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A Natural Hypomorphic Variant of the Apoptosis Regulator Gimap4/IAN1¹

Christine Carter^*, Carine Dion^2,*, Silke Schnell^2,, W. John Coadwell^*, Margaret Graham^*, Lucy Hepburn^*, Geoffrey Morgan^*, Amanda Hutchings^*, John C. Pascall^*, Heinz Jacobs, J. Ross Miller^* and Geoffrey W. Butcher^3,*

^* Babraham Institute, Cambridge, United Kingdom; and The Netherlands Cancer Institute, Amsterdam, The Netherlands

The Gimap/IAN family of GTPases has been implicated in the regulation of cell survival, particularly in lymphomyeloid cells. Prosurvival and prodeath properties have been described for different family members. We generated novel serological reagents to study the expression in rats of the prodeath family member Gimap4 (IAN1), which is sharply up-regulated at or soon after the stage of T cell-positive selection in the thymus. During these investigations we were surprised to discover a severe deficiency of Gimap4 expression in the inbred Brown Norway (BN) rat. Genetic analysis linked this trait to the Gimap gene cluster on rat chromosome 4, the probable cause being an AT dinucleotide insertion in the BN Gimap4 allele (AT(+)). This allele encodes a truncated form of Gimap4 that is missing 21 carboxyl-terminal residues relative to wild type. The low protein expression associated with this allele appears to have a posttranscriptional cause, because mRNA expression was apparently normal. Spontaneous and induced apoptosis of BN and wild-type T cells was analyzed in vitro and compared with the recently described mouse Gimap4 knockout. This revealed a "delayed" apoptosis phenotype similar to but less marked than that of the knockout. The Gimap4 AT(+) allele found in BN was shown to be rare in inbred rat strains. Nevertheless, when wild rat DNA samples were studied the AT(+) allele was found at a high overall frequency (30%). This suggests an adaptive significance for this hypomorphic allele.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Competitive Strategic Grant funding from the Biotechnology and Biological Sciences Research Council (BBSRC), BBSRC GAIN Grant 202/GAN13085 (to G.W.B. and J.R.M.), and The Netherlands Cancer Institute Grant SFN SFR 2.1.29 (to H.J.). S.S. was supported by a travel allowance from Boehringer Ingelheim Fonds.

² C.D. and S.S. contributed equally to this study and are listed alphabetically.

³ Address correspondence and reprint requests to Dr. Geoffrey W. Butcher, Babraham Institute, Cambridge, U.K. E-mail address: geoff.butcher{at}bbsrc.ac.uk

⁴ Abbreviations used in this paper: BB-DP, BioBreeding diabetes prone; BN, Brown Norway; DN, double negative; LN, lymph node; ORF, open reading frame; SNP, single nucleotide polymorphism; UTR, untranslated region.

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