Detection of the CMT1A/HNPP recombination hotspot in unrelated patients of European descent

Vincent Timmerman, Bernd Rautenstrauss, Lawrence Reiter, Thearith Koeuth, Ann Löfgren, Thomas Liehr, Eva Nelis, Klaus D. Bathke, Peter De Jonghe, Holger Grehl, Jean Jacques Martin, James R. Lupski, Christine Van Broeckhoven

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Abstract

Charcot-Marie-Tooth type 1 disease (CMT1) and hereditary neuropathy with liability to pressure palsies (HNPP) are common inherited disorders of the peripheral nervous system. The majority of CMT1 patients have a 1.5 Mb tandem duplication (CMT1A) in chromosome 17p11.2 while most HNPP patients have a deletion of the same 1.5 Mb region. The CMT1A duplication and HNPP deletion are the reciprocal products of an unequal crossing over event between misaligned flanking CMT1A-REP elements. We analysed 162 unrelated CMT1A duplication patients and HNPP deletion patients from 11 different countries for the presence of a recombination hotspot in the CMT1A-REP sequences. A hotspot for unequal crossing over between the misaligned flanking CMT1A-REP elements was observed through the detection of novel junction fragments in 76.9% of 130 unrelated CMT1A patients and in 71.9% of 32 unrelated HNPP patients. This recombination hotspot was also detected in eight out of 10 de novo CMT1A duplication and in two de novo HNPP deletion patients. These data indicate that the hotspot of unequal crossing over occurs in several populations independently of ethnic background and is directly involved in the pathogenesis of CMT1A and HNPP. We conclude that the detection of junction fragments from the CMT1A-REP element on Southern blot analysis is a simple and reliable DNA diagnostic tool for the identification of the CMT1A duplication and HNPP deletion in most patients.

Original languageEnglish (US)
Pages (from-to)43-49
Number of pages7
JournalJournal of medical genetics
Volume34
Issue number1
StatePublished - Jan 1 1997

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Genetic Recombination
Charcot-Marie-Tooth Disease
Peripheral Nervous System Diseases
Southern Blotting
Chromosomes
DNA
Population

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Timmerman, V., Rautenstrauss, B., Reiter, L., Koeuth, T., Löfgren, A., Liehr, T., ... Van Broeckhoven, C. (1997). Detection of the CMT1A/HNPP recombination hotspot in unrelated patients of European descent. Journal of medical genetics, 34(1), 43-49.

Detection of the CMT1A/HNPP recombination hotspot in unrelated patients of European descent. / Timmerman, Vincent; Rautenstrauss, Bernd; Reiter, Lawrence; Koeuth, Thearith; Löfgren, Ann; Liehr, Thomas; Nelis, Eva; Bathke, Klaus D.; De Jonghe, Peter; Grehl, Holger; Martin, Jean Jacques; Lupski, James R.; Van Broeckhoven, Christine.

In: Journal of medical genetics, Vol. 34, No. 1, 01.01.1997, p. 43-49.

Research output: Contribution to journalArticle

Timmerman, V, Rautenstrauss, B, Reiter, L, Koeuth, T, Löfgren, A, Liehr, T, Nelis, E, Bathke, KD, De Jonghe, P, Grehl, H, Martin, JJ, Lupski, JR & Van Broeckhoven, C 1997, 'Detection of the CMT1A/HNPP recombination hotspot in unrelated patients of European descent', Journal of medical genetics, vol. 34, no. 1, pp. 43-49.
Timmerman V, Rautenstrauss B, Reiter L, Koeuth T, Löfgren A, Liehr T et al. Detection of the CMT1A/HNPP recombination hotspot in unrelated patients of European descent. Journal of medical genetics. 1997 Jan 1;34(1):43-49.
Timmerman, Vincent ; Rautenstrauss, Bernd ; Reiter, Lawrence ; Koeuth, Thearith ; Löfgren, Ann ; Liehr, Thomas ; Nelis, Eva ; Bathke, Klaus D. ; De Jonghe, Peter ; Grehl, Holger ; Martin, Jean Jacques ; Lupski, James R. ; Van Broeckhoven, Christine. / Detection of the CMT1A/HNPP recombination hotspot in unrelated patients of European descent. In: Journal of medical genetics. 1997 ; Vol. 34, No. 1. pp. 43-49.
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abstract = "Charcot-Marie-Tooth type 1 disease (CMT1) and hereditary neuropathy with liability to pressure palsies (HNPP) are common inherited disorders of the peripheral nervous system. The majority of CMT1 patients have a 1.5 Mb tandem duplication (CMT1A) in chromosome 17p11.2 while most HNPP patients have a deletion of the same 1.5 Mb region. The CMT1A duplication and HNPP deletion are the reciprocal products of an unequal crossing over event between misaligned flanking CMT1A-REP elements. We analysed 162 unrelated CMT1A duplication patients and HNPP deletion patients from 11 different countries for the presence of a recombination hotspot in the CMT1A-REP sequences. A hotspot for unequal crossing over between the misaligned flanking CMT1A-REP elements was observed through the detection of novel junction fragments in 76.9{\%} of 130 unrelated CMT1A patients and in 71.9{\%} of 32 unrelated HNPP patients. This recombination hotspot was also detected in eight out of 10 de novo CMT1A duplication and in two de novo HNPP deletion patients. These data indicate that the hotspot of unequal crossing over occurs in several populations independently of ethnic background and is directly involved in the pathogenesis of CMT1A and HNPP. We conclude that the detection of junction fragments from the CMT1A-REP element on Southern blot analysis is a simple and reliable DNA diagnostic tool for the identification of the CMT1A duplication and HNPP deletion in most patients.",
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