes of
administration resulted in a marked delay in the onset and a decrease in
the incidence of diabetes relative to mice given the control peptide, a
tetanus toxin. The protective effect was associated with reduced T-cell
proliferative response to B-(9-23) in B-(9-23)-treated mice.

Amrani et al. (2000) demonstrated that progression of pancreatic islet
inflammation to overt diabetes in NOD mice is driven by the 'avidity
maturation' of a prevailing, pancreatic beta-cell-specific T lymphocyte
population carrying the CD8 antigen (186910). This T lymphocyte
population recognizes 2 related peptides, NRP and NRP-A7, in the context
of H-2K(d) class I molecules of the major histocompatibility complex. As
prediabetic NOD mice age, their islet-associated CD8+ T lymphocytes
contain increasing numbers of NRP-A7-reactive cells, and these cells
bind NRP-A7/H-2K(d) tetramers with increased specificity, increased
avidity, and longer half-lives. Repeated treatment of prediabetic NOD
mice with soluble NRP-A7 peptide blunts the avidity maturation of the
NRP-A7-reactive-CD8+ T cell population. This inhibits the local
production of T cells that are cytotoxic to beta cells, and halts the
progression from severe insulitis to diabetes. Amrani et al. (2000)
concluded that avidity maturation of pathogenic T-cell populations may
be the key event in the progression of benign inflammation to overt
disease in autoimmunity.

Given the presence of islet beta-cell-reactive autoantibodies in
prediabetic nonobese diabetic mice, Greeley et al. (2002) abrogated the
maternal transmission of such antibodies in order to assess their
influence on susceptibility of progeny to diabetes. First, they used B
cell-deficient NOD mothers to eliminate the transmission of maternal
immunoglobulins. In a complementary approach, they used immunoglobulin
transgenic NOD mothers to exclude autoreactive specificities from the
maternal B-cell repertoire. Finally, the authors implanted NOD embryos
in pseudopregnant mothers of a nonautoimmune strain. In a commentary on
the publication of Greeley et al. (2002), von Herrath and Bach (2002)
noted that in the first experiment the incidence of diabetes was reduced
to 25%, compared with 65% in offspring of B cell-competent mothers. The
second experiment resulted in a more significant reduction: 20% of
offspring developed diabetes versus 70% of offspring of nontransgenic
mothers. In the third experiment, diabetes incidence was only 15% of
offspring versus 73% of offspring of NOD mothers. Greeley et al. (2002)
concluded that the maternal transmission of antibodies is a critical
environmental parameter influencing the ontogeny of T cell-mediated
destruction of islet beta cells in NOD mice.

Lang et al. (2005) investigated the circumstances under which CD8+ T
cells specific for pancreatic beta islet antigens induce disease in mice
expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP)
as a transgene under the control of the rat insulin promoter. In
contrast to infection with LCMV, immunization with LCMV-GP-derived
peptide did not induce autoimmune diabetes despite large numbers of
autoreactive cytotoxic T cells; only subsequent treatment with Toll-like
receptor (see 601194) ligands elicited overt diabetes. This difference
was critically regulated by the pancreas itself, which upregulated class
I major histocompatibility complex (MHC) in response to systemic
Toll-like receptor-triggered interferon-alpha (147660) production. Lang
et al. (2005) concluded that the 'inflammatory status' of the target
organ is a separate and limiting factor determining the development of
autoimmune disease.

The NOD mouse is not only the best model for spontaneous type 1
diabetes, but also for Sjogren syndrome (270150). In NOD mice, in which
loss of salivary secretory function develops spontaneously (as in human
Sjogren syndrome), Winer et al. (2002) found that disruption of the
Ica69 gene (147625), which is expressed in salivary and lacrimal glands,
prevented lacrimal gland disease and greatly reduced salivary gland
disease. These animals developed type 1 diabetes with slight delay but
at much the same incidence as wildtype animals, assigning a facultative
rather than obligate role to ICA69 in the development of diabetes.

Nakayama et al. (2005) showed that the proinsulin/insulin molecules have
a sequence that is a primary target of the autoimmunity that causes
diabetes of the NOD mouse. They created insulin-1 and insulin-2 gene
knockouts combined with a mutated proinsulin transgene, in which residue
16 on the B chain was changed to alanine, in NOD mice. This mutation
abrogated the T-cell stimulation of a series of the major insulin
autoreactive NOD T-cell clones. Female mice with only the altered
insulin did not develop insulin autoantibodies, insulitis, or autoimmune
diabetes, in contrast with mice containing at least 1 copy of the native
insulin gene. Nakayama et al. (2005) suggested that proinsulin is a
primary autoantigen of the NOD mouse and speculated that
organ-restricted autoimmune disorders with marked major
histocompatibility complex restriction of disease are likely to have
specific primary autoantigens.

Treatment of NOD mice with end-stage disease by injection of donor
splenocytes and complete Freund adjuvant eliminates autoimmunity and
permanently restores normoglycemia. The return of endogenous insulin
secretion is accompanied by the reappearance of pancreatic beta cells.
Kodama et al. (2003) showed that live donor male or labeled splenocytes
administered to diabetic NOD females contain cells that rapidly
differentiate into islet or ductal epithelial cells within the pancreas.
Treatment with irradiated splenocytes is also followed by islet
regeneration, but at a slower rate. The islets generated in both
instances are persistent, functional, and apparent in all NOD hosts with
permanent disease reversal.

Chong et al. (2006), Nishio et al. (2006), and Suri et al. (2006)
replicated the studies of Kodama et al. (2003). Chong et al. (2006)
cured 32% of NOD mice of established diabetes (greater than 340
milligrams per deciliter blood glucose), although beta cells in these
mice were not derived from donor splenocytes. Nishio et al. (2006)
provided data indicating that the recovered islets were all of host
origin, reflecting that the diabetic NOD mice actually retained
substantial beta cell mass, which can be rejuvenated/regenerated to
reverse disease upon adjuvant-dependent dampening of autoimmunity. Their
study reported a 70% reversion rate to spontaneous diabetes among the
treated animals compared to an 8% reversion rate in the study by Kodama
et al. (2003). Suri et al. (2006) found that islet transplantation and
immunization with Freund complete adjuvant along with multiple
injections of allogeneic male splenocytes allowed for survival of
transplanted islets and recovery of endogenous beta-cell function in a
proportion of mice, but with no evidence for allogeneic
splenocyte-derived differentiation of new islet beta cells. Suri et al.
(2006) concluded that control of autoimmune disease at a crucial time in
diabetogenesis can result in recovery of beta-cell function.

In a commentary on the papers of Chong et al. (2006), Nishio et al.
(2006), and Suri and Unanue (2006), Faustman et al. (2006) stated that
while these groups did not find that donor spleen cells contribute to
the regeneration of the pancreas, Faustman et al. (2006) confirmed the
results of Kodama et al. (2003) of a direct splenocyte contribution to
insulin-expressing cells of the islets. In response to the comments by
Faustman et al. (2006), Chong et al. (2006), Nishio et al. (2006), Suri
and Unanue (2006) stated that they could not detect spleen cell
transdifferentiation of spleen cells into beta cells in NOD mice.

Faustman (2007) refuted comments made by Nishio et al. (2006) that they
did not use the appropriate controls.

Wen et al. (2008) showed that specific pathogen-free NOD mice lacking
Myd88 (602170), an adaptor for multiple innate immune receptors that
recognize microbial stimuli, do not develop type 1 diabetes. The effect
is dependent on commensal microbes because germ-free Myd88-negative NOD
mice develop robust diabetes, whereas colonization of these germ-free
Myd88-negative NOD mice with a defined microbial consortium
(representing bacterial phyla normally present in human gut) attenuates
type 1 diabetes. Wen et al. (2008) also found that Myd88 deficiency
changes the composition of the distal gut microbiota, and that exposure
to the microbiota of specific pathogen-free Myd88-negative NOD donors
attenuates type 1 diabetes in germ-free NOD recipients. Wen et al.
(2008) concluded that, taken together, their findings indicated that
interaction of the intestinal microbes with the innate immune system is
a critical epigenetic factor modifying type 1 diabetes predisposition.

- Reviews

Tisch and McDevitt (1996) reviewed the molecular understanding of the
pathogenesis of this autoimmune disease. Complete molecular
understanding may permit the design of rational and effective means of
prevention. Prevention could then replace insulin therapy, which is
effective but associated with long-term renal, vascular, and retinal
complications. They pointed to the concordance rate of only 50% in
monozygotic twins, indicating as yet unidentified environmental factors.
There is a north-south gradient in incidence of the disease, with the
highest incidence in northern Europe (1% to 1.5% in Finland) and
decreasing incidence in more southerly and tropical locations. Although
this suggests the effect of infectious agents in the nonobese diabetic
(NOD) mouse, germ-free NOD mice have the highest incidence (nearly 100%)
that has been seen in any NOD colony. Tisch and McDevitt (1996) reviewed
the role of the major histocompatibility complex, the autoantigens
targeted in IDDM, the T-cell response in IDDM, and experience to date
with immunotherapy. Even if safe, effective, and long-lasting
immunotherapies are developed, their application presents a formidable
challenge. Only 15% of new cases of IDDM occur in families with a
previous case. Overt diabetes develops only when beta cell destruction
is nearly complete, and the patient is asymptomatic for months or years
until that point is reached. Thus, immunotherapy must be preventive,
which requires inexpensive and accurate genetic, autoantibody, and T
cell screening techniques.

As indicated, linkage studies have shown that type I diabetes in NOD
mice is a polygenic disease involving more than 15 chromosome
susceptibility regions. Despite extensive investigation, the
identification of individual susceptibility genes either within or
outside the major histocompatibility complex region has proved
problematic because of the limitations of linkage analysis.
Hamilton-Williams et al. (2001) provided evidence implicating a single
diabetes susceptibility gene that lies outside the MHC region, namely,
beta-2-microglobulin (B2M; 109700). Using allelic reconstitution by
transgenic rescue, they showed that NOD mice expressing the B2m*a allele
developed diabetes, whereas NOD mice expressing a murine B2m*b or human
allele of B2M were protected. The murine B2m*a allele differs from the
B2m*b allele at only a single amino acid. Mechanistic studies indicated
that the absence of the NOD B2m*a isoform on nonhematopoietic cells
inhibited the development or activation of diabetogenic T cells.
Hamilton-Williams et al. (2001) stated that it was not yet possible to
determine whether subtle variations in B2M may also contribute to
autoimmune diabetes in humans because the extent of polymorphism in this
gene had not been extensively investigated. However, they noted that the
B2m*a allele implicated as a dominant diabetes susceptibility gene in
NOD mice is not a biologically aberrant variant but rather a common
physiologically normal allele, which may exert its pathogenic functions
only in certain combinatorial contexts. This supports the hypothesis of
combinatorial context of 'normal' alleles (Nerup et al., 1994). They
also noted that further support for this concept is strong linkage
disequilibrium implicating a number of other physiologically normal
cytokine variants as candidate susceptibility genes for diabetes (Lyons
et al., 2000; Morahan et al., 2001); see 605998.

Vyse and Todd (1996) gave a general review of genetic analyses of
autoimmune diseases, including this one.

HISTORY

Using synalbumin insulin antagonism as a test, Vallance-Owen (1966)
studied 9 families containing 16 overt cases of diabetes mellitus and
concluded that the state of synalbumin positivity is a dominant.

*FIELD* SA
Adams et al. (1984); Barbosa et al. (1982); Creutzfeldt et al. (1976);
Neel (1977); Neel et al. (1965); Pyke (1970); Renold et al. (1972);
Risch (1984); Rosenthal et al. (1976); Simpson (1964); Steinberg
et al. (1970); Suarez et al. (1978); Vinik et al. (1974); Zonana and
Rimoin (1976)
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*FIELD* CS
Endocrine:
Diabetes mellitus

Metabolic:
Ketoacidosis;
Abnormally increased gluconeogenesis;
Insufficient glucose disposal

Immunology:
Pancreatic autoimmunity

GI:
Polydipsia;
Polyphagia

GU:
Polyuria;
Hyperglycemia-induced osmotic diuresis

Lab:
Hyperglycemia;
Relative insulin deficiency

Inheritance:
Autosomal recessive susceptibility;
heterogeneous

*FIELD* CD
John F. Jackson: 6/19/1996

*FIELD* ED
joanna: 05/24/1999

*FIELD* CN
George E. Tiller - updated: 9/16/2013
Marla J. F. O'Neill - updated: 5/10/2012
Marla J. F. O'Neill - updated: 9/22/2011
Ada Hamosh - updated: 4/28/2010
Marla J. F. O'Neill - updated: 4/19/2010
Marla J. F. O'Neill - updated: 1/29/2010
Marla J. F. O'Neill - updated: 10/12/2009
Ada Hamosh - updated: 9/8/2009
Marla J. F. O'Neill - updated: 4/28/2009
Ada Hamosh - updated: 4/16/2009
Marla J. F. O'Neill - updated: 2/11/2009
Ada Hamosh - updated: 11/26/2008
Marla J. F. O'Neill - updated: 3/20/2008
Marla J. F. O'Neill - updated: 11/9/2007
Ada Hamosh - updated: 8/13/2007
Ada Hamosh - updated: 7/31/2007
Ada Hamosh - updated: 7/19/2007
Marla J. F. O'Neill - updated: 2/26/2007
Ada Hamosh - updated: 1/25/2007
Victor A. McKusick - updated: 9/26/2006
Cassandra L. Kniffin - updated: 4/17/2006
Ada Hamosh - updated: 4/11/2006
Marla J. F. O'Neill - updated: 1/4/2006
Marla J. F. O'Neill - updated: 7/8/2005
Ada Hamosh - updated: 5/25/2005
Marla J. F. O'Neill - updated: 3/21/2005
George E. Tiller - updated: 2/23/2005
Victor A. McKusick - updated: 5/7/2004
John A. Phillips, III - updated: 2/9/2004
Ada Hamosh - updated: 12/3/2003
Victor A. McKusick - updated: 11/27/2002
Ada Hamosh - updated: 4/9/2002
John A. Phillips, III - updated: 3/14/2002
George E. Tiller - updated: 2/4/2002
Victor A. McKusick - updated: 12/20/2001
Victor A. McKusick - updated: 11/1/2001
Victor A. McKusick - updated: 10/23/2001
John A. Phillips, III - updated: 7/27/2001
John A. Phillips, III - updated: 7/11/2001
John A. Phillips, III - updated: 3/5/2001
Michael J. Wright - updated: 1/8/2001
Ada Hamosh - updated: 12/15/2000
Ada Hamosh - updated: 11/30/2000
Ada Hamosh - updated: 8/14/2000
John A. Phillips, III - updated: 8/10/2000
Victor A. McKusick - updated: 7/14/2000
George E. Tiller - updated: 6/30/2000
Ada Hamosh - updated: 4/20/2000
John A. Phillips, III - updated: 4/3/2000
Victor A. McKusick - updated: 2/7/2000
John A. Phillips, III - updated: 9/21/1999
Victor A. McKusick - updated: 2/27/1999
Victor A. McKusick - updated: 6/24/1998
Victor A. McKusick - updated: 3/25/1998

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
mgross: 10/04/2013
alopez: 9/16/2013
carol: 4/18/2013
terry: 4/1/2013
terry: 11/27/2012
terry: 8/31/2012
terry: 7/6/2012
carol: 5/10/2012
terry: 5/10/2012
carol: 9/23/2011
terry: 9/22/2011
wwang: 11/19/2010
terry: 11/12/2010
alopez: 11/11/2010
alopez: 11/10/2010
mgross: 9/3/2010
terry: 8/24/2010
alopez: 4/29/2010
terry: 4/28/2010
alopez: 4/22/2010
alopez: 4/21/2010
terry: 4/19/2010
carol: 2/4/2010
alopez: 1/29/2010
wwang: 10/29/2009
terry: 10/12/2009
alopez: 9/10/2009
alopez: 9/9/2009
terry: 9/8/2009
wwang: 7/29/2009
wwang: 5/6/2009
terry: 4/28/2009
alopez: 4/22/2009
terry: 4/16/2009
terry: 2/20/2009
carol: 2/13/2009
wwang: 2/12/2009
terry: 2/11/2009
carol: 1/7/2009
alopez: 12/9/2008
terry: 11/26/2008
alopez: 8/28/2008
wwang: 3/25/2008
terry: 3/20/2008
wwang: 11/19/2007
terry: 11/9/2007
carol: 8/14/2007
terry: 8/13/2007
terry: 7/31/2007
alopez: 7/24/2007
terry: 7/19/2007
carol: 6/13/2007
wwang: 2/26/2007
alopez: 1/25/2007
terry: 1/25/2007
terry: 11/15/2006
alopez: 10/4/2006
terry: 9/26/2006
wwang: 4/24/2006
ckniffin: 4/17/2006
alopez: 4/11/2006
terry: 4/11/2006
alopez: 3/15/2006
wwang: 1/9/2006
terry: 1/4/2006
wwang: 7/20/2005
wwang: 7/15/2005
terry: 7/8/2005
wwang: 6/23/2005
wwang: 6/21/2005
tkritzer: 5/26/2005
terry: 5/25/2005
wwang: 3/23/2005
wwang: 3/21/2005
tkritzer: 3/7/2005
terry: 2/23/2005
alopez: 9/9/2004
carol: 5/25/2004
alopez: 5/17/2004
terry: 5/7/2004
carol: 3/17/2004
alopez: 2/9/2004
alopez: 12/8/2003
terry: 12/3/2003
tkritzer: 11/27/2002
alopez: 4/19/2002
cwells: 4/17/2002
cwells: 4/11/2002
terry: 4/9/2002
alopez: 3/14/2002
terry: 3/8/2002
cwells: 2/25/2002
cwells: 2/20/2002
cwells: 2/18/2002
cwells: 2/4/2002
alopez: 1/11/2002
cwells: 1/9/2002
terry: 12/20/2001
carol: 11/20/2001
mcapotos: 11/20/2001
mcapotos: 11/15/2001
terry: 11/1/2001
carol: 10/31/2001
mcapotos: 10/30/2001
terry: 10/23/2001
mgross: 7/27/2001
alopez: 7/11/2001
carol: 6/5/2001
alopez: 3/14/2001
alopez: 3/5/2001
mcapotos: 2/21/2001
alopez: 1/8/2001
mgross: 12/15/2000
terry: 12/15/2000
carol: 12/1/2000
terry: 11/30/2000
carol: 10/25/2000
alopez: 8/16/2000
terry: 8/14/2000
mgross: 8/10/2000
carol: 7/14/2000
terry: 7/14/2000
alopez: 6/30/2000
alopez: 4/20/2000
mgross: 4/19/2000
terry: 4/3/2000
mcapotos: 2/11/2000
terry: 2/7/2000
alopez: 12/3/1999
carol: 9/29/1999
mgross: 9/21/1999
jlewis: 6/25/1999
carol: 4/4/1999
carol: 2/27/1999
dkim: 12/9/1998
dkim: 7/24/1998
dholmes: 7/22/1998
alopez: 6/29/1998
terry: 6/24/1998
terry: 5/29/1998
alopez: 3/25/1998
terry: 3/19/1998
jenny: 7/2/1997
mark: 8/22/1996
terry: 8/21/1996
terry: 8/20/1996
terry: 8/19/1996
terry: 8/17/1996
mark: 8/15/1996
marlene: 8/6/1996
terry: 8/2/1996
mark: 2/9/1996
terry: 2/8/1996
mark: 12/13/1995
mark: 10/22/1995
terry: 6/24/1995
phil: 3/7/1995
carol: 1/23/1995
davew: 8/26/1994
mimadm: 4/26/1994

MIM 605093
*RECORD*
*FIELD* NO
605093
*FIELD* TI
*605093 SH2B ADAPTOR PROTEIN 3; SH2B3
;;LYMPHOCYTE ADAPTOR PROTEIN; LNK
*FIELD* TX
read more
DESCRIPTION

T-cell activation requires stimulation of the T-cell receptor (TCR; see
186880)-CD3 (see CD3Z; 186780) complex, followed by recruitment of an
array of intracellular signaling proteins (e.g., GRB2 (108355) and PLCG1
(172420)). Mediating the interaction between the extracellular receptors
and intracellular signaling pathways are adaptor proteins such as LAT
(602354), TRIM (604962), and LNK.

CLONING

By PCR using primers based on the rat Lnk sequence and by screening a
Jurkat cDNA library, Li et al. (2000) obtained a cDNA encoding human
SH2B3, which they called LNK. Sequence analysis predicted that the
575-amino acid LNK protein contains an N-terminal proline-rich region, a
pleckstrin homology (PH) domain, and an Src homology 2 (SH2) domain; the
PH and SH2 domains are similar to those of the APS protein. Northern
blot analysis detected low expression of a 6.8-kb LNK transcript in
various lymphoid cell lines. Confocal fluorescence microscopy showed
that the majority of LNK is located in the juxtanuclear region with some
found near the plasma membrane.

MAPPING

The International Radiation Hybrid Mapping Consortium mapped the SH2B3
gene to chromosome 12 (TMAP stSG3591). The SH2B3 gene maps to chromosome
12q24 (Wellcome Trust Case Control Consortium, 2007).

GENE FUNCTION

Immunoprecipitation analysis by Li et al. (2000) demonstrated that LNK
is phosphorylated by LCK (153390) but not by SYK (600085) and that LNK
binds to the tyrosine-phosphorylated TCR zeta chain via its SH2 domain.
Functional analysis indicated that LNK inhibits the activation of NFAT
(see 600489) in stimulated T cells.

Velazquez et al. (2002) found that cells from Lnk-deficient mice showed
an increased sensitivity to several cytokines and altered activation of
the RAS/MAPK (see 190020) pathway in response to IL3 (147740) and stem
cell factor (SCF; 184745). Lnk -/- mice exhibited extramedullary
hemopoiesis with increased numbers of CD41 (see 607759)-positive
megakaryocytes as well as erythrocytes in splenic red pulp. In normal
mice, Lnk was highly expressed in multipotent cells in bone marrow,
lymph nodes, and in nonhemopoietic tissues such as testis, brain, and
muscle, but expression was low in spleen. Velazquez et al. (2002)
concluded that Lnk regulates proliferation of several hemopoietic cell
lineages.

Using Lnk -/- mice, Bersenev et al. (2008) found that Lnk controlled
hematopoietic stem cell (HSC) quiescence and self-renewal predominantly
through the thrombopoietin receptor, Mpl (159530). Lnk -/- HSCs
displayed potentiated activation of Jak2 (147796) in response to
thrombopoietin (THPO; 600044). Biochemical experiments revealed that Lnk
directly bound phosphorylated tyrosine residues in Jak2 following Thpo
stimulation. In addition, a JAK2 mutant, val617 to phe (V617F
147796.0001), which is found at a high frequency in myeloproliferative
diseases, retained the ability to bind Lnk. Bersenev et al. (2008)
concluded that LNK is a negative regulator of JAK2 in stem cells and
that THPO, MPL, JAK2, and LNK form a regulatory pathway controlling stem
cell self-renewal and quiescence.

MOLECULAR GENETICS

For discussion of an association between variation in the SH2B3 gene and
type 1 diabetes, see IDDM20 (612520).

For discussion of an association between variation in the SH2B3 gene and
celiac disease, see CELIAC13 (612011).

- Somatic Mutations

In 2 (6%) of 33 unrelated patients with various myeloproliferative
neoplasms, Oh et al. (2010) identified 2 different somatic mutations in
the SH2B3 gene. A 5-bp deletion resulting in premature termination was
found in a patient with primary myelofibrosis (254450), and a
glu208-to-gln (E208Q) substitution was found in a patient with essential
thrombocythemia (187950). The deletion was predicted to result in the
absence of both the PH and SH2 domains, whereas the missense mutation
was in the PH domain. In vitro functional expression studies showed that
the truncating mutation was unable to inhibit TPO (600044)-mediated
growth, and the missense mutation resulted in partial loss of this
inhibitory activity. Both mutations were associated with increased
activation of the JAK-STAT (see, e.g., 147796) signaling pathway,
resulting in cellular proliferation. In addition, both mutations were
present in early progenitor cells (CD34+) from the hematopoietic
compartments of these patients. The findings indicated that disruption
of an inhibitor of JAK-STAT signaling can phenocopy diseases that result
from activating mutations in these tyrosine kinases.

Lasho et al. (2010) reported 2 patients with somatic mutations in the
SH2B3 gene associated with isolated erythrocytosis: E208X and A215V,
respectively. Both mutations occurred in exon 2 and affected the PH
domain. Neither patient had other features of polycythemia vera (PV;
263300). Lasho et al. (2010) suggested that SH2B3 mutations may provide
the 'missing link' for JAK2-negative erythrocytosis or PV.

ANIMAL MODEL

Takaki et al. (2000) generated Lnk-deficient mice and found that
although they had unimpaired T-cell development in thymus, pre-B and
immature B cells accumulated in enlarged spleens. In bone marrow, there
was also an increase in B-lineage cells, reflecting enhanced production
of B-cell progenitors due in part to hypersensitivity to SCF (KITLG;
184745) in the presence or absence of IL7 (146660). Western blot
analysis showed that mouse Lnk is actually a 68-kD protein.

To determine whether Lnk might act as a physiologic negative regulator
of cytokine-induced HSC expansion, Buza-Vidas et al. (2006) analyzed HSC
expansion in Lnk -/- mice. They found that Lnk -/- HSCs continued to
expand postnatally, up to 24-fold above normal by 6 months of age.
Within the stem cell compartment, this expansion was highly selective
for self-renewing long-term HSCs, which showed enhanced Thpo
responsiveness. Lnk -/- HSC expansion was dependent on Thpo, and
12-week-old Lnk -/- Thpo -/- mice had 65-fold fewer long-term HSCs than
Lnk -/- mice. Expansions in multiple myeloid, but not lymphoid,
progenitors in Lnk -/- mice also proved to be Thpo-dependent.

*FIELD* AV
.0001
MYELOFIBROSIS, SOMATIC
SH2B3, 5-BP DEL

In a patient with primary myelofibrosis (see 254450), Oh et al. (2010)
identified a somatic 5-bp deletion in the SC2B3 gene. The deletion was
predicted to result in the absence of both the PH and SH2 domains. In
vitro functional expression studies showed that the truncating mutant
was unable to inhibit TPO (600044)-mediated growth.

.0002
THROMBOCYTHEMIA, SOMATIC
SH2B3, GLU208GLN

In a patient with essential thrombocythemia (187950), Oh et al. (2010)
identified a somatic glu208-to-gln (E208Q) substitution in the SH2B3
gene. The mutation occurred in the PH domain. In vitro functional
expression studies showed that the mutation resulted in partial loss of
the ability to inhibit TPO (600044)-mediated growth.

.0003
ERYTHROCYTOSIS, SOMATIC
SH2B3, GLU208TER

In a patient with erythrocytosis (see 133100), Lasho et al. (2010)
identified a glu208-to-ter (E208X) mutation in exon 2 of the PH domain
of the SH2B3 gene. The patient did not have other features of
polycythemia vera.

*FIELD* RF
1. Bersenev, A.; Wu, C.; Balcerek, J.; Tong, W.: Lnk controls mouse
hematopoietic stem cell self-renewal and quiescence through direct
interactions with JAK2. J. Clin. Invest. 118: 2832-2844, 2008.

2. Buza-Vidas, N.; Antonchuk, J.; Qian, H.; Mansson, R.; Luc, S.;
Zandi, S.; Anderson, K.; Takaki, S.; Nygren, J. M.; Jensen, C. T.;
Jacobsen, S. E. W.: Cytokines regulate postnatal hematopoietic stem
cell expansion: opposing roles of thrombopoietin and LNK. Genes Dev. 20:
2018-2023, 2006.

3. Lasho, T. L.; Pardanani, A.; Tefferi, A.: LNK mutations in JAK2
mutation-negative erythrocytosis. (Letter) New Eng. J. Med. 363:
1189-1190, 2010.

4. Li, Y.; He, X.; Schembri-King, J.; Jakes, S.; Hayashi, J.: Cloning
and characterization of human Lnk, an adaptor protein with pleckstrin
homology and Src homology 2 domains that can inhibit T cell activation. J.
Immun. 164: 5199-5206, 2000.

5. Oh, S. T.; Simonds, E. F.; Jones, C.; Hale, M. B.; Goltsev, Y.;
Gibbs, K. D., Jr.; Merker, J. D.; Zehnder, J. L.; Nolan, G. P.; Gotlib,
J.: Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT
signaling in patients with myeloproliferative neoplasms. Blood 116:
988-992, 2010.

6. Takaki, S.; Sauer, K.; Iritani, B. M.; Chien, S.; Ebihara, Y.;
Tsuji, K.; Takatsu, K.; Perlmutter, R. M.: Control of B cell production
by the adaptor protein Lnk: definition of a conserved family of signal-modulating
proteins. Immunity 13: 599-609, 2000.

7. Velazquez, L.; Cheng, A. M.; Fleming, H. E.; Furlonger, C.; Vesely,
S.; Bernstein, A.; Paige, C. J.; Pawson, T.: Cytokine signaling and
hematopoietic homeostasis are disrupted in Lnk-deficient mice. J.
Exp. Med. 195: 1599-1611, 2002.

8. Wellcome Trust Case Control Consortium: Genome-wide association
study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:
661-678, 2007.

*FIELD* CN
Cassandra L. Kniffin - updated: 10/25/2010
Patricia A. Hartz - updated: 3/20/2009
Marla J. F. O'Neill - updated: 1/7/2009
Marla J. F. O'Neill - updated: 11/19/2007
Patricia A. Hartz - updated: 10/3/2006
Paul J. Converse - updated: 12/16/2002
Paul J. Converse - updated: 12/11/2000

*FIELD* CD
Paul J. Converse: 6/29/2000

*FIELD* ED
carol: 09/16/2013
carol: 7/12/2011
wwang: 10/26/2010
ckniffin: 10/25/2010
mgross: 3/24/2009
terry: 3/20/2009
carol: 1/7/2009
alopez: 4/24/2008
wwang: 11/19/2007
carol: 11/6/2006
mgross: 10/3/2006
terry: 10/3/2006
ckniffin: 5/15/2003
mgross: 12/16/2002
alopez: 4/3/2002
mgross: 12/12/2000
terry: 12/11/2000
mgross: 6/29/2000

MIM 612011
*RECORD*
*FIELD* NO
612011
*FIELD* TI
%612011 CELIAC DISEASE, SUSCEPTIBILITY TO, 13; CELIAC13
;;GLUTEN-SENSITIVE ENTEROPATHY, SUSCEPTIBILITY TO, 13
read more*FIELD* TX

DESCRIPTION

Celiac disease, also known as celiac sprue and gluten-sensitive
enteropathy, is a multifactorial disorder of the small intestine that is
influenced by both environmental and genetic factors. It is
characterized by malabsorption resulting from inflammatory injury to the
mucosa of the small intestine after the ingestion of wheat gluten or
related rye and barley proteins (summary by Farrell and Kelly, 2002).

For additional information and a discussion of genetic heterogeneity of
celiac disease, see 212750.

MAPPING

To identify risk variants contributing to celiac disease susceptibility
other than those in the HLA-DQ region (see CELIAC1, 212750), Hunt et al.
(2008) genotyped 1,020 of the most strongly associated non-HLA markers
identified by van Heel et al. (2007) in an additional 1,643 cases of
celiac disease and 3,406 controls. Hunt et al. (2008) identified 2
correlated SNPs, dbSNP rs653178 (P overall = 8 x 10(-8)) and dbSNP
rs3184504 that mapped in the vicinity of the SH2B3 gene (605093). Modest
LD was seen over a broader region of approximately 1 Mb containing
multiple other genes. Strong association with type 1 diabetes was
reported in this region with dbSNP rs3184504 entirely accounting for the
association signal (Todd et al., 2007). SH2B3 is strongly expressed in
monocytes and dendritic cells, as well as to a lesser extent in resting
B, T, and natural killer cells. Hunt et al. (2008) found SH2B3 to be
strongly expressed in small intestine; higher expression in inflamed
celiac biopsies may reflect leukocyte recruitment and activation. The
nonsynonymous SNP dbSNP rs3184504 is located in exon 3 of SH2B3, leading
to an R262W amino acid change in the pleckstrin homology domain. This
domain may be important in plasma membrane targeting. SH2B3 regulates
T-cell receptor, growth factor, and cytokine receptor-mediated signaling
implicated in leukocyte and myeloid cell homeostasis. Hunt et al. (2008)
also noted strong correlation between dbSNP rs3184504 and another SNP,
dbSNP rs653178 (r(2) = 0.99).

Smyth et al. (2008) evaluated the association between type 1 diabetes
(222100) and 8 loci related to the risk of celiac disease in 8,064
patients with type 1 diabetes, 2,828 families providing 3,064
parent-child trios, and 9,339 controls. The authors confirmed
association between IDDM20 (612520) and dbSNP rs3184504 in the SH2B3
gene, which is associated with CELIAC13.

In an Italian cohort involving 538 patients with celiac disease and 593
healthy controls, Romanos et al. (2009) confirmed association at dbSNP
rs3184504 (p = 0.0050).

POPULATION GENETICS

Zhernakova et al. (2010) assessed signatures of natural selection for 10
confirmed celiac disease loci in several genomewide data sets comprising
8,154 controls from 4 European populations and 195 individuals from a
North African population and found consistent signs of positive
selection for disease-associated alleles at 3 loci, including dbSNP
rs3184504 at SH2B3 in the European populations. Functional investigation
of the SH2B3 genotype in response to lipopolysaccharide and muramyl
dipeptide showed that carriers of the SH2B3 dbSNP rs3184504 'A' risk
allele showed stronger activation of the NOD2 recognition pathway than
did carriers of the nonrisk 'G' allele, suggesting that SH2B3 plays a
role in protection against bacterial infection and providing a possible
explanation for the selective sweep, which occurred sometime between
1,200 and 1,700 years ago.

*FIELD* RF
1. Farrell, R. J.; Kelly, C. P.: Celiac sprue. New Eng. J. Med. 346:
180-188, 2002.

2. Hunt, K. A.; Zhernakova, A.; Turner, G.; Heap, G. A. R.; Franke,
L.; Bruinenberg, M.; Romanos, J.; Dinesen, L. C.; Ryan, A. W.; Panesar,
D.; Gwilliam, R.; Takeuchi, F.; and 25 others: Newly identified
genetic risk variants for celiac disease related to the immune response. Nature
Genet. 40: 395-402, 2008.

3. Romanos, J.; Barisani, D.; Trynka, G.; Zhernakova, A.; Bardella,
M. T.; Wijmenga, C.: Six new coeliac disease loci replicated in an
Italian population confirm association with coeliac disease. J. Med.
Genet. 46: 60-63, 2009.

4. Smyth, D. J.; Plagnol, V.; Walker, N. M.; Cooper, J. D.; Downes,
K.; Yang, J. H. M.; Howson, J. M. M.; Stevens, H.; McManus, R.; Wijmenga,
C.; Heap, G. A.; Dubois, P. C.; Clayton, D. G.; Hunt, K. A.; van Heel,
D. A.; Todd, J. A.: Shared and distinct genetic variants in type
1 diabetes and celiac disease. New Eng. J. Med. 359: 2767-2777,
2008.

5. Todd, J. A.; Walker, N. M.; Cooper, J. D.; Smyth, D. J.; Downes,
K.; Plagnol, V.; Bailey, R.; Nejentsev, S.; Field, S. F.; Payne, F.;
Lowe, C. E.; Szeszko, J. S.; and 30 others: Robust associations
of four new chromosome regions from genome-wide analyses of type 1
diabetes. Nature Genet. 39: 857-864, 2007.

6. van Heel, D. A.; Franke, L.; Hunt, K. A.; Gwilliam, R.; Zhernakova,
A.; Inouye, M.; Wapenaar, M. C.; Barnardo, M. C. N. M.; Bethel, G.;
Holmes, G. K. T.; Feighery, C.; Jewell, D.; and 16 others: A genome-wide
association study for celiac disease identifies risk variants in the
region harboring IL2 and IL21. Nature Genet. 39: 827-829, 2007.

7. Zhernakova, A.; Elbers, C. C.; Ferwerda, B.; Romanos, J.; Tryunka,
G.; Dubois, P. C.; de Kovel, C. G. F.; Francke, L.; Oosting, M.; Barisani,
D.; Bardella, M. T.; Finnish Celiac Disease Study Group; Joosten,
L. A. B.; Saavalainen, P.; van Heel, D. A.; Catassi, C.; Netea,, M.
G.; Wijmenga, C.: Evolutionary and functional analysis of celiac
risk loci reveals SH2B3 as a protective factor against bacterial infection. Am.
J. Hum. Genet. 86: 970-977, 2010.

*FIELD* CN
Marla J. F. O'Neill - updated: 7/15/2010
Marla J. F. O'Neill - updated: 5/14/2009
Marla J. F. O'Neill - updated: 1/8/2009
Marla J. F. O'Neill - updated: 1/7/2009

*FIELD* CD
Ada Hamosh: 4/24/2008

*FIELD* ED
mcolton: 11/26/2013
carol: 7/15/2010
wwang: 6/1/2009
terry: 5/14/2009
carol: 1/8/2009
carol: 1/7/2009
alopez: 4/24/2008