The Effect of a Novel c.820C>T (Arg274Trp) Mutation in the Mitofusin 2 Gene on Fibroblast Metabolism and Clinical Manifestation in a Patient.
Charcot-Marie-Tooth disease type 2A (CMT2A) is an autosomal dominant axonal peripheral neuropathy caused by mutations in the mitofusin 2 gene (MFN2). Mitofusin 2 is a GTPase protein present in the outer mitochondrial membrane and responsible for regulation of mitochondrial network architecture via t...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2017-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC5226824?pdf=render |
id |
doaj-cfaefa1212b744a1b83eca09b8429cd1 |
---|---|
record_format |
Article |
spelling |
doaj-cfaefa1212b744a1b83eca09b8429cd12020-11-25T01:46:07ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01121e016999910.1371/journal.pone.0169999The Effect of a Novel c.820C>T (Arg274Trp) Mutation in the Mitofusin 2 Gene on Fibroblast Metabolism and Clinical Manifestation in a Patient.Małgorzata BeręsewiczAnna Boratyńska-JasińskaŁukasz CharzewskiMaria KawalecDagmara KabzińskaAndrzej KochańskiKrystiana A KrzyśkoBarbara ZabłockaCharcot-Marie-Tooth disease type 2A (CMT2A) is an autosomal dominant axonal peripheral neuropathy caused by mutations in the mitofusin 2 gene (MFN2). Mitofusin 2 is a GTPase protein present in the outer mitochondrial membrane and responsible for regulation of mitochondrial network architecture via the fusion of mitochondria. As that fusion process is known to be strongly dependent on the GTPase activity of mitofusin 2, it is postulated that the MFN2 mutation within the GTPase domain may lead to impaired GTPase activity, and in turn to mitochondrial dysfunction. The work described here has therefore sought to verify the effects of MFN2 mutation within its GTPase domain on mitochondrial and endoplasmic reticulum morphology, as well as the mtDNA content in a cultured primary fibroblast obtained from a CMT2A patient harboring a de novo Arg274Trp mutation. In fact, all the parameters studied were affected significantly by the presence of the mutant MFN2 protein. However, using the stable model for mitofusin 2 obtained by us, we were next able to determine that the Arg274Trp mutation does not impact directly upon GTP binding. Such results were also confirmed for GTP-hydrolysis activity of MFN2 protein in patient fibroblast. We therefore suggest that the biological malfunctions observable with the disease are not consequences of impaired GTPase activity, but rather reflect an impaired contribution of the GTPase domain to other MFN2 activities involving that region, for example protein-protein interactions.http://europepmc.org/articles/PMC5226824?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Małgorzata Beręsewicz Anna Boratyńska-Jasińska Łukasz Charzewski Maria Kawalec Dagmara Kabzińska Andrzej Kochański Krystiana A Krzyśko Barbara Zabłocka |
spellingShingle |
Małgorzata Beręsewicz Anna Boratyńska-Jasińska Łukasz Charzewski Maria Kawalec Dagmara Kabzińska Andrzej Kochański Krystiana A Krzyśko Barbara Zabłocka The Effect of a Novel c.820C>T (Arg274Trp) Mutation in the Mitofusin 2 Gene on Fibroblast Metabolism and Clinical Manifestation in a Patient. PLoS ONE |
author_facet |
Małgorzata Beręsewicz Anna Boratyńska-Jasińska Łukasz Charzewski Maria Kawalec Dagmara Kabzińska Andrzej Kochański Krystiana A Krzyśko Barbara Zabłocka |
author_sort |
Małgorzata Beręsewicz |
title |
The Effect of a Novel c.820C>T (Arg274Trp) Mutation in the Mitofusin 2 Gene on Fibroblast Metabolism and Clinical Manifestation in a Patient. |
title_short |
The Effect of a Novel c.820C>T (Arg274Trp) Mutation in the Mitofusin 2 Gene on Fibroblast Metabolism and Clinical Manifestation in a Patient. |
title_full |
The Effect of a Novel c.820C>T (Arg274Trp) Mutation in the Mitofusin 2 Gene on Fibroblast Metabolism and Clinical Manifestation in a Patient. |
title_fullStr |
The Effect of a Novel c.820C>T (Arg274Trp) Mutation in the Mitofusin 2 Gene on Fibroblast Metabolism and Clinical Manifestation in a Patient. |
title_full_unstemmed |
The Effect of a Novel c.820C>T (Arg274Trp) Mutation in the Mitofusin 2 Gene on Fibroblast Metabolism and Clinical Manifestation in a Patient. |
title_sort |
effect of a novel c.820c>t (arg274trp) mutation in the mitofusin 2 gene on fibroblast metabolism and clinical manifestation in a patient. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2017-01-01 |
description |
Charcot-Marie-Tooth disease type 2A (CMT2A) is an autosomal dominant axonal peripheral neuropathy caused by mutations in the mitofusin 2 gene (MFN2). Mitofusin 2 is a GTPase protein present in the outer mitochondrial membrane and responsible for regulation of mitochondrial network architecture via the fusion of mitochondria. As that fusion process is known to be strongly dependent on the GTPase activity of mitofusin 2, it is postulated that the MFN2 mutation within the GTPase domain may lead to impaired GTPase activity, and in turn to mitochondrial dysfunction. The work described here has therefore sought to verify the effects of MFN2 mutation within its GTPase domain on mitochondrial and endoplasmic reticulum morphology, as well as the mtDNA content in a cultured primary fibroblast obtained from a CMT2A patient harboring a de novo Arg274Trp mutation. In fact, all the parameters studied were affected significantly by the presence of the mutant MFN2 protein. However, using the stable model for mitofusin 2 obtained by us, we were next able to determine that the Arg274Trp mutation does not impact directly upon GTP binding. Such results were also confirmed for GTP-hydrolysis activity of MFN2 protein in patient fibroblast. We therefore suggest that the biological malfunctions observable with the disease are not consequences of impaired GTPase activity, but rather reflect an impaired contribution of the GTPase domain to other MFN2 activities involving that region, for example protein-protein interactions. |
url |
http://europepmc.org/articles/PMC5226824?pdf=render |
work_keys_str_mv |
AT małgorzataberesewicz theeffectofanovelc820ctarg274trpmutationinthemitofusin2geneonfibroblastmetabolismandclinicalmanifestationinapatient AT annaboratynskajasinska theeffectofanovelc820ctarg274trpmutationinthemitofusin2geneonfibroblastmetabolismandclinicalmanifestationinapatient AT łukaszcharzewski theeffectofanovelc820ctarg274trpmutationinthemitofusin2geneonfibroblastmetabolismandclinicalmanifestationinapatient AT mariakawalec theeffectofanovelc820ctarg274trpmutationinthemitofusin2geneonfibroblastmetabolismandclinicalmanifestationinapatient AT dagmarakabzinska theeffectofanovelc820ctarg274trpmutationinthemitofusin2geneonfibroblastmetabolismandclinicalmanifestationinapatient AT andrzejkochanski theeffectofanovelc820ctarg274trpmutationinthemitofusin2geneonfibroblastmetabolismandclinicalmanifestationinapatient AT krystianaakrzysko theeffectofanovelc820ctarg274trpmutationinthemitofusin2geneonfibroblastmetabolismandclinicalmanifestationinapatient AT barbarazabłocka theeffectofanovelc820ctarg274trpmutationinthemitofusin2geneonfibroblastmetabolismandclinicalmanifestationinapatient AT małgorzataberesewicz effectofanovelc820ctarg274trpmutationinthemitofusin2geneonfibroblastmetabolismandclinicalmanifestationinapatient AT annaboratynskajasinska effectofanovelc820ctarg274trpmutationinthemitofusin2geneonfibroblastmetabolismandclinicalmanifestationinapatient AT łukaszcharzewski effectofanovelc820ctarg274trpmutationinthemitofusin2geneonfibroblastmetabolismandclinicalmanifestationinapatient AT mariakawalec effectofanovelc820ctarg274trpmutationinthemitofusin2geneonfibroblastmetabolismandclinicalmanifestationinapatient AT dagmarakabzinska effectofanovelc820ctarg274trpmutationinthemitofusin2geneonfibroblastmetabolismandclinicalmanifestationinapatient AT andrzejkochanski effectofanovelc820ctarg274trpmutationinthemitofusin2geneonfibroblastmetabolismandclinicalmanifestationinapatient AT krystianaakrzysko effectofanovelc820ctarg274trpmutationinthemitofusin2geneonfibroblastmetabolismandclinicalmanifestationinapatient AT barbarazabłocka effectofanovelc820ctarg274trpmutationinthemitofusin2geneonfibroblastmetabolismandclinicalmanifestationinapatient |
_version_ |
1725020845016875008 |