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Whole Coding Region (whole + coding_region)

Distribution by Scientific Domains

Medical Sciences	75%

Selected Abstracts

Absence of c- kit gene mutations in gastrointestinal stromal tumours from neurofibromatosis type 1 patients

THE JOURNAL OF PATHOLOGY, Issue 1 2004
Kazuo Kinoshita
Abstract Most sporadic gastrointestinal stromal tumours (GISTs) have somatic c- kit gene mutations that are considered to be causal. Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene and NF1 patients have an increased risk of developing GISTs. Since most neoplasms are considered to develop as a result of the combination of several gene mutations, these findings suggest that GISTs from NF1 patients might have somatic c- kit gene mutations and that sporadic GISTs from non-NF1 patients might have somatic NF1 gene mutations. The present study analysed 29 GISTs from seven NF1 patients for c- kit gene mutations and ten sporadic GISTs from ten non-NF1 patients for NF1 mutations. Exons 9, 11, 13, and 17 of the c- kit gene were amplified and directly sequenced after the extraction of genomic DNA from wax-embedded tissues from 26 GISTs from five NF1 patients. The whole coding region of the c- kit cDNA and the whole coding region of the NF1 cDNA were amplified and directly sequenced after RNA extraction and cDNA synthesis in three fresh GIST tissues from two NF1 patients and ten fresh GIST tissues from ten non-NF1 patients. Of the ten sporadic GISTs, eight had heterozygous mutations at exon 11, and one at exon 9, of c- kit. Heterozygous NF1 gene mutations were detected in GISTs from the two NF1 patients from whom fresh tissues were available. None of the 29 GISTs derived from NF1 patients had detectable c- kit gene mutations and none of the ten GISTs derived from non-NF1 patients had detectable NF1 mutations. These results suggest that the pathogenesis of GISTs in NF1 patients is different from that in non-NF1 patients. Copyright © 2004 John Wiley & Sons, Ltd. [source]

Mitochondrial DNA depletion in progressive external ophthalmoplegia caused by POLG1 mutations

ACTA NEUROLOGICA SCANDINAVICA, Issue 2009
C. Tzoulis
Objectives , To investigate two patients with late onset, progressive external ophthalmoplegia (PEO) and sensory peripheral neuropathy. Materials & Methods , The patients aged 86 and 50 years were investigated clinically including magnetic resonance imaging of the brain, electrophysiological studies and, in one, skeletal muscle biopsy. Molecular studies included sequencing of the whole coding region of the POLG1 gene and mitochondrial DNA (mtDNA) analysis for deletions and depletion. Results , Both patients were compound heterozygous for gene encoding the catalytic subunit of the DNA-polymerase gamma (POLG1) mutations. One had the p.737R and p.W748S mutations while the other carried the p.T251I, p.P587L and p.W748S mutations. While these mutations have been previously described, these combinations are novel. mtDNA studies in skeletal muscle showed evidence of multiple deletions and approximately 64% depletion of the mitochondrial genome. Conclusion , Our findings broaden the genotypic spectrum of POLG -associated PEO and show that in addition to multiple deletions, mtDNA depletion occurs and may contribute to the pathogenesis of this disorder. [source]

Alterations of the c-kit gene in testicular germ cell tumors

CANCER SCIENCE, Issue 6 2003
Yuji Sakuma
Expression and gain-of-function mutation of the c-kit gene, that encodes a receptor tyrosine kinase (KIT), have been reported in mast cell tumors and gastrointestinal stromal tumors (GISTs). Among human testicular germ cell tumors (GCTs), seminomas and seminoma components of mixed GCTs have also been shown to express KIT, but only one study has found the c-kit gene mutation at exon 17 in seminoma. To elucidate the frequency and location of the c-kit gene mutation of testicular GCTs, we analyzed the whole coding region of the c-kit complementary DNA along with 4 mutational hot spots (exons 9, 11, 13 and 17) of the c-kit genomic DNA by polymerase chain reaction and direct sequencing. Somatic mutations were found in 4 pure seminomas of 34 testicular GCTs (11.8%). One mutation was found in exon 11 (W557R) and the others were observed in exon 17 (D816H and D816V). These types of mutations were reported in GISTs (W557R), seminoma (D816H) and mastocytosis (D816V) and were considered to be gain-of-function mutations, although there were no differences of any clinicopathological factors or outcome between patients with and without mutations. Additionally, we also demonstrated coexpression of Gly-Asn-Asn-Lys510,513 (GNNK)+ and GNNK- isoforms of the c-kit gene with dominance of the GNNK- transcript in all testicular GCTs. The mutations and/or preferential expression of GNNK- isoform of the c-kit gene might play an important role in the development of testicular GCTs, and these tumors may also be targets for STI571, which is a promising drug for advanced and metastatic GISTs. [source]

DNA sequence analysis for structure/function and mutation studies in Becker muscular dystrophy

CLINICAL GENETICS, Issue 1 2005
SA Hamed
We systematically screened the whole coding region of 18 male muscular dystrophy patients whose clinical, histological and laboratory findings suggest Becker muscular dystrophy (present but abnormal dystrophin). No systematic mutation study of a cohort of patients with dystrophin of normal quality but abnormal quantity has been published. The complete coding sequence of the dystrophin gene (11 kb) of each patient was subjected to an automated sequence analysis by using muscle biopsy RNA; 535 bp of the gene promoter and 5,UTR were likewise sequenced. We identified seven disease-causing mutations (40%). Six were novel, including missense, nonsense, small deletion and splice site mutations. Sixty percent (11/18) of patients with decreased quantities of normal molecular weight dystrophin showed no mutation, but most of them had a family history highly suggestive of X-linked inheritance, suggesting transcription or translational deleterious affection, i.e. outside what was screened. Quantitative multiplex fluorescence polymerase chain studies of mutation-negative patients showed normal levels of dystrophin mRNA. In three patients, there was some reduction of the transcript suggesting a deleterious undetected gene change resulted in the reduction of RNA levels. Our data address important structure/function and genotype/phenotype correlations and it suggests that dystrophin protein studies must be interpreted with caution in deletion-negative male muscular dystrophy patients. [source]