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Allelic variants in the 5` non-coding region of the connexin32 gene: possible pitfalls in the diagnosis of X linked Charcot-Marie-Tooth neuropathy (CMTX)
  1. C Bergmann1,
  2. K Zerres1,
  3. S Rudnik-Schöneborn1,
  4. T Eggermann1,
  5. J M Schröder2,
  6. J Senderek1
  1. 1Institut für Humangenetik, Universitätsklinikum der RWTH Aachen, Germany
  2. 2Institut für Neuropathologie, Universitätsklinikum der RWTH Aachen, Germany
  1. Correspondence to:
 Dr C Bergmann, Institut für Humangenetik, Universitätsklinikum der RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany;

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Charcot-Marie-Tooth neuropathy (CMT) or hereditary motor and sensory neuropathy (HMSN) comprises a group of inherited disorders of the peripheral nervous system. With a prevalence of about 1 in 2500 persons it represents the most common inherited neuromuscular disease. The clinical features of CMT include progressive distal muscle weakness and atrophy, foot deformities, a steppage gait, distal sensory loss, and decreased or absent tendon reflexes. Variation in age of onset and clinical presentation in CMT is wide. It ranges from minimal adult onset pes cavus to severe distal atrophy and foot deformity starting in childhood and resulting in early wheelchair dependence. CMT is genetically heterogeneous with dominant gene defects on chromosomes 17, X, 1, and 10.1 The most common molecular subtype is CMT1A associated with a 1.5 Mb duplication of the locus for the peripheral myelin protein 22 (PMP22) in the chromosomal region 17p11.2.2 Mutations in the connexin32 gene (Cx32) on chromosome Xq13.1 cause the X linked dominant type of CMT.3Cx32 mutations are now considered to be the second most common molecular cause of hereditary sensorimotor neuropathy, accounting for at least 10% of cases. Cx32 is widely expressed in human tissues,4 but only nervous tissue is affected with peripheral neuropathy and electrophysiological abnormalities in central nervous system pathways.5,6 In man, at least two different Cx32 mRNA transcripts exist that are transcribed from two alternate tissue specific promoters, P1 and P2.7,8 Transcripts initiated from promoter P1 make up the most abundant Cx32 mRNA in any other tissue except for the nervous system and contain the non-coding exon 1a separated by a large intron from exon 2, which encompasses the complete coding region. Promoter P2 used in nervous tissue is located within the large intron and primary transcripts consist of exon 1b, separated by …

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