Neurofilament heavy chain (NEFH) gene was recently identified to cause autosomal dominant axonal Charcot-Marie-Tooth disease (CMT2cc). However, the clinical spectrum of this condition and the physio-pathological pathway remain to be delineated. Here, the authors report two French families presenting with an axonal, dominantly inherited form of CMT characterized by prominent motor deficit affecting both the distal and proximal muscles, and signs of central nervous system involvement, caused by two previously unreported mutations in the NEFH gene. Unique deletions of two nucleotides causing frameshifts near the end of the NEFH coding sequence were identified: in family 1, c.3008_3009del (p.Lys1003Argfs*59), and in family 2 c.3043_3044del (p.Lys1015Glyfs*47). Both frameshifts lead to 40 additional amino acids translation encoding a cryptic amyloidogenic element. They showed that the new mutations cause protein aggregation, not only in neuroblastoma cells as similar mutations previously reported, but also in primary mouse motoneurons. Furthermore, they demonstrated that these mutations also induce neuronal apoptosis, both in neuroblastoma cells and in vivo in spinal cord neurons using in ovo chick spinal cord electroporation. Their results provide a physiological explanation for the overlap between CMT and amyotrophic lateral sclerosis (ALS) clinical features in affected patients.
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