Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Molecular genetic analysis of five cases of 3p- syndrome (del(3)(qter-->p25:)) was performed to investigate the relationship between the molecular pathology and clinical phenotype. Fluorescence in situ hybridization studies and analysis of polymorphic DNA markers from chromosome 3p25-p26 demonstrated that all four informative cases had distal deletions. However, the extent of the deletion was variable: in two patients with the most extensive deletions the deletion breakpoint mapped between RAF1 and D3S1250, in one patient the deletion breakpoint was between D3S1250 and D3S601, and in two patients the deletion commenced telomeric to D3S601 (and telomeric to D3S1317 in one of these). All five patients displayed the classical features of 3p- syndrome (mental retardation, growth retardation, microcephaly, ptosis and micrognathia) demonstrating that loss of sequences centromeric to D3S1317 is not required for expression of the characteristic 3p- syndrome phenotype. The three patients with the most extensive deletions had cardiac septal defects suggesting that a gene involved in normal cardiac development is contained in the interval D3S1250 and D3S18. The PMCA2 gene is contained within this region and deletion of this gene may cause congenital heart defects. At least three patients were deleted for the von Hippel-Lindau (VHL) disease gene although none had yet developed evidence of VHL disease. We conclude that molecular analysis of 3p- syndrome patients enhances the management of affected patients by identifying those at risk for VHL disease, and can be used to elucidate the critical regions for the 3p- syndrome phenotype.
Hum Mol Genet 1994 Jun
PMID:Molecular genetic analysis of the 3p- syndrome. 795 Dec 34

We previously described sequence tags from 58 novel directionally cloned human cDNAs from an enriched retinal pigment epithelial cell line library (Gieser and Swaroop, 1992). The nucleotide sequence of one of the cDNA clones, AA35 (D3S1231E), showed strong homology to the yeast SEC13 gene, required for vesicle biogenesis from endoplasmic reticulum during the transport of proteins. We have designated the human gene SEC13R (SEC13-Related). The amino acid sequence of the SEC13R gene product shows 70% similarity to yeast Sec13p, suggesting that SEC13R may be the human homolog of SEC13. The deduced polypeptide sequence contains several beta-transducin like 'WD40' repeats, and is rich in serine and threonine residues. The 1.4 kb transcript of SEC13R is detected by Northern analysis in many human tissues. However, RT-PCR analysis using two primer sets from different regions of the gene suggests differential expression of alternately spliced transcripts in various tissues. Somatic cell hybrid and in situ hybridization studies localized the SEC13R gene to human chromosome 3p24-p25. A related sequence was mapped to chromosome 18q11.2-q12. SEC13R was physically mapped to a yeast artificial chromosome (YAC) clone spanning the D3S720 marker from the region of the Von Hippel-Lindau disease locus. The mouse Sec13r gene was mapped to the conserved linkage group on chromosome 6 that corresponds to human chromosome 3p24-p25.
Hum Mol Genet 1994 Aug
PMID:Molecular characterization of a novel human gene, SEC13R, related to the yeast secretory pathway gene SEC13, and mapping to a conserved linkage group on human chromosome 3p24-p25 and mouse chromosome 6. 798 3

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms, most frequently retinal, cerebellar and spinal haemangioblastoma, renal cell carcinoma, phaeochromocytoma and pancreatic tumours. We have previously detected large germline deletions by Southern analysis and pulsed field gel electrophoresis in 19% and 3% of VHL patients respectively. We have now investigated 94 VHL patients without large deletions for intragenic mutations using single strand conformation polymorphism and heteroduplex analysis. Forty different mutations were identified in 55 unrelated kindreds. A wide variety of mutations were detected including missense (n = 19), nonsense (n = 6), frameshift deletions or insertions (n = 12), in frame deletions (n = 2) and a splice donor site mutation (n = 1). The two most frequent mutations, were missense mutations at codon 238 (Arg-->Gln and Arg-->Trp) and were detected in five and four unrelated kindreds, respectively. VHL disease shows marked phenotypic variability and although phaeochromocytoma occurs in only about 7% of patients, marked interfamilial differences are observed. We examined the relationship between VHL gene mutations and phenotype in 65 kindreds. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without phaeochromocytoma but only two of 12 families with phaeochromocytoma (chi 2 = 8.58; P < 0.01). Of 12 families with phaeochromocytoma 10 had missense mutations compared with 13 of 53 kindreds without phaeochromocytoma (chi 2 = 12.33; P < 0.001). In particular, substitution of an arginine at codon 238 (Arg-->Trp or Arg-->Gln) was associated with a high risk (62%) of phaeochromocytoma.(ABSTRACT TRUNCATED AT 250 WORDS)
Hum Mol Genet 1994 Aug
PMID:Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. 798 6

Von Hippel-Lindau disease is a dominantly inherited familial cancer syndrome characterised by the development of retinal angiomatosis, cerebellar and spinal hemangioblastoma, renal cell carcinoma, phaeochromocytoma and pancreatic tumours. A cDNA (g7) which detects frequent genomic rearrangements in VHL disease patients on Southern analysis, and contains the partial coding sequence of the VHL gene has been isolated recently. To characterise the nature of the genomic rearrangements in VHL disease we initially screened 116 patients with VHL disease and identified 22 patients (19%) with abnormal fragments in EcoR1 digested DNA probes with g7. We then established that the coding sequence contained within g7 is represented in 3 exons, and design exon specific probes to investigate the 22 patients with genomic rearrangements. All 22 patients were demonstrated to have germline deletions, but the deletions were heterogeneous with 7 patients having deletions confined to the 5' exon 1, and 8 with nonoverlapping deletions of exon 3. In 7 unrelated patients, including 2 new mutations, the germline deletions were similar in size and position. There was no relationship between the clinical phenotype and the deletion of individual exons. Although phaeochromocytoma was less frequent in kindreds with germline deletions than those without detectable deletions, the difference was not statistically significant (1/19 versus 16/72 respectively, chi 2 = 1.84 p > 0.1).
Hum Mol Genet 1994 Apr
PMID:Detailed mapping of germline deletions of the von Hippel-Lindau disease tumour suppressor gene. 806 5

Von Hippel Lindau disease (VHL) is a rare autosomal dominant disease associated with tumors and cysts in multiple organ systems. The VHL disease gene is tightly linked to the polymorphic DNA marker 233E2 (D3S720) and flanked by 479H4 (D3S719) on its telomeric and RAF1 on its centromeric side. Two additional markers, D3S1038 and D3S601, have also been identified, and these markers, like D3S720, are very tightly linked to VHL. Previously 93 cosmid clones were mapped to the larger region, 3p24.2-pter, surrounding the VHL disease gene. Using a Southern-based screening strategy on pools of YAC clones we have isolated a contig of overlapping YAC clones that extends about 0.7 megabase centromeric, and about 1.3 megabases telomeric of D3S720 and contains all three tightly linked VHL markers. Individual YACs in this contig were hybridized to grids containing cosmids localized between 3p24.2-pter and to several cosmids localized by fluorescent in situ hybridization (FISH) to 3p25. A total of 28 cosmids were positioned on this contig of overlapping YAC clones. We have also identified homologous YAC clones to many additional cosmid clones localized between 3p24.2-p25, although these have not yet been precisely localized relative to the contig of YAC clones. This contig of YAC clones probably contains the VHL disease gene and should facilitate the isolation and characterization of this gene.
Hum Mol Genet 1993 Aug
PMID:The isolation of a yeast artificial chromosome (YAC) contig extending for 2 megabases in the vicinity of the von Hippel Lindau disease gene. 810 27

A simple user-friendly computer programme has been developed to operate on an IBM-PC compatible machine to aid in the process of curve fitting using the McGhee and von Hippel equation [J. Mol Biol, 86 (1974), 469-489] for the analysis of ligand-DNA interactions and the experimental data on berberine-calf thymus DNA and berberine-poly(dI-dC). poly(dI-dC) for non-cooperative binding. A sensitivity analysis on binding constant (K0) and the number of binding sites (N0) show that a small variation in the latter remarkably alters the fitting curve. At a level of 1% change in N0 from the best fit value, the standard deviation grows by almost 4%, while, on the other hand, a 1% change in K0 affects the same value only by less than 0.4%.
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PMID:Sensitivity of non-cooperative binding parameters of ligand-DNA complex by computer analysis. 827 22

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome in which affected individuals have a greatly increased predisposition to the development of haemangioblastomas of the central nervous system and retina, renal cell carcinoma and phaeochromocytoma. The VHL gene has been mapped to chromosome 3p25-p26 by genetic linkage studies and we have previously demonstrated that the VHL gene is tightly linked to the D3S601 locus (Zmax = 18.86 at theta = 0.0) suggesting that D3S601 maps close to the VHL disease gene. We have constructed a long range physical map around D3S601 and screened 91 VHL patients from 80 kindreds for germline rearrangements using pulsed field gel electrophoresis. Two patients showed abnormal fragments in Mlul digested DNA probed with D3S601. Further analysis was consistent with both patients having germline deletions (approximately 120 kb and 50 kb) telomeric to D3S601. These results have (i) established the position of the VHL disease gene with respect to D3S601, (ii) refined the localisation of the VHL disease gene to a small region (approximately 50 kb) of chromosome 3p25-p26 and (iii) excluded the plasma membrane Ca(+)+-transporting ATPase isoform 2 (PMCA-2) gene as a candidate gene for VHL disease.
Hum Mol Genet 1993 Jul
PMID:Mapping the Von Hippel-Lindau disease tumour suppressor gene: identification of germline deletions by pulsed field gel electrophoresis. 836 70

With a view toward further understanding the structure-function relationships of the eukaryotic heterogeneous ribonucleoprotein (hnRNP) A1, and in particular its multiplicity of nucleic acid-interactive domains, we have studied the nucleic acid binding properties of the globular N-domain (UP1) and sequence-repetitive, flexible C-domain, the thermal denaturation of UP1 and the concomitant effects of binding polynucleotide, and the self-associative properties of the full-length protein. Utilizing protein tryptophan fluorescence as a probe, polynucleotide binding was shown to stabilize UP1 against thermal unfolding. The denaturation profile of UP1-poly(thymidylic acid) complexes was biphasic, suggesting that unfolding of the two subdomains of UP1 can occur independently. This is in agreement with a previously proposed structure in which only one of the two UP1 subdomains binds the nucleic acid. The subdomains of UP1 can be prepared by controlled proteolysis of A1, further indicating that these two globular segments within A1 are connected by an exposed, flexible linkage. Circular dichroism measurements on UP1 confirm previous data that this portion of A1 binds single-stranded nucleic acids non-co-operatively. UP1 clearly shows a preference for single-stranded nucleic acids with a 2'-OH, since its affinity for poly(U) is three times higher than for poly(dU), and five times higher than its affinity for poly(2'-OCH3U). The nucleic acid-interactive properties of the C-domain were further examined by preparing a synthetic peptide polymer (M(r) approximately 12,000) containing about seven repeats of a 16-residue sequence, GNFGGGRGGNYGGSRG, which in turn comprises two copies of the C-terminal consensus, GN(F/Y)GG(G/S)RG. The polymer of this sequence exhibited significant affinity for the fluorescent polyribonucleotide, poly(ethenoadenylic acid), binding stoichiometrically at < or = 0.2 M-Na+. Complex formation was accompanied by an increase in aggregate formation, as indicated by the appearance of scattering. For purposes of comparison, the data were analyzed via the linear co-operative model of McGhee and von Hippel, though this model may not be fully descriptive of the protein-nucleic acid complex(es) formed in this case. In contrast to the non-co-operative binding mode of the UP1 domain, the C-polymer exhibited moderate co-operativity, comparable to that seen with full-length A1. Although addition of sufficient NaCl reversed the interaction, a sigmoidal binding isotherm could still be observed (with sufficient added polymer) at 0.8 M-NaCl. This suggests that non-electrostatic interactions contribute significantly to the free energy of binding.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Biol 1993 Feb 20
PMID:Mammalian heterogeneous ribonucleoprotein A1 and its constituent domains. Nucleic acid interaction, structural stability and self-association. 844 53

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome characterised by the development of retinal and central nervous system haemangioblastomas, renal cell carcinoma and phaeochromocytoma. The gene for VHL disease has been mapped to chromosome 3p25-p26 and presymptomatic diagnosis using linked DNA markers is available. We have previously mapped the VHL disease gene to a 4 cM interval between D3S1250 and D3S18. To increase access to presymptomatic diagnosis and to accelerate progress towards isolating the VHL disease gene we attempted to identify microsatellite DNA markers linked to the disease gene by genetic linkage analysis in 29 families. We found significant linkage between the VHL disease gene and dinucleotide (CA) repeat polymorphisms at D3S1038 (Zmax = 22.24 at theta = 0.01, CI 0.0001-0.06), D3S1110 (Zmax = 11.32 at theta = 0.07, CI 0.03-0.14) and D3S651 (Zmax = 7.73 at theta = 0.04, CI 0.008-0.13). We localised D3S1038 between D3S1250 and D3S601, and mapped D3S1110 and D3S651 centromeric to D3S1250. Multipoint linkage analysis mapped the VHL disease locus between D3S1038 and D3S18 with the maximum likelihood at D3S601. There was no evidence of locus heterogeneity. This study has (i) identified three microsatellite DNA markers in chromosome 3p25 linked to the VHL disease gene and (ii) narrowed the target region for the isolation of the VHL disease gene by positional cloning techniques. These findings will improve the management of families with VHL disease by improving the accuracy and availability of presymptomatic diagnosis using linked DNA markers, and will accelerate progress towards isolating the VHL disease gene.
Hum Mol Genet 1993 Mar
PMID:Genetic linkage between von Hippel-Lindau disease and three microsatellite polymorphisms refines the localisation of the VHL locus. 849 17

VHL disease is a dominantly inherited familial cancer syndrome with variable expression and age-dependent penetrance. The diagnosis of isolated cases is often delayed compared with familial cases, and estimates of the new mutation rate have varied more than 20-fold. To investigate the frequency and origin of de novo VHL gene mutations we have analysed: (i) families with identical mutations to determine if there is a common haplotype, and (ii) apparent new mutation cases to determine whether the clinical diagnosis of such cases is reliable and to define the parental origin of de novo VHL gene mutations. Haplotyping of 12 VHL mutations occurring in two or more families (total 42 kindreds) revealed that for most mutations there was no evidence of a founder effect. A marked bias for a paternal origin of new mutations has been reported in other familial cancer syndromes such as neurofibromatosis type 1 (NF1), multiple endocrine neoplasia (MEN) 2B and bilateral retinoblastoma, but it is unclear whether this bias results from a greater susceptibility for mutagenesis during male gametogenesis because of the larger number of cell divisions compared with that in oogenesis, or from genomic imprinting effects. Analysis of 13 de novo VHL mutations in which the parent of origin could be established, showed no evidence for a bias for a paternal origin (seven paternal, six maternal), and differed significantly from that reported in NF1, MEN2B and bilateral retinoblastoma. This result demonstrates that an increased susceptibility to paternal allele mutation is not a universal finding in autosomal genetic diseases and that the origin of new mutations may be influenced by both genomic imprinting effects and the increased number of cell divisions in spermatogenesis compared with oogenesis.
Hum Mol Genet 1995 Nov
PMID:Molecular analysis of de novo germline mutations in the von Hippel-Lindau disease gene. 858 92


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