Human Molecular Genetics, 2003, Vol. 12, No. 13 1463-1474
DOI: 10.1093/hmg/ddg165
© 2003 Oxford University Press
CALL interrupted in a patient with non-specific mental retardation: gene dosage-dependent alteration of murine brain development and behavior
1Flanders Interuniversity Institute for Biotechnology (VIB) and 2University Hospital Leuven, Center for Human Genetics, Leuven, Belgium, 3Zentrum für Molekulare Neurobiologie, Eppendorf Clinic, University of Hamburg, Hamburg, Germany and 4Laboratory of Neurochemistry and Behavior, Born-Bunge Foundation, Department of Biomedical Sciences and Department of Neurology/Memory Clinic, Middelheim Hospital, University of Antwerp, Antwerp, Belgium
Received November 12, 2002; Revised April 22, 2003; Accepted April 30, 2003
Investigation of MR patients with 3p aberrations led to the identification of the translocation breakpoint in intron five of the neural Cell Adhesion L1-Like (CALL or CHL1) gene in a man with non-specific mental retardation and 46,Y, t(X;3)(p22.1;p26.3). The Xp breakpoint does not seem to affect a known or predicted gene. Moreover, a fusion transcript with the CALL gene could not be detected and no mutations were identified on the second allele. CALL is highly expressed in the central and peripheral nervous system, like the mouse ortholog ‘close homolog to L1’ (Chl1). Chl1 expression levels in the hippocampus of Chl1+/- mice were half of those obtained in wild-type littermates, reflecting a gene dosage effect. Timm staining and synaptophysin immunohistochemistry of the hippocampus showed focal groups of ectopic mossy fiber synapses in the lateral CA3 region, outside the trajectory of the infra-pyramidal mossy fiber bundle in Chl1-/- and Chl1+/- mice. Behavioral assessment demonstrated mild alterations in the Chl1-/- animals. In the probe trial of the Morris Water Maze test, Chl1-/- mice displayed an altered exploratory pattern. In addition, these mice were significantly more sociable and less aggressive as demonstrated in social exploration tests. The Chl1+/- mice showed a phenotypic spectrum ranging from wild-type to knockout behavior. We hypothesize that a 50% reduction of CALL expression in the developing brain results in cognitive deficits. This suggests that the CALL gene at 3p26.3 is a prime candidate for an autosomal form of mental retardation. So far, mutation analysis of the CALL gene in patients with non-specific MR did not reveal any disease-associated mutations.
* To whom correspondence should be addressed at: Human Genome Laboratory, VIB4, Center for Human Genetics, Herestraat 49, B-3000 Leuven, Belgium. Tel: +32 16345948; Fax: +32 16347166; Email: guy.froyen{at}med.kuleuven.ac.be
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