Hoogenraad, C. C. et al. Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice. Nature Genet. 32, 116-127

MGC Department of Cell Biology and Genetics, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
Nature Genetics (Impact Factor: 29.35). 10/2002; 32(1):116-27. DOI: 10.1038/ng954
Source: PubMed


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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    • "Although limk1 plays a critical role in long-term potentiation in the mouse hippocampus [24], research in humans with atypical deletions in the WSCR has challenged the independent contribution of LIMK1 to the visuospatial deficits seen in WS [for examples, 9,14,15]. More recently, the chromosomal region telomeric to RFC2, including CYLN2, GTF2IRD1, and GTF2I, has become a focus of interest as a possible contributor to the spatial cognitive profile in WS [6,57]. CYLN2 (also known as CLIP2), for example, encodes CLIP-115, which is expressed in dendrites and cell bodies in a number of brain regions, and has been found to effect hippocampal memory processes [57]. "
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    ABSTRACT: Background Williams syndrome (WS) is a rare neurodevelopmental disorder arising from a hemizygotic deletion of approximately 27 genes on chromosome 7, at locus 7q11.23. WS is characterised by an uneven cognitive profile, with serious deficits in visuospatial tasks in comparison to relatively proficient performance in some other cognitive domains such as language and face processing. Individuals with partial genetic deletions within the WS critical region (WSCR) have provided insights into the contribution of specific genes to this complex phenotype. However, the combinatorial effects of different genes remain elusive. Methods We report on visuospatial cognition in two individuals with contrasting partial deletions in the WSCR: one female (HR), aged 11 years 9 months, with haploinsufficiency for 24 of the WS genes (up to GTF2IRD1), and one male (JB), aged 14 years 2 months, with the three most telomeric genes within the WSCR deleted, or partially deleted. Results Our in-depth phenotyping of the visuospatial domain from table-top psychometric, and small- and large-scale experimental tasks reveal a profile in HR in line with typically developing controls, albeit with some atypical features. These data are contrasted with patient JB's atypical profile of strengths and weaknesses across the visuospatial domain, as well as with more substantial visuospatial deficits in individuals with the full WS deletion. Conclusions Our findings point to the contribution of specific genes to spatial processing difficulties associated with WS, highlighting the multifaceted nature of spatial cognition and the divergent effects of genetic deletions within the WSCR on different components of visuospatial ability. The importance of general transcription factors at the telomeric end of the WSCR, and their combinatorial effects on the WS visuospatial phenotype are also discussed.
    Full-text · Article · Jul 2014 · Journal of Neurodevelopmental Disorders
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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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    ABSTRACT: Agrin is the major factor mediating the neuronal regulation of postsynaptic structures at the vertebrate neuromuscular junction, but the details of how it orchestrates this unique three-dimensional structure remain unknown. Here, we show that agrin induces the formation of the dense network of microtubules in the subsynaptic cytoplasm and that this, in turn, regulates acetylcholine receptor insertion into the postsynaptic membrane. Agrin acted in part by locally activating phosphatidylinositol 3-kinase and inactivating GSK3β, which led to the local capturing of dynamic microtubules at agrin-induced acetylcholine receptor (AChR) clusters, mediated to a large extent by the microtubule plus-end tracking proteins CLASP2 and CLIP-170. Indeed, in the absence of CLASP2, microtubule plus ends at the subsynaptic muscle membrane, the density of synaptic AChRs, the size of AChR clusters, and the numbers of subsynaptic muscle nuclei with their selective gene expression programs were all reduced. Thus, the cascade linking agrin to CLASP2-mediated microtubule capturing at the synaptic membrane is essential for the maintenance of a normal neuromuscular phenotype.
    Full-text · Article · Jul 2012 · The Journal of Cell Biology
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    • "Dendritic spines are localized at the postsynaptic sites of excitatory synapses, and as sites of axonal-dendritic contacts, they are potential mediators of the connective plasticity underlying learning, memory, and cognition [56]. In addition to Limk1, Cyln2 [57] is another possible candidate gene contributing structural–functional abnormalities and impaired plasticity in WS. Cyln2 encodes proteins that regulate dynamic aspects of the cytoskeleton of the cells. "
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    ABSTRACT: Williams Syndrome is a genetically determined neurodevelopmental disorder characterized by an uneven cognitive profile and surprisingly large neurobehavioral differences among individuals. Previous studies have already shown different forms of memory deficiencies and learning difficulties in WS. Here we studied the capacity of WS subjects to improve their performance in a basic visual task. We employed a contour integration paradigm that addresses occipital visual function, and analyzed the initial (i.e. baseline) and after-learning performance of WS individuals. Instead of pooling the very inhomogeneous results of WS subjects together, we evaluated individual performance by expressing it in terms of the deviation from the average performance of the group of typically developing subjects of similar age. This approach helped us to reveal information about the possible origins of poor performance of WS subjects in contour integration. Although the majority of WS individuals showed both reduced baseline and reduced learning performance, individual analysis also revealed a dissociation between baseline and learning capacity in several WS subjects. In spite of impaired initial contour integration performance, some WS individuals presented learning capacity comparable to learning in the typically developing population, and vice versa, poor learning was also observed in subjects with high initial performance levels. These data indicate a dissociation between factors determining initial performance and perceptual learning.
    Full-text · Article · Jul 2012 · PLoS ONE
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