Generation of the Sotos syndrome deletion in mice
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Generation of the Sotos syndrome deletion in mice Anna M. Migdalska • Louise van der Weyden • Ozama Ismail • The Sanger Mouse Genetics Project • Alistair G. Rust • Mamunur Rashid Jacqueline K. White • Gabriela Sa´nchez-Andrade • James R. Lupski • Darren W. Logan • Mark J. Arends • David J. Adams
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Received: 11 June 2012 / Accepted: 16 July 2012 / Published online: 29 August 2012 Ó The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract Haploinsufficiency of the human 5q35 region spanning the NSD1 gene results in a rare genomic disorder known as Sotos syndrome (Sotos), with patients displaying a variety of clinical features, including pre- and postnatal overgrowth, intellectual disability, and urinary/renal abnormalities. We used chromosome engineering to generate a segmental monosomy, i.e., mice carrying a heterozygous 1.5-Mb deletion of 36 genes on mouse chromosome 13 (4732471D19Rik-B4galt7), syntenic with 5q35.2–q35.3 in humans (Df(13)Ms2Dja?/- mice). Surprisingly Df(13)Ms2Dja?/- mice were significantly smaller Electronic supplementary material The online version of this article (doi:10.1007/s00335-012-9416-0) contains supplementary material, which is available to authorized users. A. M. Migdalska L. van der Weyden A. G. Rust M. Rashid D. J. Adams (&) Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK e-mail: [email protected] O. Ismail The Sanger Mouse Genetics Project J. K. White Mouse Genetics Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK G. Sa´nchez-Andrade D. W. Logan Genetics of Instinctive Behaviour, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK J. R. Lupski Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA M. J. Arends Department of Pathology, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, UK
for their gestational age and also showed decreased postnatal growth, in contrast to Sotos patients. Df(13)Ms2Dja?/- mice did, however, display deficits in long-term memory retention and dilation of the pelvicalyceal system, which in part may model the learning difficulties and renal abnormalities observed in Sotos patients. Thus, haploinsufficiency of genes within the mouse 4732471D19Rik–B4galt7 deletion interval play important roles in growth, memory retention, and the development of the renal pelvicalyceal system.
Introduction Sotos syndrome (Sotos; MIM# 117550) is an autosomal dominant, multiple-anomaly syndrome characterized by overgrowth, a distinctive craniofacial appearance, advanced bone age, and variable learning disabilities. However, there is significant clinical heterogeneity in Sotos syndrome, with some affected individuals also showing frequent ear and chest infections, cardiac and urinary/renal defects, seizures, scoliosis, and behavioural problems (Tatton-Brown et al. 1993). The diagnosis of Sotos syndrome
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