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1.
J Hepatol ; 59(4): 904-7, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23707370

ABSTRACT

Maturity onset diabetes of the young type 3 (MODY3) and hepatocellular adenomas (HCAs) are associated with mutations in the HNF1A gene. HNF1A codes for the transcription factor HNF1α, which interacts with DNA as a homodimer or a heterodimer with HNF1ß, to regulate multiple cellular functions including glucidic metabolism, lipidic transport, and detoxication. We report three members of one family with a novel germline in-frame deletion of HNF1A exons 2-3 identified initially using array CGH and direct sequence analysis. All three family members have MODY3 in association with primary liver cell tumours (HCA, liver adenomatosis (LA), and hepatocellular carcinoma (HCC)). Additionally, a high rate of infant mortality was observed in the family. The described family demonstrates a novel HNF1A mutation associated with both benign and malignant primary liver cell tumours and MODY3.


Subject(s)
Adenoma, Liver Cell/complications , Adenoma, Liver Cell/genetics , Carcinoma, Hepatocellular/complications , Carcinoma, Hepatocellular/genetics , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Germ-Line Mutation , Hepatocyte Nuclear Factor 1-alpha/genetics , Liver Neoplasms/complications , Liver Neoplasms/genetics , Adult , Exons , Female , Humans , Infant , Infant Mortality , Male , Middle Aged , Pedigree , Sequence Deletion
2.
Nat Genet ; 26(1): 16-7, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10973239

ABSTRACT

Aberrant promoter methylation and the associated loss of gene expression is a common accompaniment of human cancers. Nonetheless, it has been challenging to demonstrate in any given tumour that methylation of a specific gene was causal and not consequent to malignant transformation. In this regard, our attention was drawn to the genesis of gastric cancers in individuals with hereditary diffuse gastric cancer (HDGC). These individuals harbour germline mutations in the gene encoding E-cadherin, CDH1, but their cancers have consistently demonstrated absence of loss of heterozygosity at the CDH1 locus. These findings suggested the hypothesis that CDH1 promoter methylation might function as the 'second genetic hit' in the genesis of these cancers.


Subject(s)
Cadherins/genetics , DNA Methylation , Promoter Regions, Genetic , Stomach Neoplasms/genetics , Alleles , Cadherins/biosynthesis , Cell Membrane/metabolism , Cytoplasm/metabolism , Family Health , Female , Gastric Mucosa/metabolism , Germ-Line Mutation , Humans , Immunohistochemistry , Loss of Heterozygosity , Male , Microsatellite Repeats/genetics , Polymorphism, Genetic , Stomach Neoplasms/metabolism
5.
Virology ; 182(1): 145-55, 1991 May.
Article in English | MEDLINE | ID: mdl-2024461

ABSTRACT

In order to investigate the function of the 29K protein of tobacco rattle virus (TRV), we introduced different mutations in the 29K protein gene and analyzed the biological properties of the subsequent transcripts in tobacco plants. Although none of the mutant RNAs was able to accumulate to a detectable level, the defects in the 29K protein could be complemented by coinoculation with wild-type TRV or tobacco mosaic virus (TMV). Complementation was also achieved in transgenic plants expressing the homologous TMV 30K protein which is involved in cell-to-cell movement, but without inducing distinctive symptoms. Transcripts of chimeric TRV clones containing duplicate genes for the 29K protein initiated infections with formation of necrotic lesions and the progeny retained only one copy of the gene. These experiments demonstrate that the 29K protein is not required for viral RNA replication and, because the TRV transcripts do not encode the coat protein, that the 29K and 30K proteins act on nonencapsidated RNA. In addition to potentiating viral movement, the TRV 29K protein may also play a role in symptom induction on tobacco.


Subject(s)
Nicotiana/microbiology , Plant Diseases , Plant Viruses/genetics , Plants, Toxic , RNA Viruses/genetics , Viral Proteins/genetics , Virus Replication , Blotting, Northern , Cloning, Molecular , DNA/genetics , DNA Mutational Analysis , Genetic Complementation Test , Plant Viruses/growth & development , RNA Viruses/growth & development , Restriction Mapping
6.
Virology ; 182(1): 61-7, 1991 May.
Article in English | MEDLINE | ID: mdl-2024479

ABSTRACT

A series of mutations has been constructed in a cDNA clone of white clover mosaic virus (WCIMV) which decreases the poly(A) tail length of run-off transcripts from 74 to 27, 10 or zero 3'-terminal (A) residues. Although transcripts with short poly(A) tails were less infectious than wild-type RNA, complete removal of the (A) tail did not abolish infectivity. Addition of nonviral nucleotides to the 3' terminus of transcripts with no 3'-terminal (A) residues eliminated infectivity. Heterogenous-length poly(A) tails, indistinguishable from the wild type, were synthesized de novo in plants inoculated with transcripts with no 3'-terminal (A) residues, demonstrating the presence of a poly(A) polymerase activity in WCIMV-infected tissue. Mutation of a putative polyadenylation motif found in the 3' noncoding region of WCIMV decreased the efficiency of polyadenylation of the progeny of transcripts with 10 3'-terminal (A) residues. The same mutation in transcripts with no 3'-terminal (A) residues abolished infectivity.


Subject(s)
Plant Viruses/genetics , Poly A/genetics , RNA Viruses/genetics , RNA, Viral/genetics , Cloning, Molecular , DNA Mutational Analysis , Oligonucleotides/chemistry , Plant Viruses/pathogenicity , RNA Viruses/pathogenicity , Regulatory Sequences, Nucleic Acid , Structure-Activity Relationship
7.
Virology ; 182(2): 607-14, 1991 Jun.
Article in English | MEDLINE | ID: mdl-2024490

ABSTRACT

The function of the 16-kDa protein encoded by tobacco rattle virus (TRV) RNA-1 was investigated by a mutational analysis of the 16-kDa protein gene. Transcripts of TRV RNA-1 produced from a full-length cDNA clone of TRV RNA-1 (SYM strain) remained infectious when the 16-kDa protein gene was disrupted by premature termination codons and a deletion which removed 73% of the coding region. A deletion which included the intergenic region between the 29-kDa protein gene and the 16-kDa protein gene, the entire 16-kDa protein coding region, and 57% of the 3' noncoding region was not infectious. Transcripts in which the 16-kDa protein coding region was replaced by the tobacco mosaic virus (TMV) (L strain) coat protein gene were also infectious and expressed TMV coat protein in infected tissue. Inclusion of the TMV origin of assembly sequence in the chimaeric constructs resulted in the accumulation of TMV-like virus particles in infected tissue.


Subject(s)
Genes, Viral , Plant Viruses/genetics , RNA Viruses/genetics , RNA, Viral/genetics , Viral Proteins/genetics , Viral Structural Proteins/genetics , Blotting, Northern , Capsid/genetics , DNA Mutational Analysis , Molecular Weight , Mutation , Tobacco Mosaic Virus/genetics , Viral Proteins/chemistry
8.
Virology ; 162(2): 459-65, 1988 Feb.
Article in English | MEDLINE | ID: mdl-3341118

ABSTRACT

The sequence of 1612 nucleotides of the 3'-terminal region of white clover mosaic virus (WCIMV) has been determined from cDNA clones. The viral sense RNA contains four open reading frames of Mr 20,684, Mr 7219, Mr 12,989, and at least Mr 17,000. The latter begins 5' to the sequence determined. The amino acid sequence of the open reading frame encoding the 20,684 polypeptide shows marked homology to the coat proteins of three other potexviruses. The putative coat protein gene was subcloned in a T7 transcription plasmid and RNAs produced by in vitro transcription were translated in the rabbit reticulocyte lysate system. The polypeptide products comigrated on SDS-polyacrylamide gels with one of those synthesized by the in vitro translation of viral RNA, and were immunoprecipitable with antiserum raised against WCIMV, confirming the location of the coat protein gene.


Subject(s)
Capsid/genetics , Genes, Viral , Mosaic Viruses/genetics , Amino Acid Sequence , Base Sequence , Cloning, Molecular , In Vitro Techniques , Molecular Sequence Data , Transcription, Genetic
9.
Virology ; 183(2): 695-702, 1991 Aug.
Article in English | MEDLINE | ID: mdl-1853569

ABSTRACT

The functions of the protein products encoded by a block of three overlapping genes (the triple gene block) of white clover mosaic potexvirus (WCIMV) have been determined. Mutations were introduced into each of the triple gene block open reading frames and in vitro RNA transcripts assayed in plants and protoplasts. None of the mutants was able to induce symptoms or spread in four systemic hosts and one local lesion host, but all were able to produce progeny genomic RNA, subgenomic RNA, coat protein, and virions in inoculated protoplasts, indicating that all the triple gene block proteins are involved in cell-to-cell spread. Based on observed homologies between the triple gene block proteins of the potex-, carla-, furo-, and hordeivirus groups and Nicotiana velutina mosaic virus, and the demonstrated transport function of the WCIMV and barley stripe mosaic virus triple gene block proteins, these proteins are proposed to constitute a new class of transport proteins.


Subject(s)
Mosaic Viruses/genetics , Viral Proteins/genetics , Amino Acid Sequence , Base Sequence , Biological Transport , Capsid/genetics , DNA, Viral , Fabaceae/microbiology , Genes, Viral , Molecular Sequence Data , Mosaic Viruses/metabolism , Mosaic Viruses/pathogenicity , Mutagenesis , Open Reading Frames , Plant Diseases , Plants, Medicinal , Protein Biosynthesis , Protoplasts/microbiology , Transcription, Genetic , Viral Proteins/metabolism
10.
J Med Genet ; 35(4): 338-9, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9598733

ABSTRACT

Vesicoureteric reflux (VUR) is a common childhood condition characterised by regurgitation of urine from the bladder to the kidney. It is the commonest cause of end stage renal failure in children and an important cause in adults. Primary VUR is often familial, suggesting that genetic factors play an important role in its aetiology. Recently, VUR was observed as part of a syndrome, involving optic nerve colobomas and renal anomalies, caused by mutations of the PAX2 gene. PAX2 is a member of the paired box family of genes and is expressed in the ureteric bud and differentiating nephrogenic mesenchyme of the developing kidney. PAX2 has been shown to play a critical role in the development of both the kidney and the ureter. The occurrence of VUR in one family with the PAX2 mutation, and the expression pattern of PAX2 in developing ureteric bud, strongly suggested that PAX2 could be the cause of primary familial VUR. Single strand conformational polymorphism (SSCP) analysis of 23 affected subjects in eight families with primary familial VUR showed no alterations in exons 2-5 of the PAX2 gene. In addition, a polymorphic dinucleotide repeat marker located within the PAX2 gene segregated independently of the disease trait in one large family who primarily had VUR or reflux nephropathy. These results suggest that PAX2 is not a major cause of primary familial reflux.


Subject(s)
DNA-Binding Proteins/genetics , Mutation , Transcription Factors/genetics , Vesico-Ureteral Reflux/genetics , Female , Genetic Diseases, Inborn , Humans , Male , PAX2 Transcription Factor , Pedigree
11.
Virology ; 191(1): 480-4, 1992 Nov.
Article in English | MEDLINE | ID: mdl-1413520

ABSTRACT

Functions of the coat protein of white clover mosaic potexvirus (WCIMV) were investigated using C-terminal deletion mutants. Whereas plants inoculated with RNA transcripts of a full-length wild-type clone of WCIMV produced typical infections, plants inoculated with transcripts of each mutant did not produce symptoms, and viral RNA species were not detected by Northern analysis. The mutants were able to replicate in protoplasts, although, relative to the wild-type RNA profile, the level of genomic RNA, but not subgenomic RNA, was reduced. These results indicate a role for the coat protein in efficient cell-to-cell transport in plants. Virus-like particles were detected in protoplast extracts inoculated with transcripts of a mutant in which the coat protein was truncated by 31 amino acids. This result suggests that the lack of detectable transport in plants was not due solely to a failure of the mutants to form virus particles. Possible roles for the coat protein in transport and replication are discussed. A 6-kDa open reading frame, internal to the coat protein gene, was shown by mutational analysis not to be essential for replication or transport.


Subject(s)
Capsid/physiology , Mosaic Viruses/physiology , Plants/microbiology , Base Sequence , Blotting, Northern , Capsid/genetics , DNA, Viral , Microscopy, Electron , Molecular Sequence Data , Mosaic Viruses/genetics , Mosaic Viruses/ultrastructure , Mutation , Plant Cells
12.
Cancer ; 92(1): 181-7, 2001 Jul 01.
Article in English | MEDLINE | ID: mdl-11443625

ABSTRACT

BACKGROUND: The CDH1 gene encodes E-cadherin, an epithelial cell adhesion molecule. Germline CDH1 mutations recently were identified in families with hereditary diffuse gastric carcinoma in a pattern suggestive of autosomal dominant inheritance with incomplete penetrance. METHODS: The proband was a woman age 47 years with a strong family history of diffuse gastric carcinoma. A germline E-cadherin gene mutation was identified in this patient, her brother, and three first cousins. All five family members underwent endoscopic evaluations, which were negative for malignancy, and elected to undergo a prophylactic total gastrectomy with Roux-en-Y esophagojejunostomy. RESULTS: Pathologic examination of the proband's stomach revealed several microscopic foci of intramucosal signet ring cell adenocarcinoma in the cardia and proximal gastric body. Postgastrectomy specimens from the proband's brother and three first cousins all showed intramucosal signet ring cell adenocarcinoma in various regions of the stomach. Immunoperoxidase studies performed on gastric tissue from these five patients demonstrated diminished or absent E-cadherin reactivity in the cancerous mucosa. CONCLUSIONS: Although total gastrectomy was performed as a prophylactic intervention, occult gastric carcinoma was discovered in all five patients. Thus, total gastrectomy should be curative for gastric carcinoma in these patients. Based on their successful outcomes and the lack of efficacious surveillance methods for diffuse gastric carcinoma, prophylactic total gastrectomy may be the management of choice for germline E-cadherin gene mutation carriers. However, prophylactic total gastrectomy should be undertaken cautiously because the procedure may be associated with considerable morbidity.


Subject(s)
Cadherins/genetics , Germ-Line Mutation , Stomach Neoplasms/genetics , Adult , Female , Gastrectomy , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Primary Prevention , Stomach Neoplasms/pathology , Stomach Neoplasms/prevention & control
13.
Hum Mutat ; 14(3): 249-55, 1999.
Article in English | MEDLINE | ID: mdl-10477433

ABSTRACT

To extend earlier observations of germline E-cadherin mutations in kindreds with an inherited susceptibility to diffuse gastric cancer, we searched for germline E-cadherin mutations in five further families affected predominantly by diffuse gastric cancer and one family with a history of diffuse gastric cancer and early-onset breast cancer. Heterozygous inactivating mutations were found in the E-cadherin gene in each of these families. No mutation hotspots were identified. These results demonstrate that germline mutation of the E-cadherin gene is a common cause of hereditary diffuse gastric cancer and suggest a role for these mutations in the incidence of breast cancer.


Subject(s)
Adenocarcinoma/genetics , Breast Neoplasms/genetics , Cadherins/genetics , Germ-Line Mutation , Stomach Neoplasms/genetics , Adult , Aged , Aged, 80 and over , DNA Mutational Analysis , Female , Humans , Leukocytes , Loss of Heterozygosity , Male , Middle Aged , Pedigree , Polymerase Chain Reaction , Polymorphism, Genetic , Syndrome
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