Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice.
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.
MGC Department of Cell Biology and Genetics, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
Casper C
CC
Hoogenraad
Bas
B
Koekkoek
Anna
A
Akhmanova
Harm
H
Krugers
Bjorn
B
Dortland
Marja
M
Miedema
Arjan
A
van Alphen
Werner M
WM
Kistler
Martine
M
Jaegle
Manoussos
M
Koutsourakis
Nadja
N
Van Camp
Marleen
M
Verhoye
Annemie
A
van der Linden
Irina
I
Kaverina
Frank
F
Grosveld
Chris I
CI
De Zeeuw
Niels
N
Galjart
D000818:Animals; D001921:Brain / Q000002:abnormalities; D000072159:Dynactin Complex; D004398:Dyneins / Q000378:metabolism; D018390:Gene Targeting; D006579:Heterozygote; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D009043:Motor Activity; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics*; D010641:Phenotype; D018980:Williams Syndrome / Q000235:genetics* / Q000503:physiopathology
D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C109878:cytoplasmic linker protein 115; C076744:cytoplasmic linker protein 170; D004398:Dyneins