Normal expression of myelin protein zero with frame‐shift mutation correlates with mild phenotype

Abstract  Mutations in the gene encoding for myelin protein zero (MPZ) cause inherited demyelinating peripheral neuropathies of different severity. The molecular and cellular mechanisms by which the MPZ mutations cause neuropathy are incompletely understood. We investigated MPZ, myelin basic protein, and peripheral myelin protein 22 (PMP22) protein expression levels in a nerve biopsy of a Charcot‐Marie‐Tooth type 1B patient heterozygous for the Val 102 frame‐shift mutation. We demonstrate by quantitative immunohistochemical as well as by Western blot analyses that MPZ expression levels were not reduced in myelin membranes, a finding that is in accordance with the mild phenotype of this patient. Our data show that heterozygous ‘loss‐of‐function’ of MPZ may not necessarily lead to reduced protein levels. In conclusion, we demonstrate that careful analysis of protein expression levels in peripheral nerve tissues provides important information with respect to the understanding of the molecular basis of these neuropathies.

[1]  C. Angiari,et al.  Segmental conduction abnormalities and myelin thickenings in Val102/fs null mutation of MPZ gene , 2004, Neurology.

[2]  M. Shy.  Charcot-Marie-Tooth disease: an update , 2004, Current opinion in neurology.

[3]  Richard A Lewis,et al.  Phenotypic clustering in MPZ mutations. , 2004, Brain : a journal of neurology.

[4]  M. Shy,et al.  Mutations in the cytoplasmic domain of P0 reveal a role for PKC-mediated phosphorylation in adhesion and myelination , 2001, The Journal of cell biology.

[5]  D. Pareyson,et al.  Heterozygous Null Mutation in the P0 Gene Associated with Mild Charcot‐Marie‐Tooth Disease , 1999, Annals of the New York Academy of Sciences.

[6]  A. Steck,et al.  Anti‐MAG IgM penetration into myelinated fibers correlates with the extent of myelin widening , 1999, Muscle & nerve.

[7]  P. Fuhr,et al.  Matrix metalloproteinase upregulation in chronic inflammatory demyelinating polyneuropathy and nonsystemic vasculitic neuropathy , 1999, Neurology.

[8]  J. Gabriel,et al.  Gene dosage effects in hereditary peripheral neuropathy , 1997, Neurology.

[9]  M. Schachner,et al.  Molecular bases of myelin formation as revealed by investigations on mice deficient in glial cell surface molecules , 1997, Glia.

[10]  J. Lupski,et al.  Clinical Phenotypes of Different MPZ (P0) Mutations May Include Charcot–Marie–Tooth Type 1B, Dejerine–Sottas, and Congenital Hypomyelination , 1996, Neuron.

[11]  A. Brice,et al.  Ultrastructural PMP22 expression in inherited demyelinating neuropathies , 1996, Annals of neurology.

[12]  J. Gabriel,et al.  Selective loss of myelin-associated glycoprotein from myelin correlates with anti-MAG antibody titre in demyelinating paraproteinaemic polyneuropathy. , 1996, Brain : a journal of neurology.

[13]  H. Hartung,et al.  Detection and quantification of antibodies to the extracellular domain of P0 during experimental allergic neuritis , 1993, Journal of the Neurological Sciences.

[14]  E. Bellone,et al.  HMSN III phenotype due to homozygous expression of a dominant HMSN II gene , 1992, Neurology.

[15]  D. Pareyson,et al.  Heterozygous null mutation in the P0 gene associated with mild Charcot-Marie-Tooth disease. , 1999, Annals of the New York Academy of Sciences.

[16]  R. Martini.  P0-deficient knockout mice as tools to understand pathomechanisms in Charcot-Marie-Tooth 1B and P0-related Déjérine-Sottas syndrome. , 1999, Annals of the New York Academy of Sciences.