CMT X: -459C>T point mutation in 5' non-coding region of human GJB1 gene is link

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J Peripher Nerv Syst. 2009 Mar;14(1):14-21.

-459C>T point mutation in 5' non-coding region of human GJB1 gene is linked to

X-linked Charcot-Marie-Tooth neuropathy.

Li M, Cheng TS, Ho PW, Chan KH, Mak W, Cheung RT, Ramsden DB, Sham PC, Song Y,

Ho SL.

Department of Biochemistry, Division of Neurology, University Department of

Medicine, and Research Center on Heart, Brain, Hormone and Healthy Aging,

University of Hong Kong, Hong Kong.

Charcot-Marie-Tooth (CMT) neuropathy is inherited with genetic and clinical

heterogeneity. The X-linked form (CMTX) is linked to mutations in the GJB1 gene.

However, the genotype-phenotype correlation between variants in the non-coding

region of GJB1 gene and CMTX is unclear.

We found two structural variants (-459C>T and -713G>A) in the 5' non-coding

region of a transcript (Ref seq ID: NM_000166) of the GJB1 gene and explored its

association with CMTX in two Chinese families.

All family members who carried the -459C>T variant either were symptomatic or

had abnormal electrophysiological studies compatible with CMTX, whereas all the

non-symptomatic family members who had normal electrophysiological studies and

10 healthy unrelated controls did not have this variant.

The other variant in the 5'-flanking region of the gene was found to be a benign

polymorphism, although it had been earlier reported to be associated with CMTX

in a Taiwanese family. Secondary structure prediction analysis of mutant mRNA

using Mfold and RNAstructure softwares indicates that the -459C>T mutation may

reduce translation efficiency of the GJB1 gene by changing its 5'-untranslated

region secondary structure and abolishing the internal ribosome entry site at

the initialization of its translation in Schwann cells.

Our study can help clarify the causal mutations of CMTX in the non-protein

coding region of GJB1.