Charcot-Marie-Tooth neuropathy type 2A: novel mutations in the mitofusin 2 gene (MFN2)

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Abstract

Background

Charcot-Marie-Tooth neuropathies are a group of genetically heterogeneous diseases of the peripheral nervous system. Mutations in the MFN2 gene have been reported as the primary cause of Charcot-Marie-Tooth disease type 2A.

Methods

Patients with the clinical diagnosis of Charcot-Marie-Tooth type 2 were screened using single strand conformation polymorphism (SSCP). All DNA samples showing band shifts in the SSCP analysis were amplified from genomic DNA and cycle sequenced.

Results

We analyzed a total of 73 unrelated patients with a clinical diagnosis of CMT 2. Overall, novel mutations were detected in 6 patients. c.380G>T (G127V), c.1128G>A (M376I), c.1040A>T (E347V), c.1403G>A (R468H), c.2113G>A (V705I), and c.2258_2259insT (L753fs).

Conclusion

We confirmed a significant role of mutations in MFN2 in the pathogenesis of Charcot-Marie-Tooth disease type 2.

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Most cited references 9

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Mitochondrial transmission during mating in Saccharomyces cerevisiae is determined by mitochondrial fusion and fission and the intramitochondrial segregation of mitochondrial DNA.

L. Murray, A Straight, John J. Nunnari … (1997)

To gain insight into the process of mitochondrial transmission in yeast, we directly labeled mitochondrial proteins and mitochondrial DNA (mtDNA) and observed their fate after the fusion of two cells. To this end, mitochondrial proteins in haploid cells of opposite mating type were labeled with different fluorescent dyes and observed by fluorescence microscopy after mating of the cells. Parental mitochondrial protein markers rapidly redistributed and colocalized throughout zygotes, indicating that during mating, parental mitochondria fuse and their protein contents intermix, consistent with results previously obtained with a single parentally derived protein marker. Analysis of the three-dimensional structure and dynamics of mitochondria in living cells with wide-field fluorescence microscopy indicated that mitochondria form a single dynamic network, whose continuity is maintained by a balanced frequency of fission and fusion events. Thus, the complete mixing of mitochondrial proteins can be explained by the formation of one continuous mitochondrial compartment after mating. In marked contrast to the mixing of parental mitochondrial proteins after fusion, mtDNA (labeled with the thymidine analogue 5-bromodeoxyuridine) remained distinctly localized to one half of the zygotic cell. This observation provides a direct explanation for the genetically observed nonrandom patterns of mtDNA transmission. We propose that anchoring of mtDNA within the organelle is linked to an active segregation mechanism that ensures accurate inheritance of mtDNA along with the organelle.

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Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta.

Y Takei, S. Terada, Tristan Nakagawa … (2001)

The kinesin superfamily motor protein KIF1B has been shown to transport mitochondria. Here, we describe an isoform of KIF1B, KIF1Bbeta, that is distinct from KIF1B in its cargo binding domain. KIF1B knockout mice die at birth from apnea due to nervous system defects. Death of knockout neurons in culture can be rescued by expression of the beta isoform. The KIF1B heterozygotes have a defect in transporting synaptic vesicle precursors and suffer from progressive muscle weakness similar to human neuropathies. Charcot-Marie-Tooth disease type 2A was previously mapped to an interval containing KIF1B. We show that CMT2A patients contain a loss-of-function mutation in the motor domain of the KIF1B gene. This is clear indication that defects in axonal transport due to a mutated motor protein can underlie human peripheral neuropathy.

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Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network

Axel Niemann, Marcel Rüegg, Veronica La Padula … (2005)

Mutations in GDAP1 lead to severe forms of the peripheral motor and sensory neuropathy, Charcot-Marie-Tooth disease (CMT), which is characterized by heterogeneous phenotypes, including pronounced axonal damage and demyelination. We show that neurons and Schwann cells express ganglioside-induced differentiation associated protein 1 (GDAP1), which suggest that both cell types may contribute to the mixed features of the disease. GDAP1 is located in the mitochondrial outer membrane and regulates the mitochondrial network. Overexpression of GDAP1 induces fragmentation of mitochondria without inducing apoptosis, affecting overall mitochondrial activity, or interfering with mitochondrial fusion. The mitochondrial fusion proteins, mitofusin 1 and 2 and Drp1(K38A), can counterbalance the GDAP1-dependent fission. GDAP1-specific knockdown by RNA interference results in a tubular mitochondrial morphology. GDAP1 truncations that are found in patients who have CMT are not targeted to mitochondria and have lost mitochondrial fragmentation activity. The latter activity also is reduced strongly for disease-associated GDAP1 point mutations. Our data indicate that an exquisitely tight control of mitochondrial dynamics, regulated by GDAP1, is crucial for the proper function of myelinated peripheral nerves.

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Author and article information

Journal

Journal ID (nlm-ta): BMC Med Genet

Title: BMC Medical Genetics

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2350

Publication date Collection: 2006

Publication date (Electronic): 8 June 2006

Volume: 7

Page: 53

Affiliations

[1 ]Department of Human Genetics, Ruhr-University Bochum, Germany

[2 ]Department of Neurology, Neuromuscular Center Ruhrgebiet, Ruhr-University Bochum, Germany

[3 ]Neurology, Evangelische Stiftung Tannenhof, Remscheid, Germany

[4 ]Neurology, St.-Marien-Hospital, Lünen, Germany

Article

Publisher ID: 1471-2350-7-53

DOI: 10.1186/1471-2350-7-53

PMC ID: 1524942

PubMed ID: 16762064

SO-VID: 454cc260-7a94-4ad7-a9d3-507e1562af07

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Charcot-Marie-Tooth neuropathy type 2A: novel mutations in the mitofusin 2 gene ( MFN2)

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Abstract

Background

Methods

Results

Conclusion

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Genes & Diseases

Most cited references 9

Mitochondrial transmission during mating in Saccharomyces cerevisiae is determined by mitochondrial fusion and fission and the intramitochondrial segregation of mitochondrial DNA.

Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta.

Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network

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