Molecular basis of Refsum disease: Identification of new mutations in the phytanoyl-CoA hydroxylase cDNA

1998 ◽  
Vol 21 (3) ◽  
pp. 288-291 ◽  
Author(s):  
G. A. Jansen ◽  
S. Ferdinandusse ◽  
O. H. Skjeldal ◽  
O. Stokke ◽  
C. J. De Groot ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Refsum Disease ◽  
Disease Identification ◽  
New Mutations

Molecular basis of Refsum disease: Sequence variations in Phytanoyl-CoA Hydroxylase (PHYH) and the PTS2 receptor (PEX7)

2004 ◽  
Vol 23 (3) ◽  
pp. 209-218 ◽  
Author(s):  
Gerbert A. Jansen ◽  
Hans R. Waterham ◽  
Ronald J. A. Wanders
Keyword(s):  
Molecular Basis ◽  
Refsum Disease ◽  
Sequence Variations

Molecular Basis of Genomic Instability and Progression in Multiple Myeloma: Potential Role of Apurinic (Apyrimidinic) Endonuclease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1561-1561
Author(s):  
Masood A. Shammas ◽  
Hemanta Koley ◽  
Paola Neri ◽  
Pierfrancesco Tassone ◽  
Ramesh B. Batchu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Genomic Instability ◽  
Cell Lines ◽  
Molecular Basis ◽  
Endonuclease Activity ◽  
Ap Endonuclease ◽  
Myeloma Cells ◽  
Genome Wide ◽  
New Mutations

Abstract Genetic instability is a prominent feature of most cancers including multiple myeloma (MM) and is responsible for ongoing accrual of mutational changes which may lead to development of drug resistance and metastasis. The molecular basis for the generation of genetic diversity in MM is therefore extremely important to understand carcinogenesis and to identify novel targets for treatment. As genomic rearrangements require excision of DNA, we hypothesized that an elevated endonuclease activity may induce recombination and subsequent genomic instability in cancer cells. We developed a plasmid degradation assay that confirmed significantly elevated endonuclease activity in MM cells compared to normal plasma cells. To identify the pre-dominating endonuclease the degradation assay was carried out in the presence of specific endonuclease inhibitors, which identified apurinic/apyrimidinic endonuclease (Ape1 and Ape2) as the predominant endonucleases in mediating increased endonuclease activity in MM. Gene expression analysis confirmed > 2 fold elevation of Ape1 or Ape2 or both in 5 of 6 MM cell lines and 12 of 15 patient samples. Both immunocytochemistry and western blot analyses confirmed upregulation of Ape1 protein in all MM cell lines and patient samples. Next, we investigated the role of elevated APE endonuclease activity in DNA recombination and subsequent genomic re-arrangements. Using a plasmid-based assay we have previously demonstrated significantly elevated homologous recombination (HR) in MM. To investigate the role of elevated AP endonuclease activity in MM, we cultured myeloma cells in the presence of methoxyamine (MX), which specifically inhibits AP endonuclease activity, and evaluated its effect on HR activity and genome-wide appearance of new mutations. Exposure of intact myeloma cells to MX resulted in > 90% inhibition of HR activity and a significant (71±10.9%; p<0.05) reduction in the appearance of new mutations compared to untreated cells, as assessed by genome-wide loss of heterozygosity (LOH) assay (Affymetrix). We also evaluated the effects of overexpression of Ape1 & 2 in normal fibroblasts which have low endonuclease activity. The transgenic upregulation of AP endonucleases (Ape1 and Ape2) in normal cells led to a significant increase in the lecombination activity, leading to a marked mutational instability as indicated by the appearance of over 20,063 and 20,143 new LOH loci per 100,000 polymorphic regions examined throughout the genome, at population doublings 25 and 50 respectively. Mutational instability was also associated with chromosomal instability confirmed by spectral karyotyping of these cells showing significant numerical and structural chromosomal abnormalities. These changes were associated with indefinite growth of cells and formation of tumors when injected in SCID mice. These data suggest that elevated AP endonuclease may be responsible for mutational and chromosomal instabilities, leading to progression of myeloma.

Gaucher disease: Identification of three new mutations in the Korean and Chinese (Taiwanese) populations

1996 ◽  
Vol 7 (3) ◽  
pp. 214-218 ◽  
Author(s):  
Jong-Won Kim ◽  
Benjamin B. Liou ◽  
Ming-Yang Lai ◽  
Elvira Ponce ◽  
Gregory A. Grabowski
Keyword(s):  
Gaucher Disease ◽  
Disease Identification ◽  
New Mutations

scholarly journals Thalassemias and Other Hemoglobinopathies in Former Yugoslavia

2008 ◽  
Vol 11 (1) ◽  
pp. 11-26
Author(s):  
G Efremov
Keyword(s):  
Molecular Basis ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Former Yugoslavia ◽  
Molecular Defect ◽  
Molecular Analyses ◽  
Hereditary Persistence ◽  
Β Chain ◽  
Codon Mutation ◽  
New Mutations

Thalassemias and Other Hemoglobinopathies in Former YugoslaviaThis review summarizes our results on the epidemiology and molecular basis of thalassemias and other hemoglobinopathies in the republics and provinces of the Former Yugoslavia. Over the past 40 years, surveys of more than 37,000 school children and more than 1,600 adults, from all over Former Yugoslavia, except Slovenia, have shown an average incidence of β-thalassemia (β-thal) trait of 1.2%, ranging from 2.9% in the south (Macedonia) to 0.8% in the northwest (Croatia). The frequency of δβ-thal was 0.2%, while that of Swiss type hereditary persistence of fetal hemoglobin (HPFH) was 0.4%. Screening of 12,680 newborns has shown that the frequency of α-thal trait was 1.5%. The molecular basis of the thalassemias in the populations of Former Yugoslavia has been completely defined. More than 700 β-thal chromosomes have been studied and their molecular defect was determined. In the Macedonian population, 16 different β-thal mutations were detected, four of which (IVS-I-110, G→A; IVS-I-6, T>C; IVS-I-1, G>A and codon 39, C>T) accounted for 85% of all β-thal chromosomes. In the Croatian population, 18 different β-thal alleles were detected. Four new mutations [nucleotide (nt) -87, C>A; IVS-II-850, G>C; initiation codon mutation T>C; polyadenylation signal (poly A), AATAAA>AATGAA)] and one new deletion (1605 bp), were characterized. Molecular analyses of DNA from over 50 unrelated cases with δβ-thal have shown that this condition was mainly caused by a 13 kb deletion (Sicilian type); in one family, a deletion of >18 to 23 kb (Macedonian-Turkish type), and in another, a deletion of 148 kb (Yugoslavian type of εγδβ-thal) of the β-globin gene complex, were discovered. Molecular analyses of α-thal from Former Yugoslavia revealed the following defects: the -20.5, -17.5 and -3.7 kb deletions, a 5 nt deletion, and Hb Icaria [α142, Term→Lys (TAA>TCA in α2)]. The incidence of abnormal hemoglobins (Hbs) in Former Yugoslavia was 0.3%. Five different α chain variants in 16 families, 16 different β chain variants in 61 families, one δ chain variant in one family, two types of Hb Lepore in 122 families and two γ chain variants, have been characterized.

Glanzmann’s Thrombasthenia: Identification of 19 New Mutations in 30 Patients

2002 ◽  
Vol 87 (06) ◽  
pp. 1034-1042 ◽  
Author(s):  
Giovanna D’Andrea ◽  
Donatella Colaizzo ◽  
Gennaro Vecchione ◽  
Elvira Grandone ◽  
Giovanni Di Minno ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Autosomal Recessive ◽  
Wide Spectrum ◽  
Bleeding Tendency ◽  
Missense Mutations ◽  
Conserved Residues ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia ◽  
New Mutations

SummaryGlanzmann’s thrombasthenia (GT) is a genetically heterogeneous autosomal recessive syndrome associated with a bleeding tendency. To elucidate molecular basis of GT we have screened for mutations 30 GT patients. On the whole, 21 different candidate causal mutations, 17 in the αIIb and 4 in the β3 gene have been found. Only two (αIIb Pro145Ala and IVS3(−3)-418del) have been previously reported. Nine mutations (42.9%) were likely to produce truncated proteins, whereas the remaining 12 were missense mutations that affected highly conserved residues in αIIb and β3 genes. Six mutations were found in different patients suggesting a possible founder effect. The wide spectrum of expressivity, ranging from mild to severe also among patients carrying the same mutations, provided evidence for a role of different loci or circumstantial factors. In conclusion, we have identified a spectrum of unreported mutations that may be of value to unravel the role of specific regions of αIIb and β3 genes.

scholarly journals Identification of Residues in Fission Yeast and Human p34cdc2 Required for S-M Checkpoint Control

Genetics ◽  
1996 ◽  
Vol 144 (4) ◽  
pp. 1413-1424
Author(s):  
Gabriele Basi ◽  
Tamar Enoch
Keyword(s):  
Cell Proliferation ◽  
Protein Expression ◽  
Fission Yeast ◽  
Molecular Basis ◽  
Normal Cell ◽  
Checkpoint Control ◽  
Checkpoint Pathway ◽  
Yeast Regulation ◽  
New Mutations

In fission yeast, regulation of p34cdc2 plays an important role in the checkpoint coupling mitosis to completion of DNA replication. The cdc2 mutations cdc2-3w (C67Y) and cdc2-4w (C67F) abolish checkpoint control without seriously affecting normal cell proliferation. However the molecular basis of this phenotype is not known. To better understand the role of p34cdc2 in checkpoint control, we have screened for more mutations in Schizosaccharomyces pombe cdc2 with this phenotype. We have isolated cdc2-3w and cdc2-4w, as well as three new cdc2 alleles: cdc2-6w (N66I), cdc2-7w (E8V) and cdc2-8w (K9E). The altered residues map to two different regions on opposite faces of the protein, suggesting that the interaction between p34cdc2 and components of the checkpoint pathway may be complex. In contrast to cdc2-3w and cdc2-4w, the new mutations alter residues that are conserved between the fission yeast cdc  + and other cdks, including the human CDC2 protein. Expression of the equivalent human CDC2 mutants in fission yeast abolishes checkpoint control, suggesting that these residues could be involved in checkpoint-dependent regulation of other eukaryotic cdks.

Molecular basis of acid ceramidase deficiency in a neonatal form of Farber disease: Identification of the first large deletion in ASAH1 gene

2013 ◽  
Vol 109 (3) ◽  
pp. 276-281 ◽  
Author(s):  
Mariana Q. Alves ◽  
Emmanuelle Le Trionnaire ◽  
Isaura Ribeiro ◽  
Stéphane Carpentier ◽  
Klaus Harzer ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Large Deletion ◽  
Acid Ceramidase ◽  
Farber Disease ◽  
Disease Identification ◽  
Ceramidase Deficiency
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