CMTX Mutation and haplotype analysis in Turkish families

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X-linked Charcot-Marie-Tooth Neuropathy: Mutation and haplotype analysis in

Turkish families

I. Akat1, E. Shugai, M. Kennerson3,4, Y. Parman2, E. BattaloiHul and G.

Nicholson3,4 IDepartment of Molecular Biology and Genetics, Bogazici University,

Istanbul (Turkey), 2Department of

Neurology, Istanbul Medical School, Istanbul University, Istanbul (Turkey),

'Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney

(Australia), 'Molecular Medicine Laboratory, Concord

Hospital, Sydney (Ausrralia)

X-linked Charcot-Marie-Tooth (CMTX) disease accounts for up to 15% of all CMT

cases. There are five known loci for X-linked CMT (CMTX1, CMTX2, CMTX3, CMTX5

and Cowchock Syndrome) To date only genes for CMTX1 (G1Bl/Cx32) arrd CMTX5

(PRPSl) have been identified.

Based on clinical arrd pedigree arralyses, we have selected 23 CMT families with

X-linked inheritance and72 isolated CMT patients which were negative for CMTlA

duplication and PMP22 arrd MPZ point mutations. A combination of SSCP, high

resolution melting arra1ysis

arrd sequencing was used to screen the cohort for G1Bl/Cx32 mutations.

Five mutations were identified in the 72 isolated CMT patients. Four of the 23

families had GJBl/Cx32 mutations.All mutations were previously reported except

for Il27L and Q255X. The incidence of Cx32

mutations in our patient cohort was found to be 9%, ten families that were

suitable for haplotype arralysis were selected from the 23 familial cases.

After exclusion of PRPSI mutations in these families, we performed haplotype

analysis for the CMTX2, CMTX3 arrd CMTX4 loci, Two families showed a CMTX3

haplotype segregating with the disease that was different to the founder

haplotype originally reported (1), These families have additional features

including cerebellar dysfunction as

previously described (2) One family, presenting with tremor, deafness and

cerebelllar dysfunction in affected males, segregated a CMTX4 haplotype in

affected individuals,lastly, a CMTX2 haplotype was found to segregate in two of

the 10 families.

The patients have no reported mental retardation in contrast to previously

reported CMTX2 phenotypes (2), The remaining five families were excluded for all

loci testedIn conclusion, this study provides further evidence for the

involvement of CMTX2, CMTX3,and CMTX410ci and further genetic heterogeneity of

X-linked CMT,(1) Brewer et al Neurogenetics (2008) 9: 191-195 (2) Ionasescu et

al American Journal of Humam Genetics (1991)48:1075-1083.