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 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00335-012-9416-0) contains supplementary material, which is available to authorized users.
Highlights
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
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
Subsequent analysis of patients clinically diagnosed with Sotos showed that haploinsufficiency of NSD1 due to intragenic NSD1 mutations, partial NSD1 deletions, or chromosomal microdeletions spanning the 5q35 region encompassing the entire NSD1 gene accounted for more than 90 % of cases
Summary
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. There is significant clinical heterogeneity in Sotos syndrome, with some affected individuals 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 relied solely on clinical criteria until haploinsufficiency of the NSD1 gene (encoding a histone methyltransferase implicated in chromatin regulation) was identified as causative (Kurotaki et al 2002). Subsequent analysis of patients clinically diagnosed with Sotos showed that haploinsufficiency of NSD1 due to intragenic NSD1 mutations, partial NSD1 deletions, or chromosomal microdeletions spanning the 5q35 region encompassing the entire NSD1 gene accounted for more than 90 % of cases (with the prevalence of intragenic NSD1 mutations and 5q35 microdeletions encompassing the NSD1 gene depending greatly on ethnic origin)
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