Wyniki wyszukiwania

1

Mutation or polymorphism in neurodegenerative disorders?

100%

Kochanski A.

Acta Neurobiologiae Experimentalis

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2007

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tom 67

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nr 3

2

How to assess the pathogenicity of mutations in Charcot-Marie-Tooth disease and other diseases?

100%

Kochanski A.

Journal of Applied Genetics

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2006

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tom 47

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nr 3

Knowledge whether a certain DNA variant is a pathogenic mutation or a harmless polymorphism is a critical issue in medical genetics, in which results of a molecular analysis may serve as a basis for diagnosis and genetic counseling. Due to its genetic heterogeneity expressed at the levels of loci, genes and mutations, Charcot-Marie-Tooth (CMT) disease can serve as a model group of clinically homogenous diseases for studying the pathogenicity of mutations. Close to a 17p11.2-p12 duplication occurring in 70% of patients with the demyelinating form of CMT disease, numerous mutations have been identified in poorly characterized genes coding for proteins of an unknown function. Functional analyses, segregation analyses of large pedigrees, and inclusion of large control groups are required to assess the potential pathogenicity of CMT mutations. Hence, the pathogenicity of numerous CMT mutations remains unclear. Some variants detected in the CMT genes and originally described as pathogenic mutations have been shown to have a polymorphic character. In contrast, polymorphisms initially considered harmless were later reclassified as pathogenic mutations. However, the process of assessing the pathogenicity of mutations, as presented in this study for CMT disorders, is a more general issue concerning all disorders with a genetic background. Since the number of DNA variants is still growing, in the near future geneticists will increasingly have to cope with the problem of pathogenicity of identified genetic variants.

3

A role for the GDAP1 gene in the molecular pathogenesis of Charcot - Marie - Tooth disease

63%

Rzepnikowska W., Kochanski A.

Acta Neurobiologiae Experimentalis

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2018

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tom 78

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nr 1

In 2002 a series of mutations in the GDAP1 gene were reported in patients suffering from Charcot-Marie-Tooth disease manifesting as early–onset, progressive distal-muscle wasting and weakness. The molecular etiology of Charcot-Marie-Tooth -GDAP1 disease has been elucidated but its pathogenesis remains unclear, especially given the seemingly contradictory function of the GDAP1 protein. Expression of GDAP1 is observed almost exclusively in neuronal cells, however, the GDAP1 protein is present in mitochondria, where it plays a role in fission, a ubiquitous process occurring in all cells. While GDAP1 contains two glutathione S-transferase (GST) domains, its GST activity is in fact very limited. Additionally, despite GDAP1 affecting mitochondrial functionality, and hence being of great importance to cellular function, the GDAP1-associated Charcot–Marie–Tooth disease is mainly characterized by axonal degeneration. Finally, mutations in the GDAP1 gene may be inherited in a recessive or dominant manner. Given the way such varied observations are hard to reconcile with one another, the investigation of GDAP1 is at one and the same time a difficult but also challenging endeavour. The purpose of this review is to summarize the current knowledge on the GDAP1 protein and its function in the cell. A further part is the characterization of GDAP1-associated Charcot–Marie–Tooth disease, its symptoms and course, as well as an outlining of the possible mechanisms underpinning the disorder.

4

Charcot - Marie - Tooth type 1A drug therapies: role of adenylyl cyclase activity and G - protein coupled receptors in disease pathomechanism

63%

Kiepura A. J., Kochanski A.

Acta Neurobiologiae Experimentalis

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2018

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tom 78

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nr 3

Charcot‑Marie‑Tooth type 1A (CMT1A) is a dysmyelinating disease of the peripheral nervous system that results in a slow progressive weakening and wasting of the distal muscles of the upper and lower limbs. Despite extensive research and clinical trials there is still no treatment for CMT1A that results in complete neurological improvement. Recent studies investigating various pharmacological modulators of adenylyl cyclase activity, including ascorbic acid and ligands of G protein‑coupled receptors (GPCRs), provide hope for future treatments of this type of hereditary motor and sensory neuropathy. A review of mechanisms of action of several compounds tested for CMT1A in pre‑clinical and clinical studies ascorbic acid, onapristone, PXT3003 (baclofen, naltrexone, and sorbitol), and ADX71441, very clearly indicates an important role for adenylyl cyclase activity and GPCRs in the pathomechanism of the disease. Metabotropic γ‑aminobutyric acid receptors (GABABR), subtype mu (µ) opioid receptors (MOR), and muscarinic acetylcholine receptors (mACh) appear to be particularly significant in both pathogenesis and treatment, and their activation may exert a similar and synergistic effect on the physiology of Schwann cells as well as neurons. These receptors participate in proliferation and differentiation of Schwann cells and influence excitatory transmission in neurons. We also hypothesize that onapristone might act through a non‑classical mechanism via membrane progesterone receptor (mPR) and cAMP signaling. This review endeavors to outline a pathway leading inversely from therapy to an indispensable role for adenylyl cyclase activity and GPCRs in the modulation of dosage sensitive peripheral myelin protein (PMP22) gene expression.

5

De novo Ser72Leu mutation in the peripheral myelin protein 22 in two Polish patients with a severe from of Charcot-Marie-Tooth disease

63%

Kochanski A., Kabzinska D.

Acta Biochimica Polonica

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2004

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tom 51

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nr 4

To date, 12 cases of heterozygous Ser72Leu mutations in the peripheral myelin protein 22 have been reported in patients suffering from severe demyelinating form of Charcot-Marie-Tooth disease (CMT1) and congenital hypomyelinating neuropathy (CHN) [MIM# 605253]. In the present study we report two cases of de novo S72L mutations in the PMP22 gene detected in patients of Polish origin suffering from CMT1 disease.

6

Molecular genetic analysis of the GJB1 gene: a study of six mutations

63%

Kochanski A., Kabzinska D.

Journal of Applied Genetics

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2004

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tom 45

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nr 1

7

Screening of the myelin protein zero gene in patients with Charcot-Marie-Tooth disease

63%

Nowakowski A., Kochanski A.

Acta Biochimica Polonica

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2004

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tom 51

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nr 1

The myelin protein zero gene (MPZ) coding for the most abundant protein of the peripheral myelin was shown to be mutated in Charcot-Marie-Tooth type 1B disease (CMT1B). Later on MPZ mutations have been shown in axonal type of CMT (CMT2). Recently three novel MPZ gene mutations were reported in congenital hypomyelinating neuropathy (CHN). In contrast to the previously reported studies, focused on CMT1B disease, we aimed to analyze the coding and promoter sequences of the MPZ gene in a group of patients with three CMT phenotypes i.e.: CMT1, CMT2 and CHN. Over 500 PCR products were screened by single strand conformation polymorphism analysis (SSCP) and heteroduplex analysis (HA). In one CMT2 family we founded the E56K mutation in the MPZ gene and in one CHN patient the T124K substitution was detected. In agreement with previously reported studies we conclude that MPZ gene screening should be performed for wide phenotype spectrum of CMT.

8

Screening of the 17p11.2-p12 region in a large cohort of patients with Charcot-Marie-Tooth [CMT] disease or hereditary neuropathy with liability to pressure palsies [HNPP]

51%

Kabzinska D., Pierscinska J., Kochanski A.

Journal of Applied Genetics

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2009

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tom 50

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nr 3

283-288

Within the last decade, numerous methods have been applied to detect the most common mutation in patients affected with Charcot-Marie-Tooth (CMT) disease, i.e. submicroscopic duplication in the 17p11.2-p12 region. In 1993, another neuropathy - known as hereditary neuropathy with liability to pressure palsies (HNPP) - has been shown to be caused by a 17p11.2-p12 deletion. Historically, Southern blot analysis was the first approach to identify CMT1A duplication or HNPP deletion. This time- and labor-consuming method requires prior selection of DNA samples. In fact, only CMT patients affected with the demyelinating form of CMT1 have been screened for CMT1A duplication. After the 17p11.2-p12 duplication was identified in the CMT1 families, subsequent studies revealed additional axonal features in the patients harboring the 17p11.2-p12 duplication. Thus it seems reasonable to test all patients affected with CMT for the presence of the 17p11.2-p12 duplication. To evaluate the utility of real-time polymerase chain reaction (Q-PCR) and restriction fragment length polymorphism PCR (RFLP-PCR), we screened a large group of 179 families with the diagnosis of CMT/HNPP for the presence of the 17p11.2-p12 duplication/deletion. Due to a high frequency of CMT1A duplication in familial cases of CMT, we propose (in contrast to the previous studies) to perform Q-PCR analysis in all patients diagnosed with CMT.

9

Mitofuzyna 2 – ważne białko obwodowego układu nerwowego i powszechnie występujący regulator metabolizmu

51%

Kawalec M., Kotruchow K., Kochanski A., Zablocka B.

Postępy Biochemii

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2011

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tom 57

|

nr 2

10

Molecular pathogenesis, experimental therapy and genetic counseling in hereditary sensory neuropathies

51%

Mroczek M., Kabzinska D., Kochanski A.

Acta Neurobiologiae Experimentalis

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2015

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tom 75

|

nr 2

Hereditary sensory and autonomic neuropathies (HSANs) represent a group of heritable peripheral nerve disorders usually taking a severe clinical course. HSAN-affected patients manifest with deep, poorly-healing ulcerations of the feet and hands. To date no definitive cure for HSANs has been developed and the molecular pathology of these disorders is complex. The aim of this review is therefore to present recent findings-in terms of HSAN molecular pathogenesis. So far, mutations in 12 genes coding for different proteins have been reported in association with HSAN and the molecular pathogenesis has been elucidated in HSANla, HSAN4 and HSAN5. The genes involved in molecular pathogenesis of HSAN code for a wide spectrum of proteins from enzymes to specific nerve growth factors. As far as HSANla is concerned, the enhanced understanding has given rise to achievements in experimental therapy particularly in respect to disease models. Despite a rapid progress in studies on the molecular background of HSAN, numerous loci and genes remain still to be discovered.

11

Two pathogenic mutations located within the 5'-regulatory sequence of the GJB1 gene affecting initiation of transcription and translation

51%

Kabzinska D., Kotruchow K., Ryniewicz B., Kochanski A.

Acta Biochimica Polonica

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2011

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tom 58

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nr 3

In contrast to mutations in the coding sequences of a genes involved in the pathogenesis of Charcot-Marie-Tooth disease (CMT), little is known about CMT phenotypes resulting from a DNA variants located in regulatory sequences of a given " CMT gene". Charcot-Marie-Tooth type X1 disease (CMTX1) is caused by mutations in the GJB1 gene coding for an ion channel known as connexin, with a molecular mass of 32 kDa (Cx32). Only 0.01% of the GJB1 gene mutations have been reported in its 5' regulatory sequence. Pathogenic mutations occured in the internal ribosome entry site (IRES) are extremely rarely reported in human genetic disorders. To the best of our knowledge, in this study we report for the first time in an Eastern European population, two CMTX1 families in which two pathogenic mutations in the 5' regulatory sequence of the GJB1 gene (c.-529T>C and -459C>T) have been found. The two mutations identified in our study disturb the 5' UTR sequence in two different ways, by affecting the transcription factor SOX10 binding site (c.-529T>C) and by the disrupting IRES element of GJB1 gene (c.-459C>T). These regions are responsible for transcription (SOX10) and initiation of translation (IRES), respectively. On the basis of our findings that, in contrast to the most DNA sequence variants reported in untranslated regulatory regions of genes, the c.-459C>T and c.-529T>C mutations remain pathogenic in the context of different ethnic background.

12

A newly identified Thr99fsX110 mutation in the PMP22 gene associated with an atypical phenotype of the hereditary neuropathy with liability to pressure palsies

51%

Moszynska I., Kabzinska D., Sinkiewicz-Darol E., Kochanski A.

Acta Biochimica Polonica

|

2009

|

tom 56

|

nr 4

627-630

Hereditary neuropathy with liability to pressure palsies (HNPP) is manifested by a spectrum of phenotypes, from the classical HNPP course associated with intermittent nerve palsies to a neuropathy resembling Charcot-Marie-Tooth type 1 (CMT1) disease. The majority of HNPP cases are associated with submicroscopical deletions in the 17p11.2-p12 region containing the PMP22 gene, while PMP22 point mutations are rare, representing about 15% of HNPP cases. In this study, we present a patient manifesting with atypical HNPP phenotype associated with a new Thr99fsX110 mutation in the PMP22 gene. We conclude that all patients who fulfill the electrophysiological criteria of HNPP, even if they lack the typical HNPP phenotype, should be tested for point mutations in the PMP22 gene.

13

Charcot-Marie-Tooth type 1A disease caused by a novel Ser112Arg mutation in the PMP22 gene, coexisting with a slowly progressive hearing impairment

51%

Kabzinska D., Sinkiewicz-Darol E., Hausmanowa-Petrusewicz I., Kochanski A.

Journal of Applied Genetics

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2010

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tom 51

|

nr 2

203-209

Among 57 mutations in the peripheral myelin protein 22 gene (PMP22) identified so far in patients affected by Charcot-Marie-Tooth disease (CMT), only 8 have been shown to segregate with a mixed phenotype of CMT and hearing impairment. In this study, we report a new Ser112Arg mutation in the PMP22 gene, identified in a patient with early-onset CMT and slowly progressive hearing impairment beginning in the second decade of life. We suggest that the Ser112Arg mutation in the PMP22 gene might have a causative role in the early-onset CMT with hearing impairment. Thus, our study extends the spectrum of CMT phenotypes putatively associated with PMP22 gene mutations.

14

The 5' regulatory sequence of the PMP22 in the patients with Charcot-Marie-Tooth disease

51%

Sinkiewicz-Darol E., Kabzinska D., Moszynska I., Kochanski A.

Acta Biochimica Polonica

|

2010

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tom 57

|

nr 3

Little is known about the molecular background of clinical variability of Charcot-Marie-Tooth type 1A (CMT1A) disease and hereditary neuropathy with liability to pressure palsies (HNPP). The CMT1A and HNPP disorders result from duplication and deletion of the PMP22 gene respectively. In a series of studies performed on affected animal transgenic models of CMT1A disease, expression of the PMP22 gene (gene dosage) was shown to correlete with severity of CMT course (gene dosage effect). In this study we hypothesized that single nucleotide polymorphisms (SNPs) located within the 5' regulatory sequence of PMP22 gene may be responsible for the CMT1A/HNPP clinical variability. We have sequenced the PMP22 5' upstream regulatory sequence in a group of 45 CMT1A/HNPP patients harboring the PMP22 duplication (37) /deletion (8). We have identified five SNPs in the regulatory sequence of the PMP22 gene. Three of them i.e. -819C>T, -4785G>T, -4800C>T were detected both in the patients and in the control group. Thus, their pathogenic role in the regulation of the expression of the PMP22 gene seems not to be significant. Two SNPs i.e. -4210T>C and -4759T>A were found only in the CMT patients. Their role in the regulation of the PMP22 gene expression can not be excluded. Additionally we have detected the Thr118Met variant in exon 4 of the PMP22 gene, which was previously reported by other authors, in one patient. We conclude that the 5' regulatory sequence of the PMP22 gene is conserved at the nucleotiode level, however rarely occurring SNPs variant in the PMP22 regulatory sequence may be associated with the gene dosage effect.

15

Patogeneza molekularna choroby Charcot-Marie-Tooth 2

51%

Kotruchow K., Kabzinska D., Karpinska K., Kochanski A.

Postępy Biochemii

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2011

|

tom 57

|

nr 3

16

Zastosowanie calego ziarna pszenicy i jeczmienia w zywieniu kurczat rzeznych

51%

Kucharski K., Rutkowski A., Kochanski A.

Roczniki Naukowe Zootechniki

|

2002

|

tom 29

|

nr 1

219-227

17

Pathogenic mutations and sequence variants within mitofusin 2 gene in Polish patients with different hereditary motor-sensory neuropathies

51%

Kotruchow K., Kabzinska D., Kochanski A.

Acta Neurobiologiae Experimentalis

|

2015

|

tom 75

|

nr 3

At the time of its first description in 2004, MFN2 was considered the most frequently mutated gene in hereditary motor and sensory neuropathy type 2 (HMSN 2). However recent studies have shown that the frequency of MFN2 gene mutations in HMSN II patients is surprisingly low. To date, no systematic studies devoted to HMSN Ila in Poland have been carried out. In this study, we searched for MFN2 gene mutations in Polish patients representing the population of nearly 40 million. We decided to include a wide spectrum of clinical phenotypes in the study, proving able to detect, in a group of 67 affected patients: 1) 3 pathogenic mutations 2) 3 sequence variants of unknown pathogenic status 3) 9 rare MFN2 gene sequence variants 4) 6 common polymorphisms The frequency of MFN2 gene mutations in the whole group of patients is 4.5%. Due to the high frequency of MFN2 gene sequence variants within single patients we could not definitely exclude the cumulative effect of these contributing to the HMSN II phenotype. The MFN2 gene should therefore be considered in Polish HMSN II patients, though it is still not possible to determine its position in HMSN II molecular diagnostics.

18

LITAF and TNF alpha genes sequence variants in the patients with Charcot-Marie-Tooth disease

45%

Sinkiewicz-Darol E., Potulska-Chromik A., Kostera-Pruszczyk A., Kabzinska D., Kochanski A.

Acta Neurobiologiae Experimentalis

|

2011

|

tom 71

|

nr 1

Recently it has been reported that Charcot-Marie-Tooth disease may coexist with chronic inflammatory neuropathy and central demyelination. There is a question, whether CMT and inflammatory disease detected in one family share a common pathogenesis or result from the random coincidence of two disorders. There is a possibility that mutations/sequence variants in the gene coding for immune response mediators (LITAF, TNF alpha) may modify the CMT phenotype. To test this hypothesis, we have sequenced the coding sequence of LITAF gene and the promoter sequence of TNF alpha gene in two families with Charcot-Marie-Tooth disease coexisting with chronic inflammatory demyelinating polyneuropathy (CIDP) and primary progressive multiple sclerosis (PPMS). The genetic analysis has revealed three sequence variants: c.274A>G (Ile92Val) and in c.334G>A (Gly112Ser) in the LITAF gene and one SNP -308G>A in the promoter region of TNF alpha gene. The sequence variants c.334G>A (Gly112Ser) in the LITAF gene and -308G>A in the TNF alpha gene were detected in family with Charcot-Marie-Tooth type 1C and primary progressive multiple sclerosis (PPMS). The sequence variants c.274A>G (Ile92Val) in the LITAF gene and -308G>A in the TNF alpha gene were detected in family with Charcot-Marie-Tooth type 1A and chronic inflammatory polyradiculoneuropathy (CIDP). In agreement with previously published data we suggest that the sequence variants in the genes coding for inflammatory mediators may contribute to the clinical variability of CMT.

19

A novel homozygous mutation in the WNK1/HSN2 gene causing hereditary sensory neuropathy type 2

45%

Potulska-Chromik A., Kabzinska D., Lipowska M., Kostera-Pruszczyk A., Kochanski A.

Acta Biochimica Polonica

|

2012

|

tom 59

|

nr 3

Hereditary sensory and autonomic neuropathy type 2 is a rare disorder caused by recessive mutations in the WNK1/HSN2 gene located on chromosome 12p13.33. Phenotype of the patients is characterized by severe sensory loss affecting all sensory modalities. We report a novel homozygous Lys179fsX182 (HSN2); Lys965fsX968 (WNK1/HSN2) mutation causing an early childhood onset hereditary sensory and autonomic neuropathy type 2, with acromutilations in upper and lower limbs, and autonomic dysfunction. To the best of our knowledge this is the first genetically proven case of hereditary sensory and autonomic neuropathy type 2 originating from East Europe.

20

A novel TPM2 gene splice-site mutation causes severe congenital myopathy with arthrogryposis and dysmorphic features

45%

Mroczek M., Kabzinska D., Chrzanowska K. H., Pronicki M., Kochanski A.

Journal of Applied Genetics

|

2017

|

tom 58

|

nr 2

Ograniczanie wyników

Mutation or polymorphism in neurodegenerative disorders?

How to assess the pathogenicity of mutations in Charcot-Marie-Tooth disease and other diseases?

A role for the GDAP1 gene in the molecular pathogenesis of Charcot - Marie - Tooth disease

Charcot - Marie - Tooth type 1A drug therapies: role of adenylyl cyclase activity and G - protein coupled receptors in disease pathomechanism

De novo Ser72Leu mutation in the peripheral myelin protein 22 in two Polish patients with a severe from of Charcot-Marie-Tooth disease

Molecular genetic analysis of the GJB1 gene: a study of six mutations

Screening of the myelin protein zero gene in patients with Charcot-Marie-Tooth disease

Screening of the 17p11.2-p12 region in a large cohort of patients with Charcot-Marie-Tooth [CMT] disease or hereditary neuropathy with liability to pressure palsies [HNPP]

Mitofuzyna 2 – ważne białko obwodowego układu nerwowego i powszechnie występujący regulator metabolizmu

Molecular pathogenesis, experimental therapy and genetic counseling in hereditary sensory neuropathies

Two pathogenic mutations located within the 5'-regulatory sequence of the GJB1 gene affecting initiation of transcription and translation

A newly identified Thr99fsX110 mutation in the PMP22 gene associated with an atypical phenotype of the hereditary neuropathy with liability to pressure palsies

Charcot-Marie-Tooth type 1A disease caused by a novel Ser112Arg mutation in the PMP22 gene, coexisting with a slowly progressive hearing impairment

The 5' regulatory sequence of the PMP22 in the patients with Charcot-Marie-Tooth disease

Patogeneza molekularna choroby Charcot-Marie-Tooth 2

Zastosowanie calego ziarna pszenicy i jeczmienia w zywieniu kurczat rzeznych

Pathogenic mutations and sequence variants within mitofusin 2 gene in Polish patients with different hereditary motor-sensory neuropathies

LITAF and TNF alpha genes sequence variants in the patients with Charcot-Marie-Tooth disease

A novel homozygous mutation in the WNK1/HSN2 gene causing hereditary sensory neuropathy type 2

A novel TPM2 gene splice-site mutation causes severe congenital myopathy with arthrogryposis and dysmorphic features