Spectrum and frequencies of mutations in the MFN2 gene and its phenotypical expression in Czech hereditary motor and sensory neuropathy type II patients

Brožková, Dana Šafka; Posadka, Jan; Laššuthová, Petra; Mazanec, Radim; Haberlová, Jana; Šišková, Dana; Sakmaryová, Iva; Neupauerová, Jana; Seeman, Pavel

doi:10.3892/mmr.2013.1730

Cited by 9 publications

(3 citation statements)

References 23 publications

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“…According to electrophysiological criteria, CMT is subdivided into two main categories: demyelinating neuropathies with upper limb motor conduction velocities (MCVs) of median or ulnar nerve reduced (˂ 38 m/s) and axonal forms, which affect mostly axons and are characterized by nearly normal MCVs (> 38 m/s) but reduced amplitude (Harding & Thomas, , Reilly et al, ). CMT2A is among the most prevalent type of axonal dominant inherited neuropathy in the Czech Republic and the situation might be similar in other populations (Zuchner & Vance, ; Cartoni & Martinou, ; Brozkova et al, ). CMT2A is caused by mutations in the mitofusin 2 (MFN2) gene (Zuchner et al, ).…”

Section: Introductionmentioning

confidence: 73%

Massively Parallel Sequencing Detected a Mutation in the MFN2 Gene Missed by Sanger Sequencing Due to a Primer Mismatch on an SNP Site

Neupauerová

Grečmalová

Seeman

et al. 2016

Annals of Human Genetics

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We describe a patient with early onset severe axonal Charcot-Marie-Tooth disease (CMT2) with dominant inheritance, in whom Sanger sequencing failed to detect a mutation in the mitofusin 2 (MFN2) gene because of a single nucleotide polymorphism (rs2236057) under the PCR primer sequence. The severe early onset phenotype and the family history with severely affected mother (died after delivery) was very suggestive of CMT2A and this suspicion was finally confirmed by a MFN2 mutation. The mutation p.His361Tyr was later detected in the patient by massively parallel sequencing with a gene panel for hereditary neuropathies. According to this information, new primers for amplification and sequencing were designed which bind away from the polymorphic sites of the patient's DNA. Sanger sequencing with these new primers then confirmed the heterozygous mutation in the MFN2 gene in this patient. This case report shows that massively parallel sequencing may in some rare cases be more sensitive than Sanger sequencing and highlights the importance of accurate primer design which requires special attention.

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Section: Introductionmentioning

confidence: 73%

Massively Parallel Sequencing Detected a Mutation in the MFN2 Gene Missed by Sanger Sequencing Due to a Primer Mismatch on an SNP Site

Neupauerová

Grečmalová

Seeman

et al. 2016

Annals of Human Genetics

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“…A study of Czech hereditary motor and sensory neuropathy type II patients detected 8 pathogenic MFN2 mutations, including two sisters affected with axonal CMT neuropathy. A novel pathogenic missense variant c.314C > G, p.(Thr105Arg) was detected in both sisters but not observed in their clinically unaffected parents [11]. To the best of our knowledge, somatic mosaicism has not been previously reported in CMT2A.…”

Section: Discussionmentioning

confidence: 99%

Mosaicism for a pathogenic MFN2 mutation causes minimal clinical features of CMT2A in the parent of a severely affected child

et al. 2017

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Charcot-Marie-Tooth disease (CMT) refers to a genetically heterogeneous group of disorders which cause a peripheral motor and sensory neuropathy. The overall prevalence is 1 in 2500 individuals. Mutations in the MFN2 gene are the commonest cause for the axonal (CMT2) type. We describe a Caucasian 5-year old girl affected by CMT2A since the age of 2 years. She presented with unsteady gait, in-turning of the feet and progressive foot deformities. Nerve conduction studies suggested an axonal neuropathy and molecular testing identified a previously reported pathogenic variant c.1090C > T, p.(Arg364Trp) in the MFN2 gene. This variant was also detected in a mosaic state in blood and saliva by Sanger sequencing in her subjectively healthy father. Next generation sequencing showed that the level of mosaicism was 21% in blood and 24% in saliva. A high recurrence risk was given because the father had proven somatic mosaicism and an affected child implying gonadal mosaicism. The parents were referred for pre-implantation genetic diagnosis. To the best of our knowledge, this is the first reported case of somatic mosaicism for MFN2. This study has important implications for genetic counselling in families with CMT2A.

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“…CMT2A is phenotypically heterogeneous with age of onset being the most predictive marker of disease severity. Patients who present with symptoms earlier tend to have more severe sensorimotor neuropathy [21][22][23][24][25][26]. Interestingly, no known MFN1 mutations cause peripheral neuropathy, which may be due to the relatively low expression of MFN1 in neurons [27,28].…”

Section: Introductionmentioning

confidence: 99%

A Novel ENU-Induced Mfn2 Mutation Causes Motor Deficits in Mice without Causing Peripheral Neuropathy

Hines

Bailey

Liu

et al. 2023

Biology

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Mitochondrial fission and fusion are required for maintaining functional mitochondria. The mitofusins (MFN1 and MFN2) are known for their roles in mediating mitochondrial fusion. Recently, MFN2 has been implicated in other important cellular functions, such as mitophagy, mitochondrial motility, and coordinating endoplasmic reticulum-mitochondria communication. In humans, over 100 MFN2 mutations are associated with a form of inherited peripheral neuropathy, Charcot–Marie–Tooth disease type 2A (CMT2A). Here we describe an ENU-induced mutant mouse line with a recessive neuromuscular phenotype. Behavioral screening showed progressive weight loss and rapid deterioration of motor function beginning at 8 weeks. Mapping and sequencing revealed a missense mutation in exon 18 of Mfn2 (T1928C; Leu643Pro), within the transmembrane domain. Compared to wild-type and heterozygous littermates, Mfn2L643P/L643P mice exhibited diminished rotarod performance and decreases in activity in the open field test, muscular endurance, mean mitochondrial diameter, sensory tests, mitochondrial DNA content, and MFN2 protein levels. However, tests of peripheral nerve physiology and histology were largely normal. Mutant leg bones had reduced cortical bone thickness and bone area fraction. Together, our data indicate that Mfn2L643P causes a recessive motor phenotype with mild bone and mitochondrial defects in mice. Lack of apparent nerve pathology notwithstanding, this is the first reported mouse model with a mutation in the transmembrane domain of the protein, which may be valuable for researchers studying MFN2 biology.

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Spectrum and frequencies of mutations in the MFN2 gene and its phenotypical expression in Czech hereditary motor and sensory neuropathy type II patients

Cited by 9 publications

References 23 publications

Massively Parallel Sequencing Detected a Mutation in the MFN2 Gene Missed by Sanger Sequencing Due to a Primer Mismatch on an SNP Site

Massively Parallel Sequencing Detected a Mutation in the MFN2 Gene Missed by Sanger Sequencing Due to a Primer Mismatch on an SNP Site

Mosaicism for a pathogenic MFN2 mutation causes minimal clinical features of CMT2A in the parent of a severely affected child

A Novel ENU-Induced Mfn2 Mutation Causes Motor Deficits in Mice without Causing Peripheral Neuropathy

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