Mutation Analysis of MFN2, GJB1, MPZ and PMP22 in Italian Patients with Axonal Charcot–Marie–Tooth Disease

Abstract

Charcot-Marie-Tooth (CMT) diseases include a group of clinically heterogeneous inherited neuropathies subdivided into demyelinating (CMT1), axonal (CMT2) and intermediate CMT forms. CMTs are associated with different genes, although mutations in some of these genes may cause both clinical pictures. To date, more than 50 CMT genes have been identified, but more than half of the cases are due to mutations in MFN2, MPZ, GJB1 and PMP22. The aim of this study was to estimate the frequency of disease mutations of these four genes in the axonal form of CMT in order to evaluate their effectiveness in the molecular diagnosis of CMT2 patients. A cohort of 38 CMT2 Italian subjects was screened for mutations in the MFN2, MPZ and GJB1 genes by direct sequencing and for PMP22 rearrangements using the MLPA technique. Overall, we identified 15 mutations, 8 of which were novel: 11 mutations (28.9 %) were in the MFN2 gene, 2 (5.3 %) in MPZ and 2 (5.3 %) in PMP22. No mutations were found in GJB1. Two patients showed rearrangements in the PMP22 gene, which is commonly associated with CMT1 or HNPP phenotypes thus usually not tested in CMT2 patients. By including this gene in the analysis, we reached a molecular diagnosis rate of 39.5 %, which is one of the highest reported in the literature. Our findings confirm the MFN2 gene as the most common cause of CMT2 and suggest that PMP22 rearrangements should be considered in the molecular diagnosis of CMT2 patients.

The Effect of a Novel c.820C>T (Arg274Trp) Mutation in the Mitofusin 2 Gene on Fibroblast Metabolism and Clinical Manifestation in a Patient

“…Boaretto and co-workers reported on an Italian family in which a new splice-site MFN2 gene mutation was associated with fulminant fatal encephalopathy in three individuals [56]. The splice-site MFN2 c.1392+2T>C mutation has been shown to generate four different splicing products most probably acting via a dominant-negative mechanism [3]. …”

“…So far, about 100 mutations of the MFN2 gene have been reported in CMT2A patients [3]. Most of these located in and around the GTPase domain of mitofusin 2.…”

MFN2‐related genetic and clinical features in a cohort of Chinese CMT2 patients

“…In Asia, MFN2 mutations account for 14% of the Han Chinese patients in Taiwan (Lin et al, ) , 24% of Korean patients, and 9% of Japanese patients, respectively (Kijima et al, ; Chung et al, ) . MFN2 was found to be the cause of CMT2 in 29% of Italian families (Bergamin et al, ) , 17% of Spanish families (Casasnovas et al, ) , and 18% of French families, respectively (Calvo et al, ) . The MFN2 mutation frequency was approximately 18% in our study.…”

Alternative Splicing in the HumanPMP22Gene: Implications in CMT1A Neuropathy

“…However, genotype–phenotype correlations are not so obvious in PMP22‐related CMT. In fact, besides different degrees of disease severity [Birouk et al., ], also variable phenotypes, including HNPP‐like and CMT2‐like, were described in CMT1A [Thomas et al., ; Bergamin et al., ; Mathis et al., ]. Finally, in a subpopulation of CMT1A patients, a genetic triplication causing a more severe phenotype was also found [Liu et al., ].…”