Biomedical subjects

Andrzej Kochański

Publications and source records attributed to Andrzej Kochański.

12 recordsLinked to original sources

PubMed2006

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

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.

Charcot-Marie-Tooth Disease↗

PubMed2006

Is a novel I214M substitution in the NEFL gene a cause of Charcot-Marie-Tooth disease? Functional analysis using cell culture models.

Recent studies have shown that mutations in neurofilament light subunit gene (NEFL) cause Charcot-Marie-Tooth (CMT) disease. Since the first description of the Gln333Pro mutation in the NEFL gene, 10 pathogenic mutations in the NEFL gene have been reported in patients affected with CMT disease. We report a novel I214M amino acid substitution in the NEFL gene in two unrelated patients affected with CMT. Because the I214M amino acid substitution in the NEFL protein was not detected in a CMT affected brother of the proband, its pathogenic effect became unclear. In order to determine whether this amino acid substitution is a benign polymorphism or causative of the disease, we performed a functional analysis of the mutant I214M neurofilament protein (NFL). Transfections of the mutant protein in cultured cells revealed an increased tendency to form highly compacted filamentous structures but no other alterations of neurofilament assembly or transport were observed. Furthermore, the sibling of one of the patients was also affected with CMT but did not have the I214M substitution. These data suggest that this I214M substitution in the NEFL gene was not a direct cause of the disease but could be a polymorphism or possibly a modifier of the CMT phenotype.

Adolescent↗

PubMed2005

A novel Met116Thr mutation in the GDAP1 gene in a Polish family with the axonal recessive Charcot-Marie-Tooth type 4 disease.

Mutations in the gene coding for ganglioside-induced differentiation-associated protein-1 (GDAP1), which maps to chromosome 8q21, have been described in families with autosomal recessive Charcot-Marie-Tooth disease (CMT4A). Interestingly, some mutations in the GDAP1 gene have been reported in the demyelinating form of CMT1 disease, whereas others were found in patients with the axonal type of CMT disease. So far, 23 mutations in the GDAP1 gene have been reported in patients of different ethnic origins. In this study we report a novel mutation Met116Thr in the GDAP1 gene identified in a three generation Polish family with axonal CMT4.

Adult↗

PubMed2005

Molecular genetics studies in Polish Charcot-Marie-Tooth families.

Charcot-Marie-Tooth (CMT) disorders are the extremely heterogeneous group of diseases of the peripheral nervous system in humans with a prevalence of 1: 2500. Up to date mutations in 30 genes have been reported in various CMT forms. In numerous CMT types only locus is known and some CMT forms were shown not to be linked with any known locus. Genetic studies in CMT disorders cover a wide spectrum of problems ranging from identification of novel mutations through studies of pathogenic nature of mutations to genotype-phenotype correlations. The aim of this study was to present the main directions of genetic analysis performed in Polish families with CMT disease.

Charcot-Marie-Tooth Disease↗

PubMed2004

Early onset Charcot-Marie-Tooth type 1B disease caused by a novel Leu190fs mutation in the myelin protein zero gene.

The spectrum of Charcot-Marie-Tooth (CMT) phenotypes segregating with mutations in the Myelin Protein Zero (MPZ) gene is wide and ranges from congenital hypomyelinating neuropathy (CHN) through demyelinating form of CMT to the axonal type of CMT disease. Within 94 MPZ gene mutations reported up to now, only a few were identified in the exon 4 of the MPZ gene. In this study we have identified a novel Leu190fs mutation in the MPZ gene. The Leu190fs mutation was found in a 14-year-old girl suffering from Charcot-Marie-Tooth type 1 disease (CMT1) with onset in early infancy. Similarly to the other MPZ gene frame-shift mutations reported as far the Leu190fs seems to have a dominant negative effect.

Adolescent↗

PubMed2004

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

Charcot-Marie-Tooth type X1 disease (CMTX1) is an X-dominant peripheral neuropathy caused by mutations in the GJB1 gene. Molecular genetic analysis of the GJB1 gene is crucial for CMTX1 diagnosis and for genetic counselling. To date, molecular genetic analysis of the GJB1 gene revealed 264 mutations in the GJB1 gene. In spite of the rising number of GJB1 gene mutations, family history was documented in only a few CMTX1 cases. The aim of this study was a molecular genetic analysis of the GJB1 gene in 7 families, performed in 19 CMTX1-affected patients and 13 healthy family members. Moreover, we attempted to report evidence of effects of 6 amino-acid substitutions described in this study. To the best of our knowledge, the G110D, V152D and K167E mutations are novel substitutions, which have not been reported so far.

Amino Acid Sequence↗

PubMed2004

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

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.

Amino Acid Substitution↗

PubMed2004

Mutations in the neurofilament light chain gene (NEFL)--a study of a possible pathogenous effect.

Neurofilaments (NFs) have been shown to be involved in the molecular pathology of numerous neurode-generative human disorders. Recently a set of mutations in the neurofilament light gene (NF-L) was reported in patients suffering from axonal and demyelinating forms of Charcot-Marie-Tooth disease (CMT1 and CMT2). Although a few of the NEFL gene sequence variants have been shown to be rather pathogenous mutations than harmless polymorphisms, the status of some of these variants remains unclear. The aim of this study was to analyse a potential pathogenous effect of the mutations in the NEFL gene identified in CMT affected patients.

Charcot-Marie-Tooth Disease↗

PubMed2004

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

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.

Amino Acid Substitution↗

PubMedDate not supplied

[Charcot-Marie Tooth type X (CMTX) disease: clinical and genetic characteristics of eleven patients].

Charcot-Marie-Tooth type X disease (CMTX) is the second most frequent inherited neuropathy, after CMT1A type associated with 17p11.2-p12 duplication. CMTX is inherited as X dominant trait and is caused by point mutations in Cx32 gene. In the study the first Polish group of 11 patients with CMTX from 4 families is presented. The following four mutations were found in Cx32 gene: Gly110Asp, Val 152 Asp, Arg 183 His and Glu 208 Gly. CMTX is characterized by X dominant trait of inheritance, a mild clinical course in affected females and slowly progressive atrophy and weakness of distal limb muscles. Both electrophysiological and sural nerve biopsy studies show axonal changes with secondary demyelination.

Atrophy↗

PubMedDate not supplied

[Charcot-Marie-Tooth disorders: past, today and tomorrow].

Both intra- and interfamiliar variability of the clinical course of Charcot-Marie-Tooth disorders (CMT) were reported in the descriptions of the CMT disease in the 19th century. In the 1950s, it was shown that CMT disorders may be classified into two main groups i.e. CMT 1 and 2 on the basis of motor nerve conduction velocity in the motor fibers of the median nerve (MNCV=38 m/s). With the neuropathological studies in the 1960s, especially electron microscopy, a further enrichment of CMT classification was possible (hypomyelinating neuropathy, CMT with focally folded myelin). Thus, CMT classification based on EMG and neuropathological studies created an enormous opportunity to develop molecular genetics studies in CMT. Since early 1980s up to date, molecular genetic studies in CMT disorders resulted in a discovery of 30 genes. The new forms have been added to CMT classification on the basis of molecular DNA studies. In the "DNA era" in CMT genetic counseling in this group of disorders may be offered to the patients. Due to a possibility of delineating CMT patients on the basis of "genetic background", myological semiology and diagnostics may be improved. The access, costs and range of molecular DNA studies are still limited in CMT disorders. It seems possible that in the near future microarray DNA technology may revolutionize CMT diagnostics. The question whether and when gene therapy will be available in CMT remains to be answered, similar to other disorders with a genetic background.

Charcot-Marie-Tooth Disease↗

PubMedDate not supplied

[Pathogenic mutation or polymorphism? (How to find criteria)].

The classification of amino-acid substitutions into pathogenic mutations and harmless polymorphisms should be revised. In the recent years it was shown that some amino-acid substitutions considered as pathogenic mutations were polymorphisms. Similarly, some 'harmless' polymorphisms have been shown to be pathogenic mutations. Functional analysis considered as a good method to estimate the pathogenic nature of mutations is also limited. The selection of DNA samples for the control group is also difficult. Due to the molecular mechanism mediated by recently discovered exonic splicing enhancers and silencers (ESE and ESS) it is hard to predict a pathogenic effect of some mutations. In addition, the phenotype variability observed between unrelated patients harboring the same mutation may reflect the effects of modifying genes as well as the lack of association between mutation and "its" phenotype. The aim of this study is to describe the problem of the pathogenic effect of mutations.

Alternative Splicing↗