Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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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

A Schizosaccharomyces pombe homolog of mammalian genes encoding G protein beta subunits, gpb1+, was cloned by the polymerase chain reaction using primer pairs that correspond to sequences conserved in several G beta genes of other species followed by screening of genomic and cDNA libraries. The gpb1 gene encodes 317 amino acids that show 47% homology with human G beta 1 and G beta 2 and 40% homology with Saccharomyces cerevisiae G beta protein. Disruption of the gpb1 gene indicated that this gene is not required for vegetative cell growth. However, gpb1-disrupted haploid cells mated and sporulated faster than wild-type cells, both in sporulation (MEA) and in complex medium (YE): when examined 23 h after transfer to sporulation medium, 35% of gpb1-disrupted haploid pairs had undergone conjugation and sporulation, whereas only 3-5% of wild-type haploid pairs had done so. Overexpression of the gpb1 gene suppressed this facilitated conjugation and sporulation phenotype of gpb1-disrupted cells but did not cause any obvious effect in wild-type cells. Co-disruption of one of the two S. pombe G alpha-subunit genes, gpa2, in the gpb1-disrupted cells did not change the accelerated conjugation and sporulation phenotype of the gpb1- cells. However, co-disruption of the ras1 gene abolished the gpb1- phenotype. These results suggest that Gpb1 is a negative regulator of conjugation and sporulation that apparently works upstream of Ras1 function in S. pombe. The possible relationship of Gpb1 to two previously identified, putative G alpha proteins of S. pombe is discussed.
Mol Gen Genet 1996 Aug 27
PMID:The G protein beta subunit Gpb1 of Schizosaccharomyces pombe is a negative regulator of sexual development. 880

A 44-year-old women was treated for hyperparathyroidism resulting from parathyroid hyperplasia. Several months later, following a flu-like episode, she developed fever, confusion, abdominal pain, and diffuse petechiae, with severe thrombocytopenia and hemolytic anemia. She died on the 11th day of hospitalization. At autopsy she had multiple endocrine neoplasia type I, with two islet cell tumors, adrenal adenoma, pituitary adenoma, and bronchial carcinoid with liver metastasis. Florid visceral microthrombi involved arterioles and capillaries of the heart, including the conduction system. Brain, kidney, pancreas, adrenal, and portal areas of the liver were also heavily involved, but thrombi were rare in the liver sinusoids and the lungs. PAS-positive subendothelial deposits were demonstrated. In spite of the disseminated malignancy, the morphologic and laboratory findings were inconsistent with disseminated intravascular coagulation (DIC), and supported the clinical diagnosis of TTP. To the best of our knowledge this is the first report association of TTP with MEN and raises the question of a genetic linkage and/or hormonal interaction.
Hematopathol Mol Hematol 1996
PMID:Fatal thrombotic thrombocytopenic purpura (TTP) presenting concurrently with metastatic multiple endocrine neoplasia (MEN) type I. 887 34

Hirschsprung disease (HSCR) is a congenital disorder associated with the absence of intrinsic ganglion cells in the distal gastrointestinal tract. Recently, many missense, nonsense and frameshift mutations of the ret proto-oncogene were found in familial and sporadic cases of HSCR. Consistent with the view that the HSCR phenotype is the result of inactivation of Ret, the missense mutations detected in the tyrosine kinase domain were demonstrated to result in a marked decrease of the kinase activity of Ret. However, the effects of missense mutations found in the extracellular domain remain unknown. We now report that five mutations in the extracellular domain examined inhibit transport of the Ret protein to the plasma membrane. As a consequence, they significantly decreased the transforming activity of Ret with multiple endocrine neoplasia (MEN) 2A mutation for which cell surface expression is required. Our results also demonstrated that long segment HSCR mutations more severely impair transport of Ret to the plasma membrane than a short segment HSCR mutation, suggesting that the level of its cell surface expression may correlate to the HSCR phenotype.
Hum Mol Genet 1996 Oct
PMID:Mechanism of ret dysfunction by Hirschsprung mutations affecting its extracellular domain. 889 91

Multiple endocrine neoplasia type 1 (MEN 1) is inherited as an autosomal dominant disorder, characterized by neoplasia and hyperplasia in specific endocrine organs. The MEN 1 gene, which is most probably a tumor suppressor gene, has been localized to a region of approximately 900 kb on chromosome 11q13. The nuclear factor-kappa B (NF-kappa B) is a transcription factor with pleiotropic expression, which is involved in the regulation of expression of many cellular genes. The p50/p65 heterodimer is the most abundant form of NF-kappa B. The gene encoding the p65 subunit (NF-kappa B3/REL A) was recently localized in the 900-kb MEN 1 region and was considered a good candidate gene for MEN 1. The structure and nucleotide sequence of the NF-kappa B3 coding region in MEN 1 patients were compared with those of non-MEN 1 subjects, to determine the potential role of this gene in MEN 1 tumorigenesis. Southern blot analysis with constitutional DNA from probands of 14 independent MEN 1 families and DNA from four MEN 1 tumor specimens did not reveal any structural abnormality of the NF-kappa B3 gene. Direct sequencing of cDNAs from two affected subjects from 2 different MEN 1 families, as well as nucleotide sequence analysis of exon/intron boundaries in these patients, did not reveal MEN 1-specific point mutations or other small structural aberrations in the NF-kappa B3 gene. These results make it very unlikely that the NF-kappa B3 gene is the gene responsible for the development of MEN 1.
Biochem Mol Med 1997 Feb
PMID:Exclusion of the nuclear factor-kappa B3 (REL A) gene as candidate for the multiple endocrine neoplasia type 1 (MEN 1) gene. 906 84

Activating germline mutations in the cysteine-rich domain of the RET proto-oncogene are found in >92% of the cases of multiple endocrine neoplasia type 2A (MEN2A) and 85% of familial medullary thyroid carcinoma (FMTC). In virtually 100% of patients with identified mutations one of five cysteines is altered by a missense mutation. In a MEN2A family with 14 affected and 11 unaffected living members, hypercalcemia was diagnosed in eight patients and histological evaluation revealed parathyroid hyperplasia in all cases examined (10/10). No member of this family showed any evidence for the existence of pheochromocytoma. This is the first documentation of a family without pheochromocytoma but with a high incidence of parathyroid disease. Genetic analysis revealed the presence of an unusual heterozygous mutation in exon 11 of the RET proto-oncogene representing a duplication of 12 bp resulting in the insertion of four amino acids between codon 634 (Cys) and 635 (Arg), thus creating an additional cysteine residue.
Hum Mol Genet 1997 Apr
PMID:A duplication of 12 bp in the critical cysteine rich domain of the RET proto-oncogene results in a distinct phenotype of multiple endocrine neoplasia type 2A. 909 63

Inherited predisposition to phaeochromocytoma (MIM No 171300) occurs in multiple endocrine neoplasia type 2 (MEN 2) (MIM No 171400), von Hippel-Lindau (VHL) disease (MIM No 199300), and neurofibromatosis type 1 (NF1) (MIM No 162200). In addition, familial phaeochromocytoma alone has also been reported and we and others have identified germline VHL mutations in five of six kindreds analysed previously. Germline mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, and in the VHL tumour suppressor gene cause MEN 2 and VHL disease, respectively. To further investigate the genetics of phaeochromocytoma predisposition, we analysed three groups of patients with no evidence of VHL disease, MEN 2 or NF1: Group A, eight kindreds with familial phaeochromocytoma; Group B, two patients with isolated bilateral phaeochromocytoma; and Group C, six cases of multiple extra-adrenal phaeochromocytoma or adrenal phaeochromocytoma with a family history of neuroectodermal tumours. Germline missense VHL mutations were identified in three of eight kindreds with familial phaeochromocytoma. A germline VHL mutation was also characterised in one of the two patients with bilateral phaeochromocytoma. No VHL or RET mutations were detected in the final group of patients with multiple extra-adrenal phaeochromocytoma or adrenal phaeochromocytoma with a family history of neuroectodermal tumours. The absence of germline VHL and RET gene mutations in many of these families suggested that other phaeochromoeytoma susceptibility loci may exist. Glial cell line-derived neurotrophic factor (GDNF) has been recently identified as a natural ligand for RET. Thus, it seems plausible that GDNF is a good candidate gene to play a role in phaeochromocytoma susceptibility. We searched for germline mutations in GDNF in 16 cases of familial phaeochromocytoma (groups A, B and C) and looked for evidence of somatic change in GDNF in 28 sporadic phaeochromocytomas, 12 MEN 2 phaeochromocytomas and five VHL phaeochromocytomas. No GDNF mutations were identified in patients with familial phaeochromocytoma disease, but a c277C-->T (R93W) sequence variant was identified in one of 28 sporadic tumours. This candidate mutation was identified in the germline and tumour tissue but was not present in 104 control GDNF alleles. GDNF sequence variants including R93W have been suggested previously to represent low penetrance susceptibility mutations for Hirschsprung disease and the R93W was not identified in 376 control alleles studied by others. These findings suggest that although GDNF mutations do not appear to have a major role in the pathogenesis of familial or sporadic phaeochromocytomas, allelic variation at the GDNF locus may modify phaeochromocytoma susceptibility.
Hum Mol Genet 1997 Jul
PMID:Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL. 921 74

Familial multiple endocrine neoplasia type 1 (FMEN1) is an autosomal dominant trait characterized by tumors of the parathyroids, gastro-intestinal endocrine tissue, anterior pituitary and other tissues. We recently cloned the MEN1 gene and confirmed its identity by finding mutations in FMEN1. We have now extended our mutation analysis to 34 more unrelated FMEN1 probands and to two related states, sporadic MEN1 and familial hyperparathyroidism. There was a high prevalence of heterozygous germline MEN1 mutations in sporadic MEN1 (8/11 cases) and in FMEN1 (47/50 probands). One case of sporadic MEN1 was proven to be a new MEN1 mutation. Eight different mutations were observed more than once in FMEN1. Forty different mutations (32 FMEN1 and eight sporadic MEN1) were distributed across the MEN1 gene. Most predicted loss of function of the encoded menin protein, supporting the prediction that MEN1 is a tumor suppressor gene. No MEN1 germline mutation was found in five probands with familial hyperparathyroidism, suggesting that familial hyperparathyroidism often is caused by mutation in another gene or gene(s).
Hum Mol Genet 1997 Jul
PMID:Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. 921 89

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by tumours of the parathyroids, pancreas and anterior pituitary that represents one of the familial cancer syndromes. The MEN1 locus has been previously localised to chromosome 11q13, and a <300 kb gene-rich region flanked centromerically by PYGM and telomerically by D11S1783 defined by combined meiotic and tumour deletion mapping studies. Two candidate genes, ZFM1 and PPP2R5B, from this region have been previously excluded, and in order to identify additional candidate genes we used a BAC to isolate cDNAs from a bovine parathyroid cDNA library by direct selection. One of the novel genes that we identified, SCG2, proved to be identical to the recently published MEN1 gene, which is likely to be a tumour suppressor gene. The SCG2 transcript was 2.9 kb in all tissues with an additional 4.2 kb transcript also being present in the pancreas and thymus. Mutational analysis of SCG2 in 10 unrelated MEN1 families identified one polymorphism and nine different heterozygous mutations (one missense, four non-sense, one insertional and three deletional frameshifts) that segregated with the disease, hence providing an independent confirmation for the identification of the MEN1 gene.
Hum Mol Genet 1997 Jul
PMID:Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. 921 90

There is increasing evidence that tumor expressed genes induce immune responses in cancer patients. To identify meningioma expressed antigens, we established a meningioma expression library which was screened with autologous serum. Out of 20 positive cDNA clones eight share high sequence homologies as determined by sequence analysis. These eight clones can be grouped into three classes which differ in length and which are characterized by specific sequence variations. The longest open reading frame was found to be 2412 bp encoding an immunoreactive antigen termed meningioma expressed antigen 6 (MEA6). Using five sequence specific primer pairs, somatic hybrid panel mapping revealed locations of the three classes on several human chromosomes including chromosomes 2, 3, 6, 7, 9, 13 and 14. The mapping results were confirmed by fluorescence in situ hybridization. RT-PCR showed consistent expression of all classes in several meningiomas and additional tissues using the same set of primer pairs as for chromosomal mapping. The expression data were confirmed by northern blot analysis. For the predicted amino acid sequence BLASTX revealed a homology to a human C219-reactive peptide which was previously isolated by an antibody directed against p-glycoprotein. Sequence properties of the MEA protein include an acidic activation domain, a proline-rich region and two coiled-coil domains indicating protein binding and activation functions.
Hum Mol Genet 1997 Nov
PMID:cDNA cloning and chromosomal mapping of a predicted coiled-coil proline-rich protein immunogenic in meningioma patients. 935 11


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