title: CALL interrupted in a patient with non-specific mental retardation: gene dosage-dependent alteration of murine brain development and behavior.
abstract: 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.
authors.affiliation: Flanders Interuniversity Institute for Biotechnology (VIB), Center for Human Genetics, Leuven, Belgium.
authors.forename: Suzanna G M
authors.initials: SG
authors.lastname: Frints
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Dieter
authors.initials: D
authors.lastname: Hartmann
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Jean
authors.initials: J
authors.lastname: Steyaert
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.forename: Bettina
authors.initials: B
authors.lastname: Rolf
authors.forename: Katleen
authors.initials: K
authors.lastname: Craessaerts
authors.forename: An
authors.initials: A
authors.lastname: Snellinx
authors.forename: Karen
authors.initials: K
authors.lastname: Hollanders
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
mesh_terms: D000368:Aged; D000483:Alleles; D000818:Animals; D002893:Chromosomes, Human, Pair 3; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D018628:Gene Dosage; D005787:Gene Frequency; D005838:Genotype; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D039842:Neural Cell Adhesion Molecule L1 / Q000096:biosynthesis* / Q000235:genetics*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016622:Silver Staining; D013997:Time Factors; D014178:Translocation, Genetic
chemical_list: D018076:DNA, Complementary; D039842:Neural Cell Adhesion Molecule L1