Two novel connexin32 mutations cause early onset X-linked Charcot-Marie-Tooth disease

• Published in: BMC neurology Vol. 7; no. 1; p. 19
• Main Authors: Braathen, Geir J, Sand, Jette C, Bukholm, Geir, Russell, Michael B
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 09-07-2007; BioMed Central; BMC
• Subjects: Adolescent; Adult; Age of Onset; Charcot-Marie-Tooth disease; Charcot-Marie-Tooth Disease - genetics; Charcot-Marie-Tooth Disease - pathology; Charcot-Marie-Tooth Disease - physiopathology; Child; Child, Preschool; Complications and side effects; Connexins - genetics; Development and progression; Female; Gap Junction beta-1 Protein; Gap Junctions - genetics; Genetic aspects; Genetic Diseases, X-Linked - genetics; Genetic Diseases, X-Linked - pathology; Genetic Diseases, X-Linked - physiopathology; Health aspects; Humans; Infant; Male; Mutation; Mutation (Biology); Nerve proteins; Pedigree; Severity of Illness Index; Norway
• ISSN: 1471-2377; 1471-2377
• DOI: 10.1186/1471-2377-7-19

X-linked Charcot-Marie Tooth (CMT) is caused by mutations in the connexin32 gene that encodes a polypeptide which is arranged in hexameric array and form gap junctions.
We describe two novel mutations in the connexin32 gene in two Norwegian families.
Family 1 had a c.225delG (R75fsX83) which causes a frameshift and premature stop codon at position 247. This probably results in a shorter non-functional protein structure. Affected individuals had an early age at onset usually in the first decade. The symptoms were more severe in men than women. All had severe muscle weakness in the legs. Several abortions were observed in this family. Family 2 had a c.536 G>A (C179Y) transition which causes a change of the highly conserved cysteine residue, i.e. disruption of at least one of three disulfide bridges. The mean age at onset was in the first decade. Muscle wasting was severe and correlated with muscle weakness in legs. The men and one woman also had symptom from their hands. The neuropathy is demyelinating and the nerve conduction velocities were in the intermediate range (25-49 m/s). Affected individuals had symmetrical clinical findings, while the neurophysiology revealed minor asymmetrical findings in nerve conduction velocity in 6 of 10 affected individuals.
The two novel mutations in the connexin32 gene are more severe than the majority of previously described mutations possibly due to the severe structural change of the gap junction they encode.