Dagmara Kabzinska - Academia.edu (original) (raw)
Papers by Dagmara Kabzinska
Acta Neurobiologiae Experimentalis, 2013
Journal of The Peripheral Nervous System, 2016
PubMed, Oct 20, 2009
THE AIM was focused on molecular analysis of the selected genes associated with autosomal recessi... more THE AIM was focused on molecular analysis of the selected genes associated with autosomal recessive Charcot-Marie-Tooth neuropathies (AR-CMT) and construction of a molecular diagnostic algorithm in this group of disorders in the Polish population. Material and methods: We analyzed a group of 138 subjects from 62 families with probably autosomal recessive inheritance and the control group of 52 individuals. The studies covered molecular genetic analysis of PMP22 gene dosage (real-time polymerase chain reaction and polymerase chain reaction restriction fragments length polymorphisms), analysis of coding regions of the GDAP1, PRX, EGR2 and CTDP1 genes using: mutation screening (single strand conformation polymorphism and heteroduplex analysis), sequencing and bioinformatics approach to the gene sequence variants. Results: Thirty sequence variants have been found in the analysed genes, 5 pathogenic mutations in the GDAP1 gene and 2 pathogenic mutations in the PRX gene. On the basis of bioinformatic analysis other nucleotide changes have been categorized as harmless polymorphisms and variants of unknown pathogenic effect. Conclusions: This is the first study focused on the autosomal recessive Charcot-Marie-Tooth disease in the Polish population. Our results show the difficulties in the interpretation of the pathogenic effect of the sequence variants (pathogenic mutation or polymorphism) which is essential for molecular diagnostics in CMT disease.
International Journal of Molecular Sciences, Jun 16, 2020
Charcot-Marie-Tooth (CMT) disease encompasses a group of rare disorders that are characterized by... more Charcot-Marie-Tooth (CMT) disease encompasses a group of rare disorders that are characterized by similar clinical manifestations and a high genetic heterogeneity. Such excessive diversity presents many problems. Firstly, it makes a proper genetic diagnosis much more difficult and, even when using the most advanced tools, does not guarantee that the cause of the disease will be revealed. Secondly, the molecular mechanisms underlying the observed symptoms are extremely diverse and are probably different for most of the disease subtypes. Finally, there is no possibility of finding one efficient cure for all, or even the majority of CMT diseases. Every subtype of CMT needs an individual approach backed up by its own research field. Thus, it is little surprise that our knowledge of CMT disease as a whole is selective and therapeutic approaches are limited. There is an urgent need to develop new CMT models to fill the gaps. In this review, we discuss the advantages and disadvantages of yeast as a model system in which to study CMT diseases. We show how this single-cell organism may be used to discriminate between pathogenic variants, to uncover the mechanism of pathogenesis, and to discover new therapies for CMT disease.
Genes, Mar 14, 2020
The question of whether a newly identified sequence variant is truly a causative mutation is a ce... more The question of whether a newly identified sequence variant is truly a causative mutation is a central problem of modern clinical genetics. In the current era of massive sequencing, there is an urgent need to develop new tools for assessing the pathogenic effect of new sequence variants. In Charcot-Marie-Tooth disorders (CMT) with their extreme genetic heterogeneity and relatively homogenous clinical presentation, addressing the pathogenic effect of rare sequence variants within 80 CMT genes is extremely challenging. The presence of multiple rare sequence variants within a single CMT-affected patient makes selection for the strongest one, the truly causative mutation, a challenging issue. In the present study we propose a new yeast-based model to evaluate the pathogenic effect of rare sequence variants found within the one of the CMT-associated genes, GDAP1. In our approach, the wild-type and pathogenic variants of human GDAP1 gene were expressed in yeast. Then, a growth rate and mitochondrial morphology and function of GDAP1-expressing strains were studied. Also, the mutant GDAP1 proteins localization and functionality were assessed in yeast. We have shown, that GDAP1 was not only stably expressed but also functional in yeast cell, as it influenced morphology and function of mitochondria and altered the growth of a mutant yeast strain. What is more, the various GDAP1 pathogenic sequence variants caused the specific for them effect in the tests we performed. Thus, the proposed model is suitable for validating the pathogenic effect of known GDAP1 mutations and may be used for testing of unknown sequence variants found in CMT patients.
Journal of Applied Genetics, Oct 10, 2016
To date, only two splice-site mutations within the TPM2 gene have been shown to be causative for ... more To date, only two splice-site mutations within the TPM2 gene have been shown to be causative for congenital myopathies. While the majority of TPM2 gene mutations are causative for nemaline myopathy, cap disease or distal arthrogryposis, some mutations in this gene have been found to be associated with nonspecific congenital myopathy. We report on a patient with such an unspecified congenital myopathy associated with distinctive facial dysmorphic features and distal arthrogryposis. Using the whole exome sequencing (WES) approach we were able to identify a novel heterozygous splice-site mutation within the TPM2 gene, showing the utility of WES in molecular diagnostics of congenital myopathies without recognizable morphological hallmarks.
Journal of The Peripheral Nervous System, Jun 1, 2015
Genes
Charcot–Marie–Tooth disorders (CMT) represent a highly heterogeneous group of diseases of the per... more Charcot–Marie–Tooth disorders (CMT) represent a highly heterogeneous group of diseases of the peripheral nervous system in which more than 100 genes are involved. In some CMT patients, a few weak sequence variants toward other CMT genes are detected instead of one leading CMT mutation. Thus, the presence of a few variants in different CMT-associated genes raises the question concerning the pathogenic status of one of them. In this study, we aimed to analyze the pathogenic effect of c.664G>A, p.Glu222Lys variant in the GDAP1 gene, whose mutations are known to be causative for CMT type 4A (CMT4A). Due to low penetrance and a rare occurrence limited to five patients from two Polish families affected by the CMT phenotype, there is doubt as to whether we are dealing with real pathogenic mutation. Thus, we aimed to study the pathogenic effect of the c.664G>A, p.Glu222Lys variant in its natural environment, i.e., the neuronal SH-SY5Y cell line. Additionally, we have checked the patho...
Acta Neurobiologiae Experimentalis, 2011
International Journal of Molecular Sciences, 2021
Charcot-Marie-Tooth disease (CMT) is a heritable neurodegenerative disease that displays great ge... more Charcot-Marie-Tooth disease (CMT) is a heritable neurodegenerative disease that displays great genetic heterogeneity. The genes and mutations that underlie this heterogeneity have been extensively characterized by molecular genetics. However, the molecular pathogenesis of the vast majority of CMT subtypes remains terra incognita. Any attempts to perform experimental therapy for CMT disease are limited by a lack of understanding of the pathogenesis at a molecular level. In this study, we aim to identify the molecular pathways that are disturbed by mutations in the gene encoding GDAP1 using both yeast and human cell, based models of CMT-GDAP1 disease. We found that some mutations in GDAP1 led to a reduced expression of the GDAP1 protein and resulted in a selective disruption of the Golgi apparatus. These structural alterations are accompanied by functional disturbances within the Golgi. We screened over 1500 drugs that are available on the market using our yeast-based CMT-GDAP1 model....
International Journal of Molecular Sciences, 2020
Charcot–Marie–Tooth (CMT) disease encompasses a group of rare disorders that are characterized by... more Charcot–Marie–Tooth (CMT) disease encompasses a group of rare disorders that are characterized by similar clinical manifestations and a high genetic heterogeneity. Such excessive diversity presents many problems. Firstly, it makes a proper genetic diagnosis much more difficult and, even when using the most advanced tools, does not guarantee that the cause of the disease will be revealed. Secondly, the molecular mechanisms underlying the observed symptoms are extremely diverse and are probably different for most of the disease subtypes. Finally, there is no possibility of finding one efficient cure for all, or even the majority of CMT diseases. Every subtype of CMT needs an individual approach backed up by its own research field. Thus, it is little surprise that our knowledge of CMT disease as a whole is selective and therapeutic approaches are limited. There is an urgent need to develop new CMT models to fill the gaps. In this review, we discuss the advantages and disadvantages of y...
Neurology, 2020
ObjectiveTo test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (... more ObjectiveTo test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (CMT) contribute to frequent but often unexplained neuropathies in the elderly, we performed genetic analysis of 230 patients with unexplained axonal neuropathies and disease onset ≥35 years.MethodsWe recruited patients, collected clinical data, and conducted whole-exome sequencing (WES; n = 126) and MME single-gene sequencing (n = 104). We further queried WES repositories for MME variants and measured blood levels of the MME-encoded protein neprilysin.ResultsIn the WES cohort, the overall detection rate for assumed disease-causing variants in genes for CMT or other conditions associated with neuropathies was 18.3% (familial cases 26.4%, apparently sporadic cases 12.3%). MME was most frequently involved and accounted for 34.8% of genetically solved cases. The relevance of MME for late-onset neuropathies was further supported by detection of a comparable proportion of cases in an independe...
Genes, 2020
The question of whether a newly identified sequence variant is truly a causative mutation is a ce... more The question of whether a newly identified sequence variant is truly a causative mutation is a central problem of modern clinical genetics. In the current era of massive sequencing, there is an urgent need to develop new tools for assessing the pathogenic effect of new sequence variants. In Charcot-Marie-Tooth disorders (CMT) with their extreme genetic heterogeneity and relatively homogenous clinical presentation, addressing the pathogenic effect of rare sequence variants within 80 CMT genes is extremely challenging. The presence of multiple rare sequence variants within a single CMT-affected patient makes selection for the strongest one, the truly causative mutation, a challenging issue. In the present study we propose a new yeast-based model to evaluate the pathogenic effect of rare sequence variants found within the one of the CMT-associated genes, GDAP1. In our approach, the wild-type and pathogenic variants of human GDAP1 gene were expressed in yeast. Then, a growth rate and mi...
Postępy Biochemii, 2018
Polineuropatie genetycznie uwarunkowane (HMSN, ang. hereditary motor and sensory neuropathies) zw... more Polineuropatie genetycznie uwarunkowane (HMSN, ang. hereditary motor and sensory neuropathies) zwane również chorobami kręgu Charcot-Marie-Tooth (CMT) stanowią niezwykle heterogenną genetycznie (ponad 80 genów) grupę chorób obwodowego układu nerwowego człowieka. Istotą chorób kręgu CMT jest powolnie postępujący zanik mięśni dystalnych kończyn dolnych (podudzia) i górnych (przedramiona). Jak dotąd nie opracowano skutecznej metody leczenia CMT. W pracy przedstawiono obecny stan wiedzy dotyczący kliniki, patogenezy molekularnej i pierwszych prób terapeutycznych w CMT. Omówiono również możliwości wynikające z zastosowania modelu drożdżowego w poszukiwaniach nowych substancji leczniczych, jak i identyfikacji substancji neurotoksycznych.
PLOS ONE, 2017
Charcot-Marie-Tooth disease type 2A (CMT2A) is an autosomal dominant axonal peripheral neuropathy... more 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.
Journal of applied genetics, Jan 10, 2016
To date, only two splice-site mutations within the TPM2 gene have been shown to be causative for ... more To date, only two splice-site mutations within the TPM2 gene have been shown to be causative for congenital myopathies. While the majority of TPM2 gene mutations are causative for nemaline myopathy, cap disease or distal arthrogryposis, some mutations in this gene have been found to be associated with non-specific congenital myopathy. We report on a patient with such an unspecified congenital myopathy associated with distinctive facial dysmorphic features and distal arthrogryposis. Using the whole exome sequencing (WES) approach we were able to identify a novel heterozygous splice-site mutation within the TPM2 gene, showing the utility of WES in molecular diagnostics of congenital myopathies without recognizable morphological hallmarks.
Brain, 2001
X-linked dominant Charcot-Marie-Tooth (CMTX) disease is a motor and sensory neuropathy caused by ... more X-linked dominant Charcot-Marie-Tooth (CMTX) disease is a motor and sensory neuropathy caused by mutations in the connexin 32 (CX32) gene. In this study we report the clinical, electrophysiological and genetic features of 93 patients (41 males, 52 females) from 37 unrelated families with CMTX. Age at onset was 15.4 ⍨ 9.6 years in males (range 1-40 years) and 18.7 ⍨ 13.1 years in females (range 1-56 years) (P ⍧ 0.22) and the duration of disease at the time of examination was 18.3 ⍨ 14.6 years in males and 23.9 ⍨ 13.7 years in females (P ⍧ 0.11). Males were more severely affected than females, with significantly more frequent muscle weakness, amyotrophy, proprioception loss, upper limb areflexia and pes cavus. Females were more frequently asymptomatic, whereas high functional disability scores were more frequently encountered in males. The electrophysiological studies showed that motor nerve conduction velocities in CMTX females, but not males, were heterogeneous between nerves compared with Charcot-Marie-Tooth type 1A (CMT1A) patients and
Acta Neurobiologiae Experimentalis, 2013
Journal of The Peripheral Nervous System, 2016
PubMed, Oct 20, 2009
THE AIM was focused on molecular analysis of the selected genes associated with autosomal recessi... more THE AIM was focused on molecular analysis of the selected genes associated with autosomal recessive Charcot-Marie-Tooth neuropathies (AR-CMT) and construction of a molecular diagnostic algorithm in this group of disorders in the Polish population. Material and methods: We analyzed a group of 138 subjects from 62 families with probably autosomal recessive inheritance and the control group of 52 individuals. The studies covered molecular genetic analysis of PMP22 gene dosage (real-time polymerase chain reaction and polymerase chain reaction restriction fragments length polymorphisms), analysis of coding regions of the GDAP1, PRX, EGR2 and CTDP1 genes using: mutation screening (single strand conformation polymorphism and heteroduplex analysis), sequencing and bioinformatics approach to the gene sequence variants. Results: Thirty sequence variants have been found in the analysed genes, 5 pathogenic mutations in the GDAP1 gene and 2 pathogenic mutations in the PRX gene. On the basis of bioinformatic analysis other nucleotide changes have been categorized as harmless polymorphisms and variants of unknown pathogenic effect. Conclusions: This is the first study focused on the autosomal recessive Charcot-Marie-Tooth disease in the Polish population. Our results show the difficulties in the interpretation of the pathogenic effect of the sequence variants (pathogenic mutation or polymorphism) which is essential for molecular diagnostics in CMT disease.
International Journal of Molecular Sciences, Jun 16, 2020
Charcot-Marie-Tooth (CMT) disease encompasses a group of rare disorders that are characterized by... more Charcot-Marie-Tooth (CMT) disease encompasses a group of rare disorders that are characterized by similar clinical manifestations and a high genetic heterogeneity. Such excessive diversity presents many problems. Firstly, it makes a proper genetic diagnosis much more difficult and, even when using the most advanced tools, does not guarantee that the cause of the disease will be revealed. Secondly, the molecular mechanisms underlying the observed symptoms are extremely diverse and are probably different for most of the disease subtypes. Finally, there is no possibility of finding one efficient cure for all, or even the majority of CMT diseases. Every subtype of CMT needs an individual approach backed up by its own research field. Thus, it is little surprise that our knowledge of CMT disease as a whole is selective and therapeutic approaches are limited. There is an urgent need to develop new CMT models to fill the gaps. In this review, we discuss the advantages and disadvantages of yeast as a model system in which to study CMT diseases. We show how this single-cell organism may be used to discriminate between pathogenic variants, to uncover the mechanism of pathogenesis, and to discover new therapies for CMT disease.
Genes, Mar 14, 2020
The question of whether a newly identified sequence variant is truly a causative mutation is a ce... more The question of whether a newly identified sequence variant is truly a causative mutation is a central problem of modern clinical genetics. In the current era of massive sequencing, there is an urgent need to develop new tools for assessing the pathogenic effect of new sequence variants. In Charcot-Marie-Tooth disorders (CMT) with their extreme genetic heterogeneity and relatively homogenous clinical presentation, addressing the pathogenic effect of rare sequence variants within 80 CMT genes is extremely challenging. The presence of multiple rare sequence variants within a single CMT-affected patient makes selection for the strongest one, the truly causative mutation, a challenging issue. In the present study we propose a new yeast-based model to evaluate the pathogenic effect of rare sequence variants found within the one of the CMT-associated genes, GDAP1. In our approach, the wild-type and pathogenic variants of human GDAP1 gene were expressed in yeast. Then, a growth rate and mitochondrial morphology and function of GDAP1-expressing strains were studied. Also, the mutant GDAP1 proteins localization and functionality were assessed in yeast. We have shown, that GDAP1 was not only stably expressed but also functional in yeast cell, as it influenced morphology and function of mitochondria and altered the growth of a mutant yeast strain. What is more, the various GDAP1 pathogenic sequence variants caused the specific for them effect in the tests we performed. Thus, the proposed model is suitable for validating the pathogenic effect of known GDAP1 mutations and may be used for testing of unknown sequence variants found in CMT patients.
Journal of Applied Genetics, Oct 10, 2016
To date, only two splice-site mutations within the TPM2 gene have been shown to be causative for ... more To date, only two splice-site mutations within the TPM2 gene have been shown to be causative for congenital myopathies. While the majority of TPM2 gene mutations are causative for nemaline myopathy, cap disease or distal arthrogryposis, some mutations in this gene have been found to be associated with nonspecific congenital myopathy. We report on a patient with such an unspecified congenital myopathy associated with distinctive facial dysmorphic features and distal arthrogryposis. Using the whole exome sequencing (WES) approach we were able to identify a novel heterozygous splice-site mutation within the TPM2 gene, showing the utility of WES in molecular diagnostics of congenital myopathies without recognizable morphological hallmarks.
Journal of The Peripheral Nervous System, Jun 1, 2015
Genes
Charcot–Marie–Tooth disorders (CMT) represent a highly heterogeneous group of diseases of the per... more Charcot–Marie–Tooth disorders (CMT) represent a highly heterogeneous group of diseases of the peripheral nervous system in which more than 100 genes are involved. In some CMT patients, a few weak sequence variants toward other CMT genes are detected instead of one leading CMT mutation. Thus, the presence of a few variants in different CMT-associated genes raises the question concerning the pathogenic status of one of them. In this study, we aimed to analyze the pathogenic effect of c.664G>A, p.Glu222Lys variant in the GDAP1 gene, whose mutations are known to be causative for CMT type 4A (CMT4A). Due to low penetrance and a rare occurrence limited to five patients from two Polish families affected by the CMT phenotype, there is doubt as to whether we are dealing with real pathogenic mutation. Thus, we aimed to study the pathogenic effect of the c.664G>A, p.Glu222Lys variant in its natural environment, i.e., the neuronal SH-SY5Y cell line. Additionally, we have checked the patho...
Acta Neurobiologiae Experimentalis, 2011
International Journal of Molecular Sciences, 2021
Charcot-Marie-Tooth disease (CMT) is a heritable neurodegenerative disease that displays great ge... more Charcot-Marie-Tooth disease (CMT) is a heritable neurodegenerative disease that displays great genetic heterogeneity. The genes and mutations that underlie this heterogeneity have been extensively characterized by molecular genetics. However, the molecular pathogenesis of the vast majority of CMT subtypes remains terra incognita. Any attempts to perform experimental therapy for CMT disease are limited by a lack of understanding of the pathogenesis at a molecular level. In this study, we aim to identify the molecular pathways that are disturbed by mutations in the gene encoding GDAP1 using both yeast and human cell, based models of CMT-GDAP1 disease. We found that some mutations in GDAP1 led to a reduced expression of the GDAP1 protein and resulted in a selective disruption of the Golgi apparatus. These structural alterations are accompanied by functional disturbances within the Golgi. We screened over 1500 drugs that are available on the market using our yeast-based CMT-GDAP1 model....
International Journal of Molecular Sciences, 2020
Charcot–Marie–Tooth (CMT) disease encompasses a group of rare disorders that are characterized by... more Charcot–Marie–Tooth (CMT) disease encompasses a group of rare disorders that are characterized by similar clinical manifestations and a high genetic heterogeneity. Such excessive diversity presents many problems. Firstly, it makes a proper genetic diagnosis much more difficult and, even when using the most advanced tools, does not guarantee that the cause of the disease will be revealed. Secondly, the molecular mechanisms underlying the observed symptoms are extremely diverse and are probably different for most of the disease subtypes. Finally, there is no possibility of finding one efficient cure for all, or even the majority of CMT diseases. Every subtype of CMT needs an individual approach backed up by its own research field. Thus, it is little surprise that our knowledge of CMT disease as a whole is selective and therapeutic approaches are limited. There is an urgent need to develop new CMT models to fill the gaps. In this review, we discuss the advantages and disadvantages of y...
Neurology, 2020
ObjectiveTo test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (... more ObjectiveTo test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (CMT) contribute to frequent but often unexplained neuropathies in the elderly, we performed genetic analysis of 230 patients with unexplained axonal neuropathies and disease onset ≥35 years.MethodsWe recruited patients, collected clinical data, and conducted whole-exome sequencing (WES; n = 126) and MME single-gene sequencing (n = 104). We further queried WES repositories for MME variants and measured blood levels of the MME-encoded protein neprilysin.ResultsIn the WES cohort, the overall detection rate for assumed disease-causing variants in genes for CMT or other conditions associated with neuropathies was 18.3% (familial cases 26.4%, apparently sporadic cases 12.3%). MME was most frequently involved and accounted for 34.8% of genetically solved cases. The relevance of MME for late-onset neuropathies was further supported by detection of a comparable proportion of cases in an independe...
Genes, 2020
The question of whether a newly identified sequence variant is truly a causative mutation is a ce... more The question of whether a newly identified sequence variant is truly a causative mutation is a central problem of modern clinical genetics. In the current era of massive sequencing, there is an urgent need to develop new tools for assessing the pathogenic effect of new sequence variants. In Charcot-Marie-Tooth disorders (CMT) with their extreme genetic heterogeneity and relatively homogenous clinical presentation, addressing the pathogenic effect of rare sequence variants within 80 CMT genes is extremely challenging. The presence of multiple rare sequence variants within a single CMT-affected patient makes selection for the strongest one, the truly causative mutation, a challenging issue. In the present study we propose a new yeast-based model to evaluate the pathogenic effect of rare sequence variants found within the one of the CMT-associated genes, GDAP1. In our approach, the wild-type and pathogenic variants of human GDAP1 gene were expressed in yeast. Then, a growth rate and mi...
Postępy Biochemii, 2018
Polineuropatie genetycznie uwarunkowane (HMSN, ang. hereditary motor and sensory neuropathies) zw... more Polineuropatie genetycznie uwarunkowane (HMSN, ang. hereditary motor and sensory neuropathies) zwane również chorobami kręgu Charcot-Marie-Tooth (CMT) stanowią niezwykle heterogenną genetycznie (ponad 80 genów) grupę chorób obwodowego układu nerwowego człowieka. Istotą chorób kręgu CMT jest powolnie postępujący zanik mięśni dystalnych kończyn dolnych (podudzia) i górnych (przedramiona). Jak dotąd nie opracowano skutecznej metody leczenia CMT. W pracy przedstawiono obecny stan wiedzy dotyczący kliniki, patogenezy molekularnej i pierwszych prób terapeutycznych w CMT. Omówiono również możliwości wynikające z zastosowania modelu drożdżowego w poszukiwaniach nowych substancji leczniczych, jak i identyfikacji substancji neurotoksycznych.
PLOS ONE, 2017
Charcot-Marie-Tooth disease type 2A (CMT2A) is an autosomal dominant axonal peripheral neuropathy... more 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.
Journal of applied genetics, Jan 10, 2016
To date, only two splice-site mutations within the TPM2 gene have been shown to be causative for ... more To date, only two splice-site mutations within the TPM2 gene have been shown to be causative for congenital myopathies. While the majority of TPM2 gene mutations are causative for nemaline myopathy, cap disease or distal arthrogryposis, some mutations in this gene have been found to be associated with non-specific congenital myopathy. We report on a patient with such an unspecified congenital myopathy associated with distinctive facial dysmorphic features and distal arthrogryposis. Using the whole exome sequencing (WES) approach we were able to identify a novel heterozygous splice-site mutation within the TPM2 gene, showing the utility of WES in molecular diagnostics of congenital myopathies without recognizable morphological hallmarks.
Brain, 2001
X-linked dominant Charcot-Marie-Tooth (CMTX) disease is a motor and sensory neuropathy caused by ... more X-linked dominant Charcot-Marie-Tooth (CMTX) disease is a motor and sensory neuropathy caused by mutations in the connexin 32 (CX32) gene. In this study we report the clinical, electrophysiological and genetic features of 93 patients (41 males, 52 females) from 37 unrelated families with CMTX. Age at onset was 15.4 ⍨ 9.6 years in males (range 1-40 years) and 18.7 ⍨ 13.1 years in females (range 1-56 years) (P ⍧ 0.22) and the duration of disease at the time of examination was 18.3 ⍨ 14.6 years in males and 23.9 ⍨ 13.7 years in females (P ⍧ 0.11). Males were more severely affected than females, with significantly more frequent muscle weakness, amyotrophy, proprioception loss, upper limb areflexia and pes cavus. Females were more frequently asymptomatic, whereas high functional disability scores were more frequently encountered in males. The electrophysiological studies showed that motor nerve conduction velocities in CMTX females, but not males, were heterogeneous between nerves compared with Charcot-Marie-Tooth type 1A (CMT1A) patients and