Is a novel I214M substitution in the NEFL gene a cause of CMT

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J Peripher Nerv Syst. 2006 Sep;11(3):225-231.

Is a novel I214M substitution in the NEFL gene a cause of Charcot-

Marie-Tooth disease? Functional analysis using cell culture models.

Kabzinska D, -Olle R, Goryunov D, Drac H, Ryniewicz B,

Hausmanowa-Petrusewicz I, Kochanski A, Liem RK.

Neuromuscular Unit, Mossakowski Medical Research Centre, Polish

Academy of Sciences, Warsaw, Poland;Department of Pathology, Columbia

University College of Physicians & Surgeons, New York, NY, USA;

andDepartment of Neurology, Medical University of Warsaw, Warsaw,

Poland.

Recent studies have shown that mutations in neurofilament light

subunit gene (NEFL) cause Charcot-Marie-Tooth (CMT) disease. Since

the first description of the Gln333Pro mutation in the NEFL gene, 10

pathogenic mutations in the NEFL gene have been reported in patients

affected with CMT disease. We report a novel I214M amino acid

substitution in the NEFL gene in two unrelated patients affected with

CMT. Because the I214M amino acid substitution in the NEFL protein

was not detected in a CMT affected brother of the proband, its

pathogenic effect became unclear.

In order to determine whether this amino acid substitution is a

benign polymorphism or causative of the disease, we performed a

functional analysis of the mutant I214M neurofilament protein (NFL).

Transfections of the mutant protein in cultured cells revealed an

increased tendency to form highly compacted filamentous structures

but no other alterations of neurofilament assembly or transport were

observed.

Furthermore, the sibling of one of the patients was also affected

with CMT but did not have the I214M substitution. These data suggest

that this I214M substitution in the NEFL gene was not a direct cause

of the disease but could be a polymorphism or possibly a modifier of

the CMT phenotype.