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Biomedical subjects

M I Lerman

Publications and source records attributed to M I Lerman.

At least 73 records · Page 4Linked to original sources
PubMed1994

Detailed mapping of germline deletions of the von Hippel-Lindau disease tumour suppressor gene.

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).

Amino Acid Sequence↗
PubMed1994

Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype.

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)

Base Sequence↗
PubMed1994

Molecular analysis of the von Hippel-Lindau disease tumor suppressor gene in human lung cancer cell lines.

The deletion of the short arm of chromosome 3 is frequently observed in lung cancer. To determine whether the von Hippel-Lindau (VHL) disease tumor suppressor gene located at 3p25 is responsible for oncogenesis in lung cancer, we searched the known open reading frame using the single-strand conformation polymorphism (SSCP) technique for mutations in the VHL gene in 72 cancer cell lines including small cell (SCLC) and non-small cell (NSCLC) lung cancers, carcinoids, and mesotheliomas. SSCP analysis showed that four cell lines have altered SSCP patterns within the coding region and one in an intron of the VHL gene. SCLC line NCI-H1672 had a somatic mutation, G to A at nucleotide (nt) 530, leading to amino acid substitution (glycine to aspartic acid) compared to normal DNA from the same patient. Mesothelioma line NCI-H28 had T to A mutation at nt 479 leading to leucine to histidine amino acid change. We found one frequent polymorphism A (0.72) or G (0.28) at nt 19 resulting in either serine or glycine at this position, changes also found in normal peripheral blood cell DNA, often in a heterozygous state. In addition, we found single rare polymorphisms which did not alter the coding region including: C to G at nt 396, G to T at nt 843, and C to T change in an intron. These results suggest that the VHL gene is only rarely mutated in thoracic malignancies.

Base Sequence↗
PubMed1993

Long range restriction map of the von Hippel-Lindau gene region on human chromosome 3p.

Von Hippel-Lindau disease is a heritable tumour syndrome caused by the loss of the function of a tumour suppressor gene on the short arm of human chromosome 3. The interval RAF1-D3S18 (3p25-3p26) has been identified by genetic linkage studies to harbour the von Hippel-Lindau gene. We have constructed a long range restriction map of this region and have succeeded in demonstrating the physical linkage of loci D3S726 (DNA probe LIB31-38), D3S18 (c-LIB-1, L162E5), D3S601 (LIB19-63) and D3S587 (LIB12-48). Since multipoint analysis has located D3S601 proximal to D3S726, the physical map should be oriented with D3S726 towards the telomere. The order and distances of probes within the von Hippel-Lindau gene region is as follows: telomere--LIB31-38--(< 280 kb)--c-LIB-1--(overlapping)--L162E5--(900-1600 kb)--(LIB19-63, LIB12-48)--centromere. In tissues that included blood, semen and Epstein-Barr-virus-transformed lymphocytes, we detected a putative CpG island flanking D3S18.

Carcinoma, Renal Cell↗
PubMed1993

Clinical and molecular analyses of deletion 3p25-pter syndrome.

Hemizygous deletion of 3p25-pter is associated with a phenotype of profound growth failure, microcephaly, characteristic facial changes, and mental retardation. Since the severity may be quite variable, we have studied 3 cases of del 3p25-pter to define the clinical manifestations and the critical chromosome region for phenotypic expression. The patient we now report died at age 6 months and provided an opportunity for a detailed necropsy analysis for only the second time in a del(3p) patient. He had marked hypoplasia of all organs, hypomyelination of white matter, and multiple renal cortical microcysts. Ordered genomic markers from the distal regions of chromosome 3p aided in determining the parent of origin of each deletion and in defining the boundaries of the deleted chromosomal segments. The deleted markers distal to the RAF1 oncogene in 2 of the 3 patients were consistently hemizygous. One patient had an interstitial deletion based on evidence of diploid inheritance of one of the most distal loci (D3S17). Available genetic linkage maps suggest that the deletion spans at least 19 centimorgans (cM).

Abnormalities, Multiple↗
PubMed1993

Mapping the Von Hippel-Lindau disease tumour suppressor gene: identification of germline deletions by pulsed field gel electrophoresis.

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.

Chromosome Mapping↗
PubMed1993

Molecular genetic studies of sporadic and familial renal cell carcinoma.

Renal cell carcinoma (RCC) occurs predominantly as a sporadic disease but has familial forms. Cytogenetic and DNA deletion analyses show that both sporadic and familial RCC tumors arise as the result of chromosomal deletions in the 3p13-p26 region. von Hippel-Lindau (VHL) disease is a hereditary, multifocal syndrome that includes, among several affected organs, multiple, bilateral renal cysts and RCC. Although the VHL disease gene maps to chromosome 3p25-p26, data indicate that the VHL and sporadic RCC disease genes are likely to be independent. The authors hypothesize that VHL disease manifestations are controlled by mutations in the VHL disease gene and that the onset of VHL-associated kidney cancer is due to a second mutation of the linked sporadic RCC gene.

Carcinoma, Renal Cell↗