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Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice.

MGC Department of Cell Biology and Genetics, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
Nature Genetics (Impact Factor: 29.65). 10/2002; 32(1):116-27. DOI: 10.1038/ng954
Source: PubMed

ABSTRACT Williams syndrome is a neurodevelopmental disorder caused by the hemizygous deletion of 1.6 Mb on human chromosome 7q11.23. This region comprises the gene CYLN2, encoding CLIP-115, a microtubule-binding protein of 115 kD. Using a gene-targeting approach, we provide evidence that mice with haploinsufficiency for Cyln2 have features reminiscent of Williams syndrome, including mild growth deficiency, brain abnormalities, hippocampal dysfunction and particular deficits in motor coordination. Absence of CLIP-115 also leads to increased levels of CLIP-170 (a closely related cytoplasmic linker protein) and dynactin at the tips of growing microtubules. This protein redistribution may affect dynein motor regulation and, together with the loss of CLIP-115-specific functions, underlie neurological alterations in Williams syndrome.

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    • "In the case of the Clip2 gene we inserted a loxP-neo-loxP casette at the 5 end of the gene and a loxP-Puro-loxP-LacZ casette (where Puro indicates the puromycin resistance gene, and LacZ the -galactosidase gene) at the 3 end of the gene. Cre-mediated recombination in ES cells yielded the Clip2 knockout allele (Hoogenraad et al., 2002). Single Clip1 and Clip2 knockout and GFP-Clip170 ki mice were obtained by germline transmission of the modified alleles in chimeric mice, which were in turn obtained by injecting ES cells carrying the modified alleles into recipient blastocysts. "
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    • "Indeed, the hypothesis of structurally impaired HF is consistent with the fact individuals with WS consistently display difficulties in visual-spatial navigation tasks and long-term memory, both in verbal and spatial domains (Brock et al. 2006; O'Hearn et al. 2005; Sampaio et al. 2008; Vicari et al. 2003, 1996). Finally, this possibility is in agreement with the same evidence of enlargement of HF in other neurodevelopmental disorders (Schumann et al. 2004) and with data obtained from knock out mice models with a WS-like genotype, that show volume preservation despite evidence of structural (e.g., defects in neuronal structure like abnormal morphology of dendritic spines) and functional abnormalities (Hoogenraad et al. 2002; Zhao et al. 2005). Irrespective, however, of the underlying cognitive correlations , the preservation of HF volume in WS subjects is important and illustrates a differential neurodevelopmental pattern, when compared to other brain regions. "
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    • "The identification of individuals with smaller, overlapping deletions has helped geneticists tease apart the contribution of specific genes to the WBS phenotype (Tassabehji et al. 1999; Gagliardi et al. 2003), but since these individuals are rare, this approach has been complemented by the generation of transgenic animal models. Several mouse models have been described in which genes in the WBS critical region have been deleted and these have enabled the assessment of the contribution of individual genes to WBS (Li et al. 1998; Hoogenraad et al. 2002; Meng et al. 2002; Crackower et al. 2003; Young et al. 2008; Osborne 2010). One of the most striking features of WBS is that of altered social behavior. "
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