The C264Y missense mutation in the extracellular domain of L1 impairs protein trafficking in vitro and in vivo

TY - JOUR

T1 - The C264Y missense mutation in the extracellular domain of L1 impairs protein trafficking in vitro and in vivo

AU - Rünker, Annette E

AU - Bartsch, Udo

AU - Nave, Klaus-Armin

AU - Schachner, Melitta

PY - 2003/1/1

Y1 - 2003/1/1

N2 - The neural cell adhesion molecule L1, a member of the immunoglobulin superfamily, performs important functions in the developing and adult nervous system and is implicated in neuronal migration and survival, elongation, fasciculation and pathfinding of axons, and synaptic plasticity. This view is in line with the fact that mutations in the L1 gene result in severe neurological syndromes in humans. Patients with missense mutations in the extracellular domain of L1 often develop severe phenotypes. Here, we characterized in vitro and in vivo the missense mutation C264Y, which is located in the extracellular domain of L1 and causes a severe phenotype in humans. Transfection studies in vitro demonstrate that L1 carrying this missense mutation is not expressed at the cell surface but instead is located intracellularly, most likely within the endoplasmic reticulum. Lack of cell surface expression of L1 with a C264Y mutation was confirmed in a transgenic mouse line expressing the C264Y mutation under the control of the L1 promoter in an L1-deficient background. Analysis of these transgenic mice indicates that they represent functional null mutants, phenotypically indistinguishable from L1-deficient mice. These observations corroborate the view that impaired cell surface expression of mutated variants of L1 is a potential explanation for the high number of severe pathogenic mutations identified within the human L1 gene.

AB - The neural cell adhesion molecule L1, a member of the immunoglobulin superfamily, performs important functions in the developing and adult nervous system and is implicated in neuronal migration and survival, elongation, fasciculation and pathfinding of axons, and synaptic plasticity. This view is in line with the fact that mutations in the L1 gene result in severe neurological syndromes in humans. Patients with missense mutations in the extracellular domain of L1 often develop severe phenotypes. Here, we characterized in vitro and in vivo the missense mutation C264Y, which is located in the extracellular domain of L1 and causes a severe phenotype in humans. Transfection studies in vitro demonstrate that L1 carrying this missense mutation is not expressed at the cell surface but instead is located intracellularly, most likely within the endoplasmic reticulum. Lack of cell surface expression of L1 with a C264Y mutation was confirmed in a transgenic mouse line expressing the C264Y mutation under the control of the L1 promoter in an L1-deficient background. Analysis of these transgenic mice indicates that they represent functional null mutants, phenotypically indistinguishable from L1-deficient mice. These observations corroborate the view that impaired cell surface expression of mutated variants of L1 is a potential explanation for the high number of severe pathogenic mutations identified within the human L1 gene.

KW - Animals

KW - Axons

KW - CHO Cells

KW - Cell Membrane

KW - Cerebellum

KW - Cricetinae

KW - Hippocampus

KW - Mice

KW - Mice, Transgenic

KW - Molecular Weight

KW - Mutation, Missense

KW - Neural Cell Adhesion Molecule L1

KW - Neurons

KW - Phenotype

KW - Protein Structure, Tertiary

KW - Protein Transport

KW - Sciatic Nerve

KW - Sequence Deletion

KW - Journal Article

M3 - SCORING: Journal article

C2 - 12514225

VL - 23

SP - 277

EP - 286

JO - J NEUROSCI

JF - J NEUROSCI

SN - 0270-6474

IS - 1

ER -