Pontocerebellar hypoplasia type 1 (PCH1) is characterized by cerebellar and anterior horn motor neuron degeneration and loss, signs of spinal muscular atrophy plus. Patients manifest severe perinatal weakness, hypotonia, and respiratory insufficiency, causing death frequently before the age of 1 year. Recently, causative mutations in EXOSC3 were reported in a majority of PCH1 patients, but the detailed clinical phenotype caused by EXOSC3 mutations, genotype-phenotype correlations, and prevalent mutations in specific ethnic groups is not yet known. Three unrelated Czech Roma patients with PCH1 were investigated clinically, electrophysiologically, neuroradiologically, and neuropathologically (patients 1 and 2). The entire coding region of the EXOSC3 gene, including the adjacent intron sequences, was sequenced in all three patients. The same mutation c.92G→C, p.G31A in EXOSC3 was found in all three affected patients in homozygous state and in heterozygous state in the parents from two of the families. Haplotype analysis with four flanking microsatellite markers showed identical haplotype in 9 out of 11 haplotypes carrying the c.92G→C, p.G31A mutation. Furthermore, four heterozygotes for this mutation were found in anonymous DNA samples from 90 unrelated Roma individuals. All four of these samples shared the same haplotype. No heterozygous sample was found among 120 anonymous DNA samples from Czech non-Roma individuals with no familial relation. It may therefore be concluded that EXOSC3 c.92G→C, p.G31A mutation is a founder mutation with high prevalence among the Czech Roma causing a similar and particularly severe phenotype of PCH1. These observations from the Czech Roma may have consequences also for other Roma from other countries. PCH1 caused by EXOSC3 founder mutation c.92G→C, p.G31A extends the list of autosomal recessive disorders rare among the general population but more frequent among Roma at least in the Czech Republic.

• MeSH
• exozom genetika   MeSH
• fenotyp MeSH
• haplotypy MeSH
• homozygot MeSH
• kojenec MeSH
• lidé MeSH
• mutace * MeSH
• novorozenec MeSH
• olivopontocerebelární atrofie genetika   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• proteiny vázající RNA genetika   MeSH
• Romové genetika   MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• EXOSC3 protein, human MeSH Prohlížeč
• exozom MeSH
• proteiny vázající RNA MeSH

Charcot-Marie-Tooth (CMT) neuropathy is the most common inherited neuromuscular disorder. CMT is genetically very heterogeneous. Mutations in the SH3TC2 gene cause Charcot-Marie-Tooth neuropathy type 4C (CMT4C), a demyelinating form with autosomal recessive inheritance. In this study, two novel splice site mutations in the SH3TC2 gene have been studied (c.279G → A, c.3676-8G → A). Mutation c.279G → A was detected on one allele in two unrelated families with CMT4C in combination with a known pathogenic mutation (c.2860 C →T in one family, c.505T → C in the other) on the second allele of SH3TC2 gene. Variant c.3676-8G → A was detected in two patients from unrelated families on one allele of the SH3TC2 gene in combination with c.2860C →T mutation on the other allele. Several in silico tests were performed and exon trap experiments were undertaken in order to prove the effect of both mutations on proper splicing of SH3TC2. Fragments of SH3TC2 were subcloned into pET01 exon trap vector (Mobitec) and transfected into COS-7 cells. Aberrant splicing was predicted in silico for both mutations, which was confirmed by exon trap analysis. For c.279G → A mutation, 19 bases from intron 3 are retained in cDNA. The mutation c.3676-8G→ A produces a novel splice acceptor site for exon 17 and complex changes in splicing were observed. We present evidence that mutations c.279G → A and c.3676-8G →A in the SH3TC2 gene cause aberrant splicing and are therefore pathogenic and causal for CMT4C.

• MeSH
• Cercopithecus aethiops MeSH
• Charcotova-Marieova-Toothova nemoc genetika   patologie   patofyziologie   MeSH
• COS buňky MeSH
• dospělí MeSH
• intracelulární signální peptidy a proteiny MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace genetika   MeSH
• nervové vedení genetika   MeSH
• počítačová simulace * MeSH
• proteiny genetika   MeSH
• referenční hodnoty MeSH
• transfekce MeSH
• zdraví rodiny MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• intracelulární signální peptidy a proteiny MeSH
• proteiny MeSH
• SH3TC2 protein, human MeSH Prohlížeč

Mutations in the Dynamin 2 gene (DNM2) cause autosomal dominant centronuclear myopathy or autosomal dominant (AD) Charcot-Marie-Tooth (CMT) disease. Here the authors report one large Czech family with 15 members affected with an AD CMT phenotype of extraordinary variability. Genetic linkage analysis using SNP arrays revealed a locus of about 9.6 Mb on chromosome 19p13.1-13.2. In this critical interval, 373 genes were located. The only gene herein known to be associated with an intermediate type of CMT was Dynamin 2 (DNM2). Subsequent sequence analysis of the DNM2 gene in the index patient revealed a novel missense mutation p.Met580Thr. This missense mutation segregated with the neuropathy, indicating the causal character of this mutation. The phenotype of CMT in this family shows mild to moderate impairment with relatively preserved upper limbs and a very broad range of the onset of clinical symptoms from an early onset around the age of 12 to the late onset during the fifth decade. Electrophysiology showed an intermediate type of peripheral neuropathy. The motor median nerve conduction velocity varied from 36 m/s to normal values with signs of asymmetrical affection of peripheral nerves. No additional symptoms such as cranial nerve involvement, cataract, and signs of neutropenia or myopathy syndrome were observed in any member of the family yet. The progression was slow with no loss of ambulation. The authors suggest that the characterization of clinical variability in a single family may help to direct the genetic analysis directly to the rarely observed DNM2 mutations.

• MeSH
• Charcotova-Marieova-Toothova nemoc diagnóza   genetika   metabolismus   MeSH
• dítě MeSH
• dospělí MeSH
• dynamin II nedostatek   genetika   MeSH
• fenotyp MeSH
• genetická predispozice k nemoci etnologie   genetika   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• missense mutace genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• rodokmen MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Československo MeSH
• Názvy látek
• dynamin II MeSH

Forty Duchenne muscular dystrophy patients from the province of Moravia in the Czech Republic, who were previously found negative for large deletions in the dystrophin gene, were tested for the presence of point mutations in selected exons. Besides several intron and exon polymorphisms, two cases of nonsense mutations were detected in exon 70, thus causing the loss of the C-terminal domain of dystrophin. One of these, the mutation, S3365X, is newly reported here while the other, R3381X, has been described previously. These mutations, only 16 bp distant from each other, have a very different impact on the mental abilities of the corresponding patients.

• MeSH
• bodová mutace * MeSH
• dítě MeSH
• dystrofin genetika   MeSH
• elektroforéza v polyakrylamidovém gelu MeSH
• lidé MeSH
• mentální retardace komplikace   genetika   MeSH
• polymerázová řetězová reakce MeSH
• polymorfismus konformace jednovláknové DNA MeSH
• svalové dystrofie komplikace   genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dystrofin MeSH