Nature Genetics
32, 116 - 127 (2002)
Published online: 26 August 2002; Corrected online: 22 August 2002 | doi:10.1038/ng954
There is an Erratum (October 2002) associated with this Article.
Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in miceCasper C. Hoogenraad1, 2, Bas Koekkoek2, Anna Akhmanova1, Harm Krugers3, Bjorn Dortland1, Marja Miedema1, Arjan van Alphen2, Werner M. Kistler2, Martine Jaegle1, Manoussos Koutsourakis1, Nadja Van Camp4, Marleen Verhoye4, Annemie van der Linden4, Irina Kaverina5, Frank Grosveld1, Chris I. De Zeeuw2
& Niels Galjart11
MGC Department of Cell Biology and Genetics, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. 2
MGC Department of Neuroscience, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. 3
Swammerdam Institute for Life Sciences, University of Amsterdam, The Netherlands. 4
Bio-Imaging Lab, University of Antwerp (RUCA), Belgium. 5
Institute of Molecular Biology, Austrian Academy of Sciences, Salzburg, Austria.
Correspondence should be addressed to Chris I. De Zeeuw galjart@ch1.fgg.eur.nl or Niels Galjart dezeeuw@anat.fgg.eur.nlWilliams 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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