Finding the CMTX3 gene: Positional Candidate Gene Mapping in a Modern Age

[Guest guest]

(Oral presentation at the Antwerp Consortium July 2009)

Finding the CMTX3 gene: Positional Candidate Gene Mapping in a Modern Age.

M. Brewer1

,2, G. Nicholson1

,2,3, R. Chaudhry!, P. PoIly4,5 and M. Kennerson1 ,2,3

'Northcott Neuroscience laboratory, ANZAC RI, NSW, 'Faculty of Medicine,

University of Sydney, NSW, 'Molecular Medicine laboratory, Concord Hospital,

NSW, 'Cancer Pharmacology Unit, Concord Hospital,

NSW, 'Department of Pathology, University of New South Wales, NSW, Australia

Positional candidate gene mapping techniques have been effectively used to

identify many Mendelian disease genes including numerous CMT genes, The X-linked

CMTX310cus was first reported in 1991 1 and has since been confilmed and refined

to a 25 Mb region on chromosome Xq26 3-q27 3 2 3, There are II annotated genes

within the region, all of whichhave been excluded fOI pathogenic mutations in

the coding and untranslated regions.

We therefore propose that the CMTX3 mutation dismpts eithel splicing or

regulatory elements or an uncharacteIised novel gene or exon

Identifying pathogenic mutations in uncharactelised promoters or intronic

regulatory regions can be expensive and time-consuming, The recent development

of high-resolution custom allay technologies and high throughput new generation

sequencing enabled us to analyse the

whole region in a cost-effective manner. This data has been used to examine the

entire clinical CMTX3 interval for mutations that may dismpt a regulatory motif.

In addition, we are continuing to examine paltial transcIipts in the CMTX3

intelval to

identify new genes for their involvement in CMTX3 ,

Our gene finding strategies demonstrate an effective combination of traditional

and new

techniques employed in our effoits to identify the elusive CMTX3 mutation.

L Ionasescu et at Am J Hum Genet (1991) 48, 1075-1083

2 " Huttner IG et al, Neurology (2006) 67, 2016-21

3 Brewer