Myelin protein zero gene mutated in Charcot-Marie-tooth type 1B patients.

Abstract

Autosomal dominant of Charcot-MarieTooth disease (CMT), whose gene is type 1B (CMT1B), has slow nerve conduction with demyelinated Schwann cells. In this study the abundant peripheral myelin protein zero (MPZ) gene, MPZ, was mapped 130 kb centromeric to the Fc receptor immunoglobulin gene cluster in band 1q22, and a major MPZ point mutation was found to cosegregate with CMTIB in one large CMT1B family. The MPZ point mutation in 18 of 18 related CMT1B pedigree 1 patients converts a positively charged lysine in codon 96 to a negatively charged glutamate. The same MPZ locus cosegregates with the CMTIB disease gene in a second CMT1B family [total multipoint logarithm of odds (lod) = 11.4 at 0 = 0.00] with a splice junction mutation. Both mutations occur in MPZ protein regions otherwise conserved identically in human, rat, and cow since these species diverged 100 million years ago. MPZ protein, expressed exclusively in myelinated peripheral nerve Schwann cells, constitutes >50% of myelin protein. These mutations are anticipated to disrupt homophilic MPZ binding and result in CMT1B peripheral nerve demyelination.

Glial cells: Old cells with new twists

“…The relative importance of each of these molecules has been further proven by studies with mice deficient in each of these molecules. Thus, as expected, lack of Po in humans and mice causes demyelination in the PNS (Giese et al, 1992;Su et al, 1993), while mutations of the Plp gene have been shown to cause Pelizaeus-Merzbacher disease, spastic paraplegia type 2 and demyelinating disorders in a range of animal species (Garbern et al, 1997;Griffiths et al, 1995;Shy et al, 2003). Both of these proteins are responsible for the compaction of the intraperiod line of myelin which corresponds to two extracellular layers of plasma membranes adhering in a zipper manner (Shapiro et al, 1996).…”

The IgG Fc receptor, FcγRIIB, is a target for deregulation by chromosomal translocation in malignant lymphoma

“…A number of overlapping expressed sequence tags (AA693721, AA746047, and N36002) corresponding to the 3Ј region of a novel gene of unknown function and sequences homologous to genes encoding the low affinity IgG Fc receptors Fc␥RII (CD32) and Fc␥RIII (CD16) were identified. Three Fc␥RII genes (FCGR2A, -B, and -C) and two Fc␥RIII genes (FCGR3A and -B) have been described and physically mapped to a region of Ϸ200 kb in 1q22 (21,24,27,30). Accordingly, FISH with PAC986b4 on normal lympho- cyte prometaphase chromosomes showed signals consistently localizing to proximal 1q22 (Fig.…”

“…Further mapping of PAC986b4 and derived cosmid subclones (cos34 and cos2) [compared to published maps (21,27)] showed the B593 1q22 breakpoint to interrupt the low affinity Fc receptor locus just upstream of the FCGR3B promoter region and 20 kb telomeric of FCGR2B (Fig. 2), thereby juxtaposing the 5Ј region of the latter with the IGL 3Ј enhancer element.…”

Genomic organization of classical human low-affinity Fcγ receptor genes

“…This estimate is similar to the estimates based on the YAC clones that contain the Fc␥R cluster. 25 Fc␥RIIC is of particular interest because of its physical proximity to Fc␥RIIIA and because a single nucleotide polymorphism (SNP) encoding a stop codon in exon 3, which corresponds to extracellular domain 1, would have a major impact on protein expression. Fc␥RIIC, which may have resulted from an unequal crossover event between Fc␥RIIA and Fc␥RIIB, 20,24 also demonstrates a unique cell type-specific expression by natural killer cells.…”

“…[42][43][44][45] The transcriptional orientation of Fc␥RIIA and Fc␥RIIIB was determined and they are in agreement with the previous studies. 20 The transcriptional orientation of other genes and the approximate sizes of the genes were inferred from the previous studies 20,25 and the information provided by NCBI. The 158 kb assembled contig that contains Fc␥RIIB, FcRL, DUSP12 and ATF6 genes is available in the NCBI database (AL 359541).…”