CMT 2K: The GST domain of GDAP1 is a frequent target of mutations in the dominan

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The GST domain of GDAP1 is a frequent target of mutations in the dominant form

of axonal Charcot Marie Tooth type 2K.

Crimella C, Tonelli A, Airoldi G, Baschirotto C, D'Angelo MG, Bonato S, Losito

L, Trabacca A, Bresolin N, Bassi MT.

1Laboratory of Molecular Biology, E. Medea Scientific Institute, Bosisio Parini,

Italy.

Abstract

Background Mutations in GDAP1 associate with demyelinating (CMT4A) and axonal

(CMT2K) forms of CMT. While CMT4A shows recessive inheritance, CMT2K can present

with either recessive (AR-CMT2K) or dominant segregation pattern (AD-CMT2K), the

latter being characterised by milder phenotypes and later onset.

The majority of the GDAP1 mutations are associated with CMT4A and AR-CMT2K, with

only four heterozygous mutations identified in AD-CMT2K.

Methods We screened GDAP1 gene in a series of 43 index patients, 39 with CMT2

and 4 with intermediate CMT, with sporadic and familial occurrence of the

disease.

Results Three novel mutations were identified in three families with dominant

segregation of the disease: two missense changes, p.Arg226Ser and p.Ser34Cys,

affecting the GST domain of the GDAP1 protein and a novel deletion (c.23delAG)

leading to early truncation of the protein upstream the GST domain. Wide

variability in clinical presentation is shared by all three families mostly in

terms of age at onset and disease severity. A rare variant p.Gly269Arg, located

within the GST domain, apparently acts as phenotype modulator in the family

carrying the deletion.

Conclusion The results obtained reveal a GDAP1 mutation frequency of 27% in the

dominant families analysed, a figure still unreported for this gene, thus

suggesting that GDAP1 involvement in dominant CMT2 might be higher than

expected.

[Guest guest]

Does this mean we should periodically be re-tested?

Thank You

Jerry Walfish

[Guest guest]

Jerry,

No, no need to re-test.

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> Thank You

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> Jerry Walfish

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