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PMID: 19888301 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Copy number variation upstream of PMP22 in Charcot-Marie-Tooth disease.

European journal of human genetics : EJHG ·Vol. 18 ·No. 4 ·2010-04-00 ·Pages 421-8

Weterman MA, van Ruissen F, de Wissel M, Bordewijk L, Samijn JP, van der Pol WL, Meggouh F, Baas F

Abstract

In several individuals with a Charcot-Marie-Tooth (CMT) phenotype, we found a copy number variation (CNV) on chromosome 17p12 in the direct vicinity of the peripheral myelin protein 22 (PMP22) gene. The exact borders and size of this CNV were determined by Southern blot analysis, MLPA, vectorette PCR, and microarray hybridization analyses. All patients from six apparently unrelated families carried an identical 186-kb duplication different from the commonly reported 1.5-Mb duplication associated with CMT1A. This ancestral mutation that was not reported in the human structural variation database was only detected in affected individuals and family members. It was absent in 2124 control chromosomes and 40 patients with a chronic inflammatory demyelinating polyneuropathy (CIDP) and therefore should be regarded as causative for the disease. This variant escapes most routine diagnostic screens for CMT1A, because copy numbers of PMP22 probes were all normal. No indications were found for the involvement of the genes that are located within this duplication. A possible association of this duplication with a mutation in the PMP22 coding regions was also excluded. We suggest that this CNV proximal of the PMP22 gene leads to CMT through an unknown mechanism affecting PMP22 expression.

MeSH Terms
Adult Blotting, Southern Charcot-Marie-Tooth Disease/genetics Chromosome Segregation Comparative Genomic Hybridization Female Gene Dosage/genetics Gene Duplication Genetic Variation/genetics Haplotypes Humans Male Microtubule Proteins/genetics Middle Aged Mutation/genetics Myelin Proteins/genetics,metabolism Oligonucleotide Array Sequence Analysis Pedigree Phenotype Polymerase Chain Reaction Young Adult
Chemicals
Microtubule Proteins Myelin Proteins PMP22 protein, human tektins
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Weterman Marian A J
Neurogenetics Lab, Department of Neurogenetics K2-213, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. m.a.weterman@amc.uva.nl
van Ruissen Fred
de Wissel Marit
Bordewijk Lou
Samijn Johnny P A
van der Pol W Ludo
Meggouh Farid
Baas Frank
References (39)
39 references, click to expand
  1. Elevated expression of messenger RNA for peripheral myelin protein 22 in biopsied peripheral nerves of patients with Charcot-Marie-Tooth disease type 1A.
    Ann Neurol. 1994 Apr;35(4):445-50 PMID: 7512319
  2. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project.
    Nature. 2007 Jun 14;447(7146):799-816 PMID: 17571346
  3. Genes specifically expressed at growth arrest of mammalian cells.
    Cell. 1988 Sep 9;54(6):787-93 PMID: 3409319
  4. Identification of the regulatory region of the peripheral myelin protein 22 (PMP22) gene that directs temporal and spatial expression in development and regeneration of peripheral nerves.
    Mol Cell Neurosci. 2002 May;20(1):93-109 PMID: 12056842
  5. A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene.
    Am J Hum Genet. 2000 Jul;67(1):37-46 PMID: 10841809
  6. Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect.
    Ann Neurol. 2006 Feb;59(2):398-403 PMID: 16374829
  7. Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth disease type 2E.
    Ann Neurol. 2001 Feb;49(2):245-9 PMID: 11220745
  8. Is the duplication present in all family members affected with Charcot-Marie-Tooth neuropathy type 1 A?
    Rom J Neurol Psychiatry. 1993 Jul-Dec;31(3-4):179-87 PMID: 8011481
  9. Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit.
    Nat Genet. 1992 Dec;2(4):292-300 PMID: 1303282
  10. Peripheral myelin protein-22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot-Marie-Tooth 1A.
    Nat Genet. 1992 Jun;1(3):176-9 PMID: 1303231
  11. DNA duplication associated with Charcot-Marie-Tooth disease type 1A.
    Cell. 1991 Jul 26;66(2):219-32 PMID: 1677316
  12. Hereditary neuropathy with liability to pressure palsies with a partial deletion of the region often duplicated in Charcot-Marie-Tooth disease, type 1A.
    J Neurol Neurosurg Psychiatry. 1996 Nov;61(5):535-6 PMID: 8937360
  13. Alternatively sized duplication in Charcot-Marie-Tooth disease type 1A.
    Hum Mol Genet. 1993 Dec;2(12):2143-6 PMID: 8111385
  14. Genome-wide transcription and the implications for genomic organization.
    Nat Rev Genet. 2007 Jun;8(6):413-23 PMID: 17486121
  15. The peripheral myelin gene PMP-22/GAS-3 is duplicated in Charcot-Marie-Tooth disease type 1A.
    Nat Genet. 1992 Jun;1(3):166-70 PMID: 1303229
  16. Peripheral myelin protein 22 is regulated post-transcriptionally by miRNA-29a.
    Glia. 2009 Sep;57(12):1265-79 PMID: 19170179
  17. Peripheral myelin protein-22 expression in Charcot-Marie-Tooth disease type 1a sural nerve biopsies.
    J Neurosci Res. 1994 Apr 1;37(5):654-9 PMID: 8028042
  18. Recent segmental duplications in the human genome.
    Science. 2002 Aug 9;297(5583):1003-7 PMID: 12169732
  19. Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse.
    Am J Hum Genet. 2002 Mar;70(3):726-36 PMID: 11799477
  20. Direct assignment of the human beta B2 and beta B3 crystallin genes to 22q11.2----q12: markers for neurofibromatosis 2.
    Cytogenet Cell Genet. 1991;56(3-4):171-5 PMID: 2055112
  21. Hypermyelination and demyelinating peripheral neuropathy in Pmp22-deficient mice.
    Nat Genet. 1995 Nov;11(3):274-80 PMID: 7581450
  22. Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence.
    Nat Genet. 2009 Mar;41(3):359-64 PMID: 19234473
  23. DNA deletion associated with hereditary neuropathy with liability to pressure palsies.
    Cell. 1993 Jan 15;72(1):143-51 PMID: 8422677
  24. Tektin3 encodes an evolutionarily conserved putative testicular microtubules-related protein expressed preferentially in male germ cells.
    Mol Reprod Dev. 2004 Mar;67(3):295-302 PMID: 14735490
  25. The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1A.
    Nat Genet. 1992 Jun;1(3):159-65 PMID: 1303228
  26. A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease.
    Hum Mol Genet. 2001 Feb 15;10(4):415-21 PMID: 11157804
  27. A transgenic rat model of Charcot-Marie-Tooth disease.
    Neuron. 1996 May;16(5):1049-60 PMID: 8630243
  28. Identical point mutations of PMP-22 in Trembler-J mouse and Charcot-Marie-Tooth disease type 1A.
    Nat Genet. 1992 Dec;2(4):288-91 PMID: 1303281
  29. Regulation of tissue-specific expression of alternative peripheral myelin protein-22 (PMP22) gene transcripts by two promoters.
    J Biol Chem. 1994 Oct 14;269(41):25795-808 PMID: 7929285
  30. Distinct elements of the peripheral myelin protein 22 (PMP22) promoter regulate expression in Schwann cells and sensory neurons.
    Mol Cell Neurosci. 2003 Nov;24(3):803-17 PMID: 14664827
  31. Dejerine-Sottas syndrome associated with point mutation in the peripheral myelin protein 22 (PMP22) gene.
    Nat Genet. 1993 Nov;5(3):269-73 PMID: 8275092
  32. A novel, rapid method for the isolation of terminal sequences from yeast artificial chromosome (YAC) clones.
    Nucleic Acids Res. 1990 May 25;18(10):2887-90 PMID: 2161516
  33. A leucine-to-proline mutation in the putative first transmembrane domain of the 22-kDa peripheral myelin protein in the trembler-J mouse.
    Proc Natl Acad Sci U S A. 1992 May 15;89(10):4382-6 PMID: 1374899
  34. Genomic sequencing.
    Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991-5 PMID: 6326095
  35. The peripheral myelin protein gene PMP-22 is contained within the Charcot-Marie-Tooth disease type 1A duplication.
    Nat Genet. 1992 Jun;1(3):171-5 PMID: 1303230
  36. Periaxin mutations cause recessive Dejerine-Sottas neuropathy.
    Am J Hum Genet. 2001 Feb;68(2):325-33 PMID: 11133365
  37. Array comparative genomic hybridization analysis of a familial duplication of chromosome 13q: a recognizable syndrome.
    Am J Med Genet A. 2005 Jul 1;136(1):76-80 PMID: 15889415
  38. Construction of a mouse model of Charcot-Marie-Tooth disease type 1A by pronuclear injection of human YAC DNA.
    Hum Mol Genet. 1996 May;5(5):563-9 PMID: 8733121
  39. Trembler mouse carries a point mutation in a myelin gene.
    Nature. 1992 Mar 19;356(6366):241-4 PMID: 1552943
Article Info
Journal
European journal of human genetics : EJHG
Abbr.
Eur J Hum Genet
ISSN
1476-5438
DOI
10.1038/ejhg.2009.186
Email
m.a.weterman@amc.uva.nl
Published
2010-04-00
Epub
2009-00-04
Pages
421-8
Language
English
Region
England
NLM ID
9302235
PMCID
PMC2987248
Subset
IM
External Links
PubMed source DOI: 10.1038/ejhg.2009.186 PMC Full Text View journal details
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