Gene/Protein Disease Symptom Drug Enzyme Compound
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A great deal of information is currently available on the Internet concerning the complex and life-threatening genetic disorder cystic fibrosis (CF). The disease is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). World Wide Web (WWW) sites offer a range of information from gene structure and function to individual discussion groups. Specifically, they allow access to CFTR nucleic predicted protein sequences, pages for medical doctors and researchers, and support-group sites directed towards CF patients, their families and friends.
Mol Med Today 1996 Apr
PMID:Cystic fibrosis resources on the World Wide Web. 879 75

Severe glutathione synthetase (GS) deficiency is a rare genetic disorder with neonatal onset. The enzymatic block of the gamma-glutamyl cycle leads to a generalized glutathione deficiency. Clinically affected patients present with severe metabolic acidosis, 5-oxoprolinuria, increased rate of hemolysis and defective function of the central nervous system. The disorder is inherited in an autosomal recessive mode and, until recently, the molecular basis has remained unknown. We have sequenced 18 GS alleles associated with enzyme deficiency and we detected missense mutations by direct sequencing of cDNAs and genomic DNA. In total, 13 different mutations were identified. Four patients were found to be compound heterozygotes and two individuals were apparently homozygous. Reduced enzymatic activities were demonstrated in recombinant protein expressed from cDNAs in four cases with different missense mutations. The results from biochemical analysis of patient specimens, supported by the properties of the expressed mutant proteins, indicate that a residual activity is present in affected individuals. Our results suggest that complete loss of function of both GS alleles is probably lethal. It is postulated that missense mutations will account for the phenotype in the majority of patients with severe GS deficiency.
Hum Mol Genet 1997 Jul
PMID:Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction. 921 86

This paper reviews the relationship between mutations in the cystic fibrosis (CF) gene (CFTR mutations) and congenital bilateral absence of the vas deferens (CBAVD). Two CFTR mutations were identified in 14.5% of the 449 man with CBAVD thus far reported in the literature while one CFTR mutation was found in another 48.1%. CBAVD appears to be a heterogeneous genetic condition, many cases being mild forms of cystic fibrosis, others having no relationship with CF. The 5T allele has also been found in 46% of men with CBAVD, but is not associated by the 'classical' picture of cystic fibrosis. The role of the CFTR gene presumably extends beyond a normal development of the vas deferens, possibly playing a role in spermatogenesis. The detection of CFTR mutations in CBAVD had considerable implications in genetic counselling. Couples requesting microsurgical epididymal sperm aspiration/in-vitro fertilization and those in which the man has CF should be offered CFTR mutations screening if CBAVD is the cause of the male infertility.
Mol Hum Reprod 1996 Sep
PMID:Mutations in the cystic fibrosis gene in men with congenital bilateral absence of the vas deferens. 923 81

Mutation of the essential Schizosaccharomyces pombe rad4/cut5 gene causes sensitivity to UV and ionising radiation at the permissive temperature whilst at the restrictive temperature cells fail to undergo DNA replication but still attempt mitosis owing to a defective S-phase checkpoint response. Many mutations in genes encoding DNA replication proteins also abolish checkpoint responses, possibly because the replication machinery is a pre-requisite for the generation of the signal. We demonstrate here that rad4/cut5 cells fail to arrest cell division when treated with the replication inhibitor hydroxyurea at the semi-permissive temperature 32 degrees C, but retain essentially normal replicative capacity. This demonstrates that the replication and checkpoint function of the rad4/cut5 gene product can be separated and that the Rad4 protein differs from other replication proteins in being directly involved in generating the S-phase checkpoint signal. Furthermore, we have investigated the checkpoint response or rad4/cut5-deficient cells to gamma-irradiation and UV-mimetic drugs. We find that, at the restrictive temperature, the rad4-/cut5- cells fail to delay mitosis in response to gamma-irradiation whilst retaining a normal checkpoint response to the UV-mimetic drug 4-nitroquinoline-1-oxide. The lack of the gamma-irradiation checkpoint is reminiscent of the deficiency associated with mutation of the human ATM locus, the causative deficiency of the heritable disorder ataxia telangiectasia. The implications of our results for the organisation of distinct checkpoint-response pathways in both fission yeast and mammalian cells are discussed. Moreover the data are consistent with a model in which the generation of the S-Phase checkpoint signal is DNA polymerase epsilon dependent.
Mol Gen Genet 1997 Jul
PMID:Characterisation of the Schizosaccharomyces pombe rad4/cut5 mutant phenotypes: dissection of DNA replication and G2 checkpoint control function. 926 24

PKD1 is the major locus of the common genetic disorder autosomal dominant polycystic kidney disease (ADPKD). Analysis of the predicted protein sequence of the human PKD1 gene, polycystin, shows a large molecule with a unique arrangement of extracellular domains and multiple putative transmembrane regions. The precise function of polycystin remains unclear with a paucity of mutations to define key structural and functional domains. To refine the structure of this protein we have cloned the genomic region encoding the Fugu PKD1 gene. Fugu PKD1 spans 36 kb of genomic DNA and has greater complexity with 54 exons compared with 46 in man. Comparative analysis of the predicted protein sequences shows a lower level of homology than in similar studies with identity of 40 and 59% similarity. However key structural motifs including leucine rich repeats (LRR), a C-type lectin and LDL-A like domains and 16 PKD repeats are maintained. A region of homology with the sea urchin REJ protein was also confirmed in Fugu but found to extend over 1000 amino acids. Several highly conserved intra- and extra-cellular regions, with no known sequence homologies, that are likely to be of functional importance were detected. The likely structure of the membrane associated region has been refined with similarity to the PKD2 protein and voltage gated Ca2+ and Na+ channels highlighted over part of this area. The overall protein structure has therefore been clarified and this comparative analysis derived structure will form the basis for the functional study of polycystin and its individual domains.
Hum Mol Genet 1997 Sep
PMID:Comparative analysis of the polycystic kidney disease 1 (PKD1) gene reveals an integral membrane glycoprotein with multiple evolutionary conserved domains. 928 85

Non-syndromic neurosensory autosomal recessive deafness (NSRD) is the most common form of genetic hearing loss. Previous studies defined at least 15 human NSRD loci. Recently we demonstrated that DFNB1, located on the long arm of chromosome 13, accounts for approximately 80% of cases in the Mediterranean area. Further analysis with additional markers now identifies several recombinants which narrow the candidate region to approximately 5 cM, encompassed by markers D13S141 and D13S232 and including several ESTs and candidate genes, including the connexin26 (GJB2) gene. Analysis of PCR products from our affected patients' DNA shows two frameshift mutations in the connexin26 gene. Deletion of a G within a stretch of six Gs at position 35 of the GJB2 cDNA (mutation 35delG) leads to premature chain termination and is present in 63% of NSRD chromosomes, demonstrating linkage to chromosome 13. Deletion of a T at position 167 of GJB2 (mutation 167delT), also resulting in premature chain termination, was detected in another patient. Four neutral sequence polymorphisms were also identified. These findings are in agreement with a recent study showing that mutations in the connexin26 gene are associated with genetic forms of deafness in three Pakistani families and that GJB2 is DFNB1. Connexin26 is a member of a large family of proteins involved in formation of gap junctions, which are involved in electrical synapses and the direct transfer of small molecules and ionic currents between neighboring cells. The identification of GJB2 as the DFNB1 gene should provide a better understanding of the biology of normal and abnormal hearing, help form the basis for diagnosis and may facilitate development of strategies for treatment of this common genetic disorder.
Hum Mol Genet 1997 Sep
PMID:Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. 928

Neurofibromatosis type 1 (NF1) is a common genetic disorder which predisposes affected individuals to a variety of clinical features including tumors of the central and peripheral nervous systems. The product of the NF1 gene, neurofibromin, is a tumor suppressor which most likely acts through the interaction of its GTPase activating protein (GAP) related domain (GRD) with RAS to regulate cellular growth. Two intriguing features of NF1 are the wide range of potentially affected tissues and the great variation in expressivity of disease traits across those affected. To date, the underlying source of this variation remains somewhat unclear, but evidence suggests that aberrations in normal NF1 RNA processing may be involved. This evidence includes: (i) differences in the relative ratios of the type I and type II splice variants in NF1 tumors compared with nontumor tissues; (ii) unequal expression of mutant and normal NF1 alleles in cultured cells derived from NF1 patients; (iii) the existence of NF1 tumors which display NF1 mRNA editing levels that are greater than that seen in non-NF1 tumors; and (iv) tissue-specific and developmental stage-specific expression of particular alternative NF1 transcripts. These findings suggest that the classical 2-hit model for tumor suppressor inactivation used to explain NF1 tumorigenesis can be expanded to include the post-transcriptional mechanisms which regulate NF1 gene expression. Aberrations in these mechanisms may lead to the pathogenesis of NF1 and may play a role in the observed clinical variability.
Hum Mol Genet 1997
PMID:RNA processing and clinical variability in neurofibromatosis type I (NF1). 930 Jun 63

Craniofrontonasal syndrome (CFNS, OMIM 304110) is a distinctive genetic disorder whose main clinical manifestations include coronal synostosis, widely spaced eyes, clefting of the nasal tip and various skeletal anomalies. CFNS originally was thought to be transmitted as an autosomal dominant trait, but recent studies suggest that it is X-linked dominant, whereby all daughters of males are affected, whereas none of their sons are affected. Here we report data confirming that CFNS is X-linked, mapping to a 13 cM interval in Xp22 with a maximum two-point lod score of 3.9 (theta = 0) at DXS8022 and a multipoint lod score of 5.08 at DXS1224. Detailed phenotypic analysis shows that females are more severely affected than males, a highly unusual characteristic for an X-linked disorder. CFNS represents the first multiple congenital anomaly syndrome with this unusual phenotypic pattern of X-linked inheritance.
Hum Mol Genet 1997 Oct
PMID:A novel phenotypic pattern in X-linked inheritance: craniofrontonasal syndrome maps to Xp22. 930 74

Canavan disease (CD), a rare recessive autosomal genetic disorder, is characterized by early onset and a progressive spongy degeneration of the brain involving loss of the axon's myelin sheath. After a relatively normal birth, homozygous individuals generally develop clinical symptoms within months, and usually die within several years of the onset of the disease. A biochemical defect associated with this disease results in reduced activity of the enzyme N-acetyl-L-aspartate amidohydrolase (aspartoacylase) and affected individuals have less ability to hydrolyze N-acetyl-L-asparate (NAA) in brain and other tissues. As a result of aspartoacylase deficiency, NAA builds up in extracellular fluids (ECF) and is excreted in urine. From an analysis of the NAA biochemical cycle in various tissues of many vertebrate species, evidence is presented that there may be two distinct NAA circulation patterns related to aspartoacylase activity. These include near-field circulations in the brain and the eye, and a far-field systemic circulation involving the liver and kidney, the purpose of which in each case is apparently to regenerate aspartate (Asp) in order for it to be recycled into NAA as part of the still unknown function of the NAA cycle. Based on the authors' analysis, they have also identified several metabolic outcomes of the genetic biochemical aspartoacylase lesion. First, there is a daily induced Asp deficit in the central nervous system (CNS) that is at least six times the static level of available free Asp. Second, there is up to a 50-fold drop in the intercompartmental NAA gradient, and third, the ability of the brain to perform its normal intercompartmental cycling of NAA to Asp is terminated, and as a result, the only remaining long-term source of Asp for NAA synthesis is via nutritional supplementation of Asp or its metabolic precursors. Finally, the authors identify a potential maternal-fetal interaction that may be responsible for observed normal fetal development in utero, and that provides a rationale for, and suggests how, CD might respond to far-field nutritional, transplantation, or genetic engineering techniques to alter the course of the disease.
J Mol Neurosci 1997 Oct
PMID:Canavan disease. Analysis of the nature of the metabolic lesions responsible for development of the observed clinical symptoms. 940 92

Cystic fibrosis is the most common life-threatening autosomal recessive genetic disorder in Caucasian populations. It is a disease primarily of epithelial tissues, including the airway, pancreatic duct, intestine, genital tract and sweat glands. The affected gene was cloned and characterized in 1989. In the absence of an identified natural animal model of the disease, a major effort has been made to develop transgenic cystic fibrosis mice, by disrupting the gene in these laboratory animals. Such mice show many, but not all, of the symptoms of cystic fibrosis. In this article, the major past and present contributions of other animal systems to our understanding of cystic fibrosis are examined and their potential for future studies of this disease are discussed. It is intended to give the reader a broad overview of the field, exploring the usefulness of animal studies, rather than dealing more fully with specific aspects of cystic fibrosis.
Mol Med Today 1995 Oct
PMID:Animal studies of cystic fibrosis. 941 74


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