Identification and in silico analysis of 14 novel GJB1, MPZ and PMP22 gene mutat

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Eur J Hum Genet. 2009 Mar 4.

Identification and in silico analysis of 14 novel GJB1, MPZ and PMP22 gene

mutations.

Miltenberger-Miltenyi G, Schwarzbraun T, Löscher WN, Wanschitz J, Windpassinger

C, Duba HC, Seidl R, Albrecht G, Weirich-Schwaiger H, Zoller H, Utermann G,

Auer-Grumbach M, Janecke AR.

1Division of Clinical Genetics, Innsbruck Medical University, Innsbruck,

Austria.

Duplication within the chromosome 17p11.2 (CMT1Adup), peripheral myelin protein

22 (PMP22), myelin protein zero (MPZ) and gap junction beta1-protein (GJB1) gene

mutations are frequent causes of the Charcot-Marie-Tooth disease (CMT). A large

number of mutations in these genes are listed in databases. Sequence variants

identified in patients are frequently reported as mutations without further

evaluation.

We analyzed 250 consecutively recruited unrelated Austrian CMT patients for

CMT1Adup by microsatellite marker typing, real-time PCR or MLPA, and found 79

duplications (31.6%). The coding regions of the PMP22, MPZ and GJB1 genes were

analyzed by direct sequencing in the remaining patients; 28 patients showed

mutations, 14 of which were novel. We scored the pathogenicity of novel missense

mutations by segregation studies and by their exclusion in control samples.

Our comprehensive literature study found that up to 60% of the reported

mutations in these genes had not been evaluated regarding their pathogenicity,

and the PANTHER bioinformatics tool was used to score novel and published

missense variants. The PANTHER program scored known polymorphisms as such, but

scored approximately 82-88% only of the published and novel mutations as most

likely deleterious.

Mutations associated with axonal CMT were less likely to be classified as

deleterious, and the PMP22 S72L mutation repeatedly associated with severe CMT

was classified as a polymorphism using default parameters. Our data suggest that

this in silico analysis tool could be useful for assessing the functional impact

of DNA variations only as a complementary approach. The CMT1Adup, GJB1, MPZ and

PMP22 mutation frequencies were in the range of those described in other CMT

patient collectives with different ethnical backgrounds.