Contribution of CYLN2 and GTF2IRD1 to neurological and cognitive symptoms in Williams Syndrome J.M. van Hagen, a,1 J.N. van der Geest, b,1, ⁎ R.S. van der Giessen, b G.C. Lagers-van Haselen, b H.J.F.M.M. Eussen, c J.J.P. Gille, a L.C.P. Govaerts, c C.H. Wouters, c I.F.M. de Coo, d C.C. Hoogenraad, b S.K.E. Koekkoek, b N. van Camp, e A. van der Linden, e M.C.E. Jansweijer, f S.S. Thorgeirsson, g and C.I. De Zeeuw b a Department of Clinical Genetics and Human Genetics, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands b Department of Neuroscience, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands c Department of Clinical Genetics, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands d Department of Child Neurology, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands e Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium f Department of Pediatrics, Academic Medical Center, PO Box 22700, 1100 DE Amsterdam, The Netherlands g Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, MD, USA Received 6 July 2006; revised 12 October 2006; accepted 6 December 2006 Available online 20 December 2006 Williams Syndrome (WS, [MIM 194050]) is a disorder caused by a hemizygous deletion of 25–30 genes on chromosome 7q11.23. Several of these genes including those encoding cytoplasmic linker protein-115 (CYLN2) and general transcription factors (GTF2I and GTF2IRD1) are expressed in the brain and may contribute to the distinct neurological and cognitive deficits in WS patients. Recent studies of patients with partial deletions indicate that hemizygosity of GTF2I probably contributes to mental retardation in WS. Here we investigate whether CYLN2 and GTF2IRD1 contribute to the motoric and cognitive deficits in WS. Behavioral assessment of a new patient in which STX1A and LIMK1, but not CYLN2 and GTF2IRD1, are deleted showed that his cognitive and motor coordination functions were significantly better than in typical WS patients. Comparative analyses of gene specific CYLN2 and GTF2IRD1 knockout mice showed that a reduced size of the corpus callosum as well as deficits in motor coordination and hippocampal memory formation may be attributed to a deletion of CYLN2, while increased ventricle volume can be attributed to both CYLN2 and GTF2IRD1. We conclude that the motor and cognitive deficits in Williams Syndrome are caused by a variety of genes and that heterozygous deletion of CYLN2 is one of the major causes responsible for such dysfunctions. © 2006 Elsevier Inc. All rights reserved. Keywords: Human; Mice; Motor behavior; Cognition; Genetic disorder Introduction Williams Syndrome (WS, also known as Williams–Beuren syndrome, MIM 194050) is a genetically determined neurodeve- lopmental disorder, which is characterized by a rather unique combination of distinct facial features and medical complications on the one hand and characteristic behavioral patterns and cognitive disabilities on the other hand (for reviews see, e.g., Bellugi et al., 1999; Morris and Mervis, 2000; Mervis, 2003; Tassabehji, 2003). The facial features include a broad nasal tip, a long philtrum and full cheeks and lips, while the medical complications are dominated by supravalvular aortic stenosis (SVAS) and pulmonary arterial stenosis (PAS), growth retardation, intermittent hypercalcemia, hyperacusis and dental abnormalities. The behavioral and cognitive abnormalities are also reflected in a wide variety of symptoms including abnormal gait, impaired stair and surface stepping, dysmetria of saccadic eye movements, a low mean IQ varying from 40 to 79, poor visual–motor integration and attention deficits (Trauner et al., 1989; Bellugi et al., 1990; Chapman et al., 1996; Gosch and Pankau, 1996; Withers, 1996; Mervis et al., 2001; van der Geest et al., 2004; van der Geest et al., 2005). In contrast to the neuropsychological features listed above, language and musical skills of WS patients are relatively spared, and their personalities are usually friendly, social and engaging (Bellugi et al., 1999). Because of their outgoing character, the mental retardation of WS patients is often underestimated. The peculiar sets of symptoms and features of WS patients generally result from a 1.55 Mb submicroscopic deletion of 25–30 genes in chromosome band 7q11.23, which is called the WS critical region (Ewart et al., 1993; Francke, 1999; Osborne, 1999; Koren- berg et al., 2000). However, some patients suffer from a smaller www.elsevier.com/locate/ynbdi Neurobiology of Disease 26 (2007) 112 – 124 Abbreviations: WS, Williams (–Beuren) syndrome; FISH, fluorescent in situ hybridization; MLPA, multiplex ligation-dependent probe amplification; WISC- RN, Wechsler Intelligence Scale—revised Dutch version; WT, wild type mice. ⁎ Corresponding author. Department of Neuroscience, Erasmus MC, PO Box 2040, NL-3000-CA Rotterdam, The Netherlands. Fax: +31 10 4089459. E-mail address: j.vandergeest@erasmusmc.nl (J.N. van der Geest). 1 Both authors contributed equally. Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2006.12.009 M.A. Frens, b