CMT X : Evaluation of Functional Significance of GJB1 Gene-215 G>A Variant

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Charcot-Marie-Tooth Neuropathy Type X: Evaluation of Functional

Significance of GJB1 Gene -215 G>A Variant

(AAN April 17, 2008)

Spaggiari Federica, Paola Rimessi, Francesca Gualandi, Fabrizio

Salvi, Bologna, Italy, Alessandra Ferlini, Ferrara, Italy

OBJECTIVE: We aimed at establishing the pathogenic significance of

the -215 variation located within the promoter region of CX32 gene

and its meaning in the CMTX phenotype.

BACKGROUND: Mutations in GJB1 gene (CX32) account for about 90% of

cases of X-linked Charcot-Marie-Tooth motor and sensory neuropathy

(CMTX) and in most cases are localized in the coding region of the

gene but are also described in promoter P2 nerve-specific.

DESIGN/METHODS: Molecular analysis of the genomic promoter region of

CX32 gene in patients as well as control population was performed.

Level of transcritpion of the CX32 mRNA were detected by RT- Realtime

PCR on one peripherale nerve (sural) biopsy from a CMT patient

carrying the -215 mutation as well as in control nerves.

RESULTS: We have performed molecular analysis for 32 patients with

peripheral neuropathy compatible with a CMTX diagnosis and we found 5

males hemizygous for CX32-P2 -215 G>A allele. This variant is

described in literature of controversial significance for conflicting

results of two former studies regarding people of two different

ethnic group. In this study we have tested 510 control DNA samples

(1020 chromosomes) from North Italian females and we found the -215

G>A with allelic frequency of 57,8%. We enlarged the genomic sequence

analysed in the 5 hemizygous patients in order to include the large

region located upstream of exon 2 and comprising the promoter P2 and

exon 1B transcribed but not translated. We did not identify sequence

variants in linkage disequilibrium with the -215 allele. Realtime

CX32 level of transcritpion in patient and control nerves seem

comparable. More control nerves studies are in course.

CONCLUSIONS/RELEVANCE: From our results the -215 variations seems to

represent a very common polymorphism in Italian population. This

result has implications in genetic diagnosis of CX32-related CMT

diseases.