title: Cellular characterization of MPZ mutations presenting with diverse clinical phenotypes.
abstract: Mutations in MPZ, which encodes myelin protein zero (P(0)), may lead to different subtypes of Charcot-Marie-Tooth disease (CMT). The aim of this study was to characterize the cellular manifestations of various MPZ mutations associated with CMT1, Dejerine-Sottas syndrome (DSS) and CMT2, and to correlate their cellular and clinical phenotypes. Nine P(0) mutants associated with CMT1 (P(0)S63F, R98H, R277S, and S233fs), DSS (P(0) I30T and R98C), and CMT2 (P(0)S44F, D75V, and T124M), were investigated. Wild-type and mutant P(0) fused with fluorescent proteins were expressed in vitro to monitor their intracellular localization. An adhesiveness assay was used to evaluate the adhesiveness of the transfected cells. Protein localization and cell adhesiveness of each mutant protein were compared and correlated with their clinical phenotypes. Three different intracellular localization patterns of the mutant P(0) were observed. Wild-type P(0), P(0)I30T, S44F, S63F, D75V, T124M, and R227S were mostly localized on the cell membrane, P(0)R98H, and R98C were found in the endoplasmic reticulum (ER) or Golgi apparatus, and P(0)S233fs formed aggregates within the ER. Cells expressing mutant P(0), as compared with those expressing wild-type P(0), demonstrated variable degrees of reduction in the cell adhesiveness. The molecular patho-mechanisms of MPZ mutations are likely very complex and the clinical phenotype must be influenced by many genetic or environmental factors. This complexity may contribute to the highly variable clinical manifestations resulting from different MPZ mutations.
authors.affiliation: Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.
authors.forename: Yi-Chung
authors.initials: YC
authors.lastname: Lee
authors.forename: Kon-Ping
authors.initials: KP
authors.lastname: Lin
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Chang
authors.forename: Yi-Chu
authors.initials: YC
authors.lastname: Liao
authors.forename: Ching-Piao
authors.initials: CP
authors.lastname: Tsai
authors.forename: Kwong-Kum
authors.initials: KK
authors.lastname: Liao
authors.forename: Bing-Wen
authors.initials: BW
authors.lastname: Soong
mesh_terms: D000818:Animals; D016466:CHO Cells / Q000378:metabolism / Q000648:ultrastructure; D002448:Cell Adhesion / Q000235:genetics; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D015417:Hereditary Sensory and Motor Neuropathy; D006801:Humans; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D018993:Myelin P0 Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D013997:Time Factors; D014162:Transfection
chemical_list: D018993:Myelin P0 Protein; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
references.citation: Muscle Nerve. 2007 May;35(5):667-9
references.pmid: 17143884
references.citation: J Cell Biol. 1996 Sep;134(6):1531-41
references.pmid: 8830780
references.citation: Brain. 1999 Feb;122 ( Pt 2):281-90
references.pmid: 10071056
references.citation: J Neuropathol Exp Neurol. 2003 Jul;62(7):751-64
references.pmid: 12901701
references.citation: J Neurosci Res. 2006 May 1;83(6):957-64
references.pmid: 16493674
references.citation: Neuron. 1996 Sep;17(3):451-60
references.pmid: 8816708
references.citation: Brain. 2004 Feb;127(Pt 2):371-84
references.pmid: 14711881
references.citation: Neuron. 2008 Feb 7;57(3):393-405
references.pmid: 18255032
references.citation: Hum Mol Genet. 2008 Jul 1;17(13):1877-89
references.pmid: 18337304
references.citation: Neurology. 2008 Jan 22;70(4):273-7
references.pmid: 18209201
references.citation: J Neurosci Res. 1990 Nov;27(3):286-97
references.pmid: 1711125
references.citation: Nat Genet. 1993 Sep;5(1):31-4
references.pmid: 7693129
references.citation: Neurology. 1998 May;50(5):1397-401
references.pmid: 9595994
references.citation: J Biol Chem. 1994 Apr 8;269(14):10764-70
references.pmid: 7511605
references.citation: Neuron. 1988 Mar;1(1):73-83
references.pmid: 2483091
references.citation: J Neurosci. 2006 Feb 22;26(8):2358-68
references.pmid: 16495463
references.citation: BMC Cell Biol. 2002 Nov 26;3:29
references.pmid: 12450416
references.citation: Acta Neuropathol. 2002 May;103(5):501-8
references.pmid: 11935267
references.citation: Neuron. 1996 Sep;17(3):435-49
references.pmid: 8816707
references.citation: Am J Hum Genet. 2005 Nov;77(5):841-50
references.pmid: 16252242
references.citation: J Neurochem. 1973 Apr;20(4):1207-16
references.pmid: 4697881
references.citation: Neuron. 1991 Nov;7(5):845-55
references.pmid: 1720626
references.citation: J Neurol. 2005 Feb;252(2):151-5
references.pmid: 15729519
references.citation: J Neurol Neurosurg Psychiatry. 2000 Dec;69(6):806-11
references.pmid: 11080237
references.citation: Nat Genet. 1995 Nov;11(3):281-6
references.pmid: 7581451
references.citation: Cell Mol Life Sci. 2002 Nov;59(11):1851-71
references.pmid: 12530518
references.citation: Annu Rev Cell Dev Biol. 2002;18:575-99
references.pmid: 12142265
references.citation: J Cell Biol. 2001 Oct 29;155(3):439-46
references.pmid: 11673479
references.citation: Neuron. 1990 Mar;4(3):449-60
references.pmid: 1690568