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.

L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth

“…Differences in L1-CAM and NCAM signaling pathways during development may generate distinct patterns of cortical connectivity in different neuronal populations or brain regions. Disruption of this signaling likely contributes to distinct developmental neuropsychiatric disorders that are associated with mutation or genetic polymorphisms in genes encoding L1 (X-linked mental retardation) [44], CHL1 (low IQ, speech and motor delay) [45], and NCAM (schizophrenia, bipolar disorder) [39,46,47].…”

DSCAM Deficiency Causes Loss of Pre-Inspiratory Neuron Synchroneity and Perinatal Death

“…To understand the cellular mechanisms leading to these defects, additional investigations are required. (Stork et al, 1997;Frints et al, 2003). In addition, these DSCAM-dependent abnormalities are also highly genetic background dependent.…”

Glial Scar Expression of CHL1, the Close Homolog of the Adhesion Molecule L1, Limits Recovery after Spinal Cord Injury

“…Mutations in the CHL1 gene in humans have been linked to mental retardation (Angeloni et al, 1999;Frints et al, 2003) and schizophrenia (Sakurai et al, 2002;Chen et al, 2005). CHL1-deficient mice have normal appearance and motor abilities, but their social and exploratory behavior, reactivity to novelty, and ability to gate sensorimotor information are altered (MontagSallaz et al, 2002;Irintchev et al, 2004;Morellini et al, 2007).…”