Úvod. Mutace genu pro periferní myelin protein zero (MPZ, PO) jsou již 10 let jednou ze známých příčin demyelinizačního typu choroby Charcot-Marie-Tooth (CMT) kam kromě klasické formy CMTl patří i Časně začínající a těžká forma Déjerineovy-Sottasovy neuropatie (DSS) a ještě časnější a těžší kongenitální hypomyelinizační neuropatie (CHN). PO protein je hlavní součástí periferního myelinu a hraje zásadní roli v procesu periferní myelinizace. V posledních letech byly popsány rodiny s axonálním typem CMT v důsledku mutací v PO genu. Pacienti a výsledky. Popisujeme 3 české rodiny s výskytem dvou zcela odlišných začátků, průběhů a forem choroby CMT, u kterých byly jako příčiny choroby prokázány mutace v PO genu. Šlo o mutace již dříve popsané v jiných zemích a sice: Arg98Cys u dvou rodin se třemi postiženými, jednou ve 2 generacích, s těžkou demylinizační formou, infantilním začátkem a stabilním průběhem a s extrémně nízkou rychlostí vedení periferním nervem a dále mutaci Thrl24Met u pacientky s pozdním začátkem axonální formy CMT na konci 4. dekády, abnormní fotoreakcí a poměrně rychlou progresí nemoci. U mutace Arg98Cys šlo v obou rodinách o vznik de-novo, a u mutace Thrl24Met sice nebylo možné rodiče pacientky dovyšetřit, ale anamnestický trpí matka pacientky chorobou CMT. U syna i dcery pacientky, u kterých dosud nejsou žádné klinické známky polyneuropatie je též abnormní fotoreakce a u syna byla též prokázána stejná mutace, u dcery nebylo vyšetření provedeno. Závěry. Těžká demyelinizační dědičná neuropatie s infantilním začátkem (DSS) a axonální pozdně začínající CMT2 představují opačné póly spektra poruchy myelinizace způsobené mutacemi PO genu. Kodon 98 Arg PO genu je místem opakovaného vzniku mutací i u českých pacientů. Objasnění proč některé mutace v PO genu vedou k velmi časnému začátku demyelinizační neuropatie a jiné mutace stejného genu k pozdnímu začátku axonální neuropatie by mohlo poskytnout klíč k molekulární interakci mezi axonem a Schwannovou buňkou.

Background: Mutations of the peripheral myelin protein zero (MPZ, PO) gene have been for 10 years one of the known causes of the demyelination type of Charcot-Marie-Tooth (CMT) disease, which in addition to the classical CMTl form also includes the early onset and severe form of Déjerine-Sottas neuropathy (DSS) and yet earlier onset and more severe congenital hypomyelinating neuropathy (CHN). PO protein is the main component of peripheral myelin and plays a crucial role in the process of peripheral myelination. In the last few years, families with axonal type of CMT due to PO gene mutations have been described. Patients and Results: We describe 3 Czech families with proven PO gene mutations and completely different times of onset, clinical courses and forms of the CMT disease. The mutations found have been reported previously in other countries. Arg98Cys was found in two families with three affected members, once in 2 generations, with a severe demyelinating form, childhood onset and stable course and with extremplv low nerinheral nerve conduction velocity, and next, Thrl24Met ''lutation in a female patient with late onset of axonal form of CMT disease at the end of the fourth decade, abnormal pupillary reaction and relatively rapid progression of disease. Arg98Cys mutation occurred in both families de novo, in the Thrl24Met mutation, patient's parents could not be investigated but the patient's mother has a history compatible with CMT disease. Both son and daughter of the patient have presently no clinical signs of polyneuropathy but have abnormal pupillary reaction. The son has the same mutation, daughter has not been investigated yet. Conclusions: Severe demyelinating hereditary neuiopathy with childhood onset (DSS) and axonal late-onset CMT2 represent the opposite ends of the spectrum of myelination disorder caused by PO gene mutations. The 98 Arg codon of the PO gene is a locus of repeated occurrence of mutations found also in Czech families. Elucidation of the reason why some PO gene mutations lead to very early-onset demyelinating neuropathy and other mutations of the same gene lead to late-onset axonal neuropathy could offer a clue to molecular interactions between the axon and the Schwann cell.

• MeSH
• Charcotova-Marieova-Toothova nemoc diagnóza   genetika   terapie   MeSH
• dítě MeSH
• dospělí MeSH
• elektrodiagnostika metody   MeSH
• finanční podpora výzkumu jako téma MeSH
• hereditární motorické a senzitivní neuropatie diagnóza   genetika   terapie   MeSH
• lidé MeSH
• mutace genetika   MeSH
• mutační analýza DNA metody   MeSH
• myelinový P0 protein genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

• MeSH
• DNA primery MeSH
• genetická vazba MeSH
• mapování pomocí radiačních hybridů MeSH
• myelinový P0 protein genetika   MeSH
• savčí chromozomy genetika   MeSH
• sekvence nukleotidů MeSH
• Sus scrofa genetika   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH

The control of ticks through vaccination offers a sustainable alternative to the use of chemicals that cause contamination and the selection of resistant tick strains. However, only a limited number of anti-tick vaccines have reached commercial realization. In this sense, an antigen effective against different tick species is a desirable target for developing such vaccines. A peptide derived from the tick P0 protein (pP0) conjugated to a carrier protein has been demonstrated to be effective against the Rhipicephalus microplus, Rhipicephalus sanguineus, and Amblyomma mixtum tick species. The aim of this work was to assess the efficacy of this peptide when conjugated to the Bm86 protein against Dermacentor nitens and Ixodes ricinus ticks. An RNAi experiment using P0 dsRNA from I. ricinus showed a dramatic reduction in the feeding of injected female ticks on guinea pigs. In the follow-up vaccination experiments, rabbits were immunized with the pP0-Bm86 conjugate and challenged simultaneously with larvae, nymphs, and the adults of I. ricinus ticks. In the same way, horses were immunized with the pP0-Bm86 conjugate and challenged with D. nitens larva. The pP0-Bm86 conjugate showed efficacies of 63% and 55% against I. ricinus and D. nitens ticks, respectively. These results, combined with previous reports of efficacy for this conjugate, show the promising potential for its development as a broad-spectrum anti-tick vaccine.

• Publikační typ
• časopisecké články MeSH

BACKGROUND: Most mutations in the myelin protein zero gene (MPZ) typically cause a severe demyelinating/dysmyelinating neuropathy that begins in infancy or an adult-onset axonal neuropathy. Axonal degeneration in the late-onset H10P mutation may be caused by the disruption of axoglial interaction. OBJECTIVE: To evaluate sural nerve biopsy samples from a patient with early-onset Charcot-Marie-Tooth disease type 1B caused by an arg69-to-cys (R69C) mutation. Design and PARTICIPANTS: Biopsies of sural nerves were performed 20 years apart in a patient with an R69C mutation (early onset). In addition, peripheral nerves were obtained from autopsy material from a patient with a T95M mutation (late onset). These nerves were analyzed using light microscopy of semithin sections, teased nerve fiber immunohistochemical analysis, electron microscopy, and immunologic electron microscopy. MAIN OUTCOME MEASURES: Pathological changes in sural nerve. RESULTS: Both R69C biopsy samples showed prominent demyelination and onion bulb formation, unlike the late-onset T95M mutation, which showed primarily axonal degeneration with no onion bulbs. The sural biopsy sample obtained 20 years earlier from the R69C patient showed minimal difference from the present sample, consistent with the lack of clinical progression during the 2 decades. Teased fiber immunohistochemical analysis of R69C revealed voltage-gated sodium channel subtype 1.8 expressions at the nodes of Ranvier around the areas of segmental demyelination. Internodal length in all R69C nerve fibers was invariably short (>94% of all internodes are <150 mum). CONCLUSIONS: Morphologic abnormalities in this early-onset R69C neuropathy were severe in childhood but progressed very slowly after adolescence. The switch to voltage-gated sodium channel subtype 1.8 expression at the nodes may provide clues into the pathogenesis of this case of early-onset neuropathy, and the short internodes may contribute to the extremely slowed conduction velocities in this case (<10 m/s).

• MeSH
• axony patologie   MeSH
• Charcotova-Marieova-Toothova nemoc genetika   patofyziologie   MeSH
• elektronová mikroskopie MeSH
• gating iontového kanálu fyziologie   MeSH
• imunoelektronová mikroskopie MeSH
• imunohistochemie MeSH
• iontové kanály fyziologie   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• myelinová pochva * fyziologie   MeSH
• myelinový P0 protein * genetika   MeSH
• nervová vlákna patologie   MeSH
• nervus suralis patologie   MeSH
• nervus ulnaris patologie   MeSH
• progrese nemoci MeSH
• senioři nad 80 let MeSH
• substituce aminokyselin MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

STUDY DESIGN: Retrospective study of 175 patients with hereditary motor and sensory neuropathy (HMSN), i.e., Charcot-Marie-Tooth (CMT) disease. OBJECTIVE: To investigate the frequency, age of onset, character, familial, and genotypical incidence of spinal deformities among HMSN patients. SUMMARY OF BACKGROUND DATA: Prior studies addressing HMSN discuss the associated spinal deformities. However, these data vary significantly while inconsistently including genotypes within the classification framework. METHODS: Plain-film radiographic spine studies of 175 HMSN patients were performed to determine the incidence, character, and severity of spinal deformity. The degree of the spinal deformity was evaluated measuring Cobb's angle of the main curve. The results of the entire cohort were initially assessed before being classified by genotype. RESULTS: The incidence of spinal deformity for the entire group was 26%. Of these, 58% demonstrated scoliosis, 31% had kyphoscoliosis, and 11% had thoracic hyperkyphosis; 73% of patients with spinal deformity were classified as HMSN Type I with confirmed duplication of the PMP 22 (peripheral myelin protein) gene on chromosome 17. The incidence of spinal deformity by genotype was: duplication of the PMP 22 gene: 29% (25 of 87); deletion of the PMP 22 gene: 0% (0 of 15); Cx32 (connexin 32) gene mutation: 24% (8 of 34); and MPZ (myelin protein zero) gene mutation: 100% (6 of 6). Familial incidence of spinal deformity was found in "MPZ gene mutation" and "duplication of PMP 22 gene" subgroups. CONCLUSION: This study demonstrates a 26% incidence of spinal deformity among HMSN patients. Spinal deformity was most frequently observed in patients with the MPZ gene mutation, where the most common familial incidence was also found.

• MeSH
• dospělí MeSH
• duplikace genu MeSH
• genetická predispozice k nemoci genetika   MeSH
• genetické markery MeSH
• genotyp MeSH
• incidence MeSH
• kohortové studie MeSH
• komorbidita MeSH
• lidé MeSH
• lidské chromozomy, pár 17 genetika   MeSH
• mutace genetika   MeSH
• mutační analýza DNA MeSH
• myelinové proteiny genetika   MeSH
• myelinový P0 protein genetika   MeSH
• páteř patologie   radiografie   MeSH
• retrospektivní studie MeSH
• typy dědičnosti genetika   MeSH
• věk při počátku nemoci MeSH
• zakřivení páteře epidemiologie   genetika   radiografie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH

• MeSH
• bodová mutace MeSH
• Charcotova-Marieova-Toothova nemoc genetika   MeSH
• dospělí MeSH
• finanční podpora výzkumu jako téma MeSH
• lidé MeSH
• missense mutace MeSH
• myelinový P0 protein genetika   MeSH
• percepční nedoslýchavost genetika   MeSH
• poruchy sluchu genetika   MeSH
• reflex pupilární genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• kazuistiky MeSH

Sekvenační analýza genů Cx32, MPZ, EGR2 a PMP22, které jsou zodpovědné za fenotyp dědičných periferních neuropatií bude prováděna v již shromážděném kolektivu pacientů s dědičnými neuropatiemi s vyloučenou nejčastější mutací z oblasti 17p11.2-12.; Sequencing analysis of Charcot-Marie-Tooth type 1 disorders genes Cx32, MPZ, EGR2 and PMP22 in patients from present collection of Czech patients with inherited peripheral neuropathies without the 17 p rearrangement.

• MeSH
• bodová mutace MeSH
• Charcotova-Marieova-Toothova nemoc MeSH
• genetický kód MeSH
• konexiny MeSH
• myelinový P0 protein MeSH

• Konspekt
• Obecná genetika. Obecná cytogenetika. Evoluce
• NLK Obory
• genetika, lékařská genetika
• neurologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

Mutations in the myelin protein zero (MPZ) gene are one of the frequent causes of Charcot-Marie-Tooth (CMT) hereditary neuropathies. Because the mutation rate of MPZ gene is rather high and some mutations are reported as polymorphisms, the proper clinical, electrophysiological examination and the segregation of the new mutation in larger families are crucial for the correct interpretation of the pathogenic or non-pathogenic character of each novel mutation. We examined 11 families with novel MPZ mutations. Eight of the mutations (L48Q, T65N, E97fs, G103W, P132T, T143R, V146G, c.645+1G>T) seem to be pathogenic on the basis of perfect segregation with the CMT phenotype and two (G213R and D246N), on the contrary, seem to be non-pathogenic/rare polymorphisms because they are present in healthy relatives. The character of the V46M mutation is difficult to interpret definitely; it may cause a sensory neuropathy or may also be a rare polymorphism. Phenotypes associated with each of the new mutations include severe hereditary motor and sensory neuropathy type III (HMSN III), and mild phenotype CMT1B presented mostly with only decreased or absent reflexes, foot deformities and mild or even absent atrophies in the lower limbs. Our report and careful family investigations with genotype-phenotype correlations should help to improve genetic counselling and correct interpretation of DNA testing results in further isolated patients or smaller families worldwide where these novel mutations might be found.

• MeSH
• Charcotova-Marieova-Toothova nemoc genetika   MeSH
• dítě MeSH
• dospělí MeSH
• elektrofyziologie MeSH
• fenotyp MeSH
• genetické asociační studie MeSH
• hereditární motorické a senzitivní neuropatie genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace MeSH
• myelinový P0 protein genetika   MeSH
• polymorfismus genetický MeSH
• předškolní dítě MeSH
• předsudek MeSH
• rodina MeSH
• senioři MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• Charcotova-Marieova-Toothova nemoc MeSH
• dědičné degenerativní poruchy nervového systému MeSH
• genetické nemoci vrozené MeSH
• hereditární motorické a senzitivní neuropatie MeSH
• malformace nervového systému MeSH
• myelinový P0 protein MeSH
• Publikační typ
• sborníky MeSH

• Konspekt
• Obecná genetika. Obecná cytogenetika. Evoluce
• NLK Obory
• genetika, lékařská genetika
• neurologie

The molecular clockwork underlying the generation of circadian rhythmicity within the suprachiasmatic nucleus (SCN) develops gradually during ontogenesis. The authors' previous work has shown that rhythms in clock gene expression in the rat SCN are not detectable at embryonic day (E) 19, start to form at E20 and develop further via increasing amplitude until postnatal day (P) 10. The aim of the present work was to elucidate whether and how swiftly the immature fetal and neonatal molecular SCN clocks can be reset by maternal cues. Pregnant rats maintained under a light-dark (LD) regimen with 12 h of light and 12 h of darkness were exposed to a 6-h delay of the dark period and released into constant darkness at different stages of the fetal SCN development. Adult rats maintained under the same LD regimen were exposed to an identical shifting procedure. Daily rhythms in spontaneous c-fos, Avp, Per1, and Per2 expression were examined within the adult and newborn SCN by in situ hybridization. Exposure of adult rats to the shifting procedure induced a significant phase delay of locomotor activity within 3 days after the phase shift as well as a delay in the rhythms of c-fos and Avp expression within 3 days and Per1 and Per2 expression within 5 days. Exposure of pregnant rats to the shifting procedure at E18, but not at E20, delayed the rhythm in c-fos and Avp expression in the SCN of newborn pups at P0-1. The shifting procedure at E20 did, however, induce a phase delay of Per1 and Per2 expression rhythms at P3 and P6. Hence, 5 days were necessary for phase-shifting the pups' SCN clock by maternal cues, be it the interval between E18 and P0-1 or the interval between E20 and P3, while only 3 days were necessary for phase-shifting the maternal SCN by photic cues. These results demonstrate that the SCN clock is capable of significant phase shifts at fetal developmental stages when no or very faint molecular oscillations can be detected.

• Klíčová slova
• Period Circadian Proteins,
• MeSH
• arginin vasopresin biosyntéza   MeSH
• biologické modely MeSH
• financování organizované MeSH
• hybridizace in situ MeSH
• jaderné proteiny biosyntéza   MeSH
• krysa rodu rattus MeSH
• lokomoce MeSH
• matky MeSH
• novorozená zvířata MeSH
• nucleus suprachiasmaticus embryologie   metabolismus   MeSH
• oscilometrie MeSH
• proteiny buněčného cyklu biosyntéza   MeSH
• protoonkogenní proteiny c-fos biosyntéza   MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH