Qtl influencing autoimmune diabetes and encephalomyelitis map to a 0. 15-cm region containing il2

Access through your institution Buy or subscribe Insulin-dependent diabetes in NOD mice and mouse experimental autoimmune encephalomyelitis (EAE) are the major disease models for human type

I diabetes and multiple sclerosis, respectively. In recent genetic analyses, a number of quantitative trait loci (QTL) controlling susceptibility to these autoimmune diseases have been

identified1,2,3,4. Some QTL overlap between the two diseases, raising the possibility that there may be disease genes common to diabetes and EAE (ref. 5). Given the large number of QTL

identified and the large QTL support interval sizes attained in the genetic segregation analyses used, we investigated whether this overlap was due to a shared 'autoimmunity gene'

or merely to the coincidental grouping of two unrelated genes. Among the diabetes QTL mapped so far in NOD mice, two overlap with QTL that we identified in EAE (ref. 1). One of these QTL, in

the medial region of chromosome 3, has been further analysed through the generation of congenic mice and was found to be composed of QTL _ Idd3_, _Idd17_, _Idd10_ and _Idd18_ (refs 6,7). We

were able to more precisely examine the effect of the diabetes QTL on EAE using these NOD congenic lines, which carry diabetes-resistance alleles at one or more of these QTL (refs 6,7).

Previously, the location of _Idd3_ was narrowed to an interval of 0.35 cM and _Ccna2_, _Il2_ and _Fgf2_ were shown to map in this interval7. Using _Idd3_ congenic strains with increasingly

smaller congenic intervals, the smallest of which defines the proximal end of _Idd3_ to the 0.07-cM genetic interval between _Il2_ and _ Ccna2_ (L.S.W., unpublished data), we have now

demonstrated that an EAE-resistance gene is colocalized with the _Idd3_ diabetes resistance gene in a genetic interval of less than 0.15 cM. This interval contains _Il2_, known to differ

allelically between NOD and B6 mice4,7,9, and _Fgf2 _; thus _Il2_ and _Fgf2_ are implicated as possible genes within _ Idd3_ involved in EAE susceptibility. _Aod2_, a QTL associated with

autoimmune ovarian dysgenesis, has also been mapped to this general region10. Due to its role in T-cell growth and differentiation, _Il2_ is a candidate for involvement in EAE and diabetes

susceptibility7. To determine whether the pair of strains (SJL/J and B10.S) we used to identify the EAE-susceptibility locus on chromosome 3 differ similarly in their _ Il2_ alleles, exon 1

of _Il2_, which is known to contain a number of sequence polymorphisms in the mouse4,7,9,11, was sequenced in SJL/J and B10.S mice. It has been reported9 that SJL/J and NOD mice share an

allele of _Il2_, whereas C57BL/10 and B6 mice share another allele of _Il2_. We sequenced exon 1 of _Il2_ and confirmed that SJL/J mice have an _Il2_ sequence identical to that of NOD mice;

similarly, B10.S mice were found to have a sequence identical to that of B6 (Table 1). As in the NOD allele, the SJL/J allele differs from the B6 allele by a single base change (T to C) that

results in a serine-to-proline substitution in the sixth amino acid residue of the mature protein. The SJL/J allele also has a duplication of a 12-bp segment of DNA that results in a 4-aa

insertion, and a compensatory 12-bp deletion that results in a deletion of 4 glutamines from a stretch of 12 consecutive glutamines. This is a preview of subscription content, access via

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* Learn about institutional subscriptions * Read our FAQs * Contact customer support REFERENCES * Encinas, J.A. _ et al._ _J. Immunol._ 157, 2186– 2192 (1996). CAS  PubMed  Google Scholar 

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al._ _Nature_ 317, 355–358 (1985). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank A. Abbas and L. Nicholson for review of the manuscript. These studies were

carried out with the support of grants from the National Institutes of Health (RO1 NS 30843, RO1 NS 35685 and PO1 AI 39671) and National Multiple Sclerosis Society (RG 2571 and 2320) to

V.K.K. AUTHOR INFORMATION Author notes * C.E.S. and J.G.S. are supported by Howard Hughes Medical Institute. AUTHORS AND AFFILIATIONS * Department of Medicine, Center for Neurologic

Diseases, Brigham & Women's Hospital, Boston, 02115, Massachusetts , USA Jeffrey A. Encinas, Akiko Mukasa, Howard L. Weiner & Vijay K. Kuchroo * Department of Autoimmune

Diseases Research, Merck Research Laboratories, Rahway, 07065, New Jersey, USA Linda S. Wicker * Department of Cellular and Molecular Pharmacology, Merck Research Laboratories, Rahway,

07065, New Jersey, USA Laurence B. Peterson * Department of Veterinary Pathobiology, The University of Illinois at Urbana–Champaign, Urbana, 61802, Illinois , USA Cory Teuscher * Department

of Pathology, Stanford University School of Medicine and Laboratory Service, Veterans Affairs Medical Center, Palo Alto, 94304, California, USA Raymond Sobel * Department of Genetics and

Howard Hughes Medical Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA Christine E. Seidman & J.G. Seidman Authors * Jeffrey A. Encinas View author publications You

can also search for this author inPubMed Google Scholar * Linda S. Wicker View author publications You can also search for this author inPubMed Google Scholar * Laurence B. Peterson View

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Teuscher View author publications You can also search for this author inPubMed Google Scholar * Raymond Sobel View author publications You can also search for this author inPubMed Google

Scholar * Howard L. Weiner View author publications You can also search for this author inPubMed Google Scholar * Christine E. Seidman View author publications You can also search for this

author inPubMed Google Scholar * J.G. Seidman View author publications You can also search for this author inPubMed Google Scholar * Vijay K. Kuchroo View author publications You can also

search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Vijay K. Kuchroo. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE

Encinas, J., Wicker, L., Peterson, L. _et al._ QTL influencing autoimmune diabetes and encephalomyelitis map to a 0.15-cM region containing _Il2_. _Nat Genet_ 21, 158–160 (1999).

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