A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian family

Abstract

Charcot-Marie-Tooth (CMT) disease is the most-common form of inherited motor and sensory neuropathy. The autosomal dominant axonal form of the disease (CMT2) is currently subdivided into seven types based on genetic localization. These are CMT2A (1p35-p36), CMT2B (3q13-q22), CMT2C (unknown), CMT2D (7p14), CMT2E (8p21), HMNSP (3q13.1), and CMT2F (7q11-q21). Two loci have thus far been identified for autosomal recessive CMT2; ARCMT2A (1q21.1-q21.3) and ARCMT2B (19q13.3). Mutations in four genes (connexin 32, myelin protein zero, neurofilament-light, and kinesin) have been associated with the CMT2 phenotype. We identified a novel neurofilament-light missense mutation (C64T) that causes the disease in a large Slovenian CMT2 family. This novel mutation shows complete co-segregation with the dominantly inherited CMT2 phenotype in our family.

NEFL Pro22Arg mutation in Charcot-Marie-Tooth disease type 1

“…1b). This mutation was found in the (Yoshihara et al 2002) and c.64C [ T resulting in Pro22Ser (Fabrizi et al 2004;Georgiou et al 2002), but this Pro22Arg mutation was not reported in the inherited peripheral neuropathies mutation database. Amino acids at the mutated site are highly conserved in different species (Fig.…”

“…Particularly, two Pro22 mutations have been reported: Pro22Ser was found in CMT2E with giant axons in the sural nerve (Fabrizi et al 2004;Georgiou et al 2002), and Pro22Thr was found to be associated with CMT1F (Yoshihara et al 2002). It has been suggested that Pro22 mutations abolish the Thr-Pro phosphorylation sequence of the head domain of NEFL by proline-directed protein kinases (PDPKs) (Sasaki et al 2006).…”

Auditory nerve is affected in one of two different point mutations of the neurofilament light gene

“…Linkage and haplotype analyses supported linkage of the mutation on the CMT2E locus and sequence analysis of the NFL gene revealed the corresponding mutations, as described by Georgiou et al (2002) and Zuchner et al (2004).…”

“…We studied two Slovenian families with an axonal autosomal dominant form of Charcot-Marie-Tooth disease caused by mutations in the NF-L gene. CMT2 in the family without AN is caused by the Pro22Ser (Georgiou et al, 2002) mutation and in NFL + AN family by the Glu397Lys (Zuchner et al, 2004) mutation. The genetic defects in these two families, occurring in the same gene, have different effects on auditory nerve, auditory brainstem, and central motor pathways.…”

“…Both families were identified as having dominantly inherited disease genetically localized to 8p21 locus (Georgiou et al, 2002). We found that the disease in one family is associated with the neurofilament light (NF-L) Pro22Ser (Georgiou et al, 2002) mutation and in the other family with the (NF-L) Glu397Lys (Zuchner et al, 2004) mutation. Both families have comparable peripheral nerve involvement but only one family had an asymptomatic involvement of auditory nerve.…”