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L M Mulligan

Publications and source records attributed to L M Mulligan.

At least 55 records · Page 3Linked to original sources
PubMed1995

Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease.

Hirschsprung disease (HSCR) is a common congenital malformation (1 in 5,000 live births) due to the absence of autonomic ganglia in the terminal hindgut, and resulting in intestinal obstruction in neonates. Recently, a dominant gene for familial HSCR has been mapped to chromosome sub-band 10q11.2 and the disease has been ascribed to mutations in a tyrosine kinase receptor gene mapping to this region, the RET proto-oncogene. Studying the 20 exons of the RET gene by a combination of denaturating gradient gel electrophoresis and single strand conformation polymorphism in a large series of HSCR patients (45 sporadic cases and 35 familial forms), we found mutations of the RET gene in 50% of familial HSCR, regardless of the length of the aganglionic segment. The mean penetrance of the mutant allele in familial HSCR was significantly higher in males (72%) than in females (51%). Most interestingly, mutations at the RET locus accounted for at least 1/3 of sporadic HSCR in our series. These mutations were scattered along the length of the gene. Finally, among the mutations identified in sporadic cases (16/45), seven proved to be de novo mutations suggesting that new mutations at the RET locus significantly contribute to sporadic HSCR. Taken together, the low penetrance of the mutant gene, the lack of genotype-phenotype correlation, the sex-dependent effect of RET mutations and the variable clinical expression of the disease support the existence of one or more modifier genes in familial HSCR.

Base Sequence↗
PubMed1995

Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma.

BACKGROUND AND OBJECTIVES: Medullary thyroid carcinoma (MTC) occurs both sporadically and in the autosomal dominantly inherited multiple endocrine neoplasia (MEN) type 2 syndromes. The distinction between true sporadic MTC and a new mutation familial case is important for future clinical management of both the patient and family. The susceptibility gene for MEN 2 is the RET proto-oncogene. Systematic analysis for germline mutations of the RET proto-oncogene was performed in a series of 67 patients with apparently sporadic MTC to determine whether they were true sporadic cases or unsuspected de novo MEN 2 cases. DESIGN AND PATIENTS: Sixty-seven unselected patients with sporadic MTC were randomly ascertained from clinic patients from four centres. The diagnosis of MTC was confirmed by histopathology. Germline DNA was extracted from peripheral blood leucocytes or from paraffin-embedded tissue and subsequently used for polymerase chain reaction amplification. MEASUREMENTS: Polymerase chain reaction based RET mutation analysis was performed by direct double-stranded cycle sequencing of exons 10, 11, 13 and 16, within which the majority of MEN2 mutations have been shown to occur. RESULTS: In this series, there was one proven case of germline mutation in RET codon 620, which previously has been shown to be responsible for MEN 2, thus indicating heritable disease. No germline mutation in codon 918, typical of MEN 2B, was found. CONCLUSIONS: A figure of 1.5% germline mutations in 67 apparently sporadic MTC is lower than the incidence of familial disease reported in previous series involving clinical and biochemical screening. The presence of a germline mutation in the RET proto-oncogene in a patient with MTC indicates heritable disease. The absence of germline RET exon 10, 11, 13 or 16 mutation appears to rule out MEN 2A to a high probability, although the presence of a familial form of MTC other than classical MEN 2A cannot be excluded conclusively.

Adolescent↗
PubMed1995

Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium.

The International RET Mutation Consortium was first convened as part of the Fifth International Workshop on Multiple Endocrine Neoplasia, Stockholm, Sweden, in an attempt to analyse the relationship of RET mutation and disease phenotype in the autosomal dominantly inherited multiple endocrine neoplasia type 2 (MEN 2) syndromes. Out of 361 families studied, 41% had MEN 2A, 17.7% MEN 2B, 6.4% FMTC and the remaining subjects were unclassified. RET mutations were detected in 87.3% of families overall. Over 93% of MEN 2B families had the RET 918 ATG-->ACG mutation, while the most frequent mutation detected in MEN 2A families was cysteine codon 634 (87% of all mutations).

Carcinoma, Medullary↗
PubMed1995

Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas.

Phaeochromocytomas may occur sporadically, or as part of the inherited cancer syndromes multiple endocrine neoplasia (MEN) type 2, von Hippel-Lindau disease (VHL), and, rarely, in type 1 neurofibromatosis. In MEN 2, germline missense mutations have been found in one of eight codons within exons 10, 11, 13, 14, and 16 of the RET proto-oncogene. In VHL, germline mutations within one of the three exons are responsible for the majority of cases. To determine if somatic mutations similar to those seen in the germline in MEN 2 or VHL disease play a role in the pathogenesis of sporadic or familial phaeochromocytomas, we analysed 48 sporadic tumours and tumours from 17 MEN 2 and five VHL patients for mutations in RET exons 9, 10, 11, 13, 14, 15, and 16, and the entire coding sequence of VHL. Five of 48 sporadic phaeochromocytomas had RET mutations within exons 10, 11, and 16. Of these, one was proven to be germline and two were proven to be somatic mutations. Four of 48 had VHL mutations; these included both the bilateral cases in the series (one was proven to be a germline mutation) and two others, of which one was proven somatic.

Drosophila Proteins↗
PubMed1994

Second locus for Hirschsprung disease/Waardenburg syndrome in a large Mennonite kindred.

We have studied a large Mennonite kindred in which 20 members were affected with Hirschsprung disease (HSCR), 5 of whom had one or more manifestations of Waardenburg syndrome (WS) type II (WS2). Eleven additional relatives had signs of WS2 without HSCR. Since HSCR and WS2 each represent perturbations of neural crest migration/differentiation, this large pedigree with apparent cosegregation of HSCR and WS2 offered an opportunity to search for linkage between these loci, candidate genes, and random DNA markers, particularly in view of recent discoveries of genes for Waardenburg syndrome type I (WS1) and Hirschsprung disease (c-ret). We have examined the following possible linked markers in 69 relatives in this family: the c-ret gene (HSCR); the human PAX3 gene (HuP2) on chromosome 2q (WS1) and placental alkaline phosphatase (ALPP) on chromosome 2q (linked to WS1); argininosuccinate synthetase (ASS) on chromosome 9q, close to ABO blood groups which have shown weak linkage to WS; and the beta 1 GABA receptor gene (GABARB1) on chromosome 4q13-11, close to c-kit, deletions of which cause piebaldism. Linkage between any of these loci and HSCR/WS in this kindred was excluded, demonstrating that there is at least one further locus for HSCR other than c-ret.

Christianity↗
PubMed1994

A rapid screening method for the detection of mutations in the RET proto-oncogene in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma families.

Multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid carcinoma (FMTC) are autosomal dominant inherited cancer syndromes with incomplete penetrance. Following the identification of mutations in the RET proto-oncogene that segregate with the disease phenotype in MEN2A, MEN2B, and FMTC, genetic screening of individuals with mutations in RET may be performed. We have employed restriction endonuclease digestion of polymerase chain reaction products as an alternative to sequence analysis for rapid identification of mutant gene carriers in families in which MEN2A and FMTC are segregating. Twenty-one Australasian MEN2A and FMTC families have been screened for mutations in a cysteine-rich region of the RET proto-oncogene. Seven independent mutations were identified in key individuals in 16 of these families. We have identified a mutation in codon 620, 2053 T-->C (Cys620Arg), and two mutations in codon 634 of exon 11 of RET, 2095 T-->C (Cys634Arg) and 2096 G-->A (Cys634Tyr), all three of which were present in both MEN2A and FMTC families.

Australia↗
PubMed1994

Mutations of the RET proto-oncogene in Hirschsprung's disease.

Hirschsprung's disease (HSCR) is a common condition (1 in 5,000 live births) resulting in intestinal obstruction in neonates and megacolon in infants and adults. This disease has been ascribed to the absence of autonomic ganglion cells, which are derived from the neural crest, in the terminal hindgut. Segregation analyses have suggested incompletely penetrant dominant inheritance in familial HSCR. Recently, a gene for HSCR has been mapped to chromosome 10q11.2 (refs 6, 7). No recombination was observed between the disease locus and the locus for the RET proto-oncogene, a protein tyrosine kinase gene expressed in the cells derived from the neural crest. Here we report nonsense and missense mutations in the extracellular domain of RET protein (exons 2, 3, 5 and 6) in six unrelated probands and show that the mutant genotypes segregate with the disease in HSCR families. Mutations of RET have been previously reported in multiple endocrine neoplasia type 2A (MEN 2A). Thus, germ-line mutations of the RET gene may contribute either to developmental anomalies in HSCR or to inherited predisposition to cancer in MEN 2A.

Base Sequence↗
PubMed1994

A multiple interval physical map of the pericentromeric region of human chromosome 10.

Five intervals in the pericentromeric region of human chromosome 10 have been defined using a panel of somatic cell hybrids carrying portions of the chromosome. The map positions of twelve markers, consisting of four genes and eight anonymous DNA segments, have been localized by assignment to one of the five intervals. Several other markers could be placed in specific intervals by genetic linkage to assigned loci. When previously published data are incorporated, the summary map of the pericentromeric region encompasses thirty-two loci in bands 10p11.2-q11.2.

Base Sequence↗
PubMed1994

Allelic loss on distal chromosome 17p is associated with poor prognosis in a group of Brazilian breast cancer patients.

We examined loss of heterozygosity (LOH) for two loci on chromosome 17p (D17S5 and TP53), and erbB-2 gene amplification, in primary breast cancers from 67 Brazilian patients. We identified two distinct regions of LOH on chromosome 17p, one spanning TP53 and the other a more telomeric region (D17S5). Based on a short-term follow-up, Kaplan-Meier analyses of patients' disease-free survival showed that patients with LOH for D17S5, but retaining heterozygosity for TP53, were at higher risk of recurrence (P = 0.007) than those who retained heterozygosity for D17S5. Bivariate analyses indicated that patients with LOH for D17S5 alone had an increased risk of recurrence (hazard ratio = 7.2) over patients with erbB-2 amplification (hazard ratio = 3.7), when compared with patients with neither alteration (hazard ratio = 1.0). Further, lymph node-positive patients whose tumours had both LOH for D17S5 and erbB-2 gene amplification had a higher risk of recurrence than patients whose tumours had neither of these genetic alterations. Our data confirm previous reports of a putative tumour-suppressor gene, distinct from TP53, on distal chromosome 17p which is associated with breast cancer. They further suggest that LOH for loci in this region may provide an independent indicator to identify patients with poor prognosis.

Adult↗
PubMed1994

Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC.

We have analysed 118 families with inherited medullary thyroid carcinoma (MTC) for mutations of the RET proto-oncogene. These included cases of multiple endocrine neoplasia types 2A (MEN 2A) and 2B (MEN 2B) and familial MTC (FMTC). Mutations at one of 5 cysteines in the extracellular domain were found in 97% of patients with MEN 2A and 86% with FMTC but not in MEN 2B patients or normal controls. 84% of the MEN2A mutations affected codon 634. MEN 2A patients with a Cys634 to Arg substitution had a greater risk of developing parathyroid disease than those with other codon 634 mutations. Our data show a strong correlation between disease phenotype and the nature and position of the RET mutation, suggesting that a simple, constitutive activation of the RET tyrosine kinase is unlikely to explain the events leading to MEN 2A and FMTC.

Base Sequence↗
PubMed1994

Haplotype analysis of MEN 2 mutations.

Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome which affects thyroid C cells, and with variable frequency, the adrenal medulla, parathyroid and enteric autonomic ganglia. The syndrome is due to germline mutation in the receptor tyrosine kinase gene, RET. We have recently shown an unexpected correlation between one particular RET mutation, cys634-->arg, and the probability of parathyroid involvement in families with MEN 2A. Here we use haplotype analysis in the families to show that this correlation is not explained by a single founder chromosome which carries both the cys634-->arg mutation and a separate allele conferring susceptibility to parathyroid abnormality, but is probably due to the cys634-->arg mutation itself. The results also indicate that new mutations to MEN 2 are not infrequent.

Amino Acid Sequence↗
PubMed1994

Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene.

Mutations of the RET proto-oncogene are the underlying cause of some cases of Hirschsprung disease (HSCR) and the inherited cancer syndromes multiple endocrine neoplasia types 2A (MEN 2A) and 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). In HSCR these mutations are dispersed throughout the gene, while in MEN 2A and FMTC, they are tightly clustered in five cysteine codons of the RET extracellular domain. HSCR and MEN 2 are usually distinct but occasional families have been reported with both diseases. In each of five families with HSCR with or without MEN 2A or FMTC, we have identified a nucleotide substitution in one of the five cysteine codons previously associated with MEN 2A or FMTC. In one family, which had HSCR as its only phenotype, we detected a Cys-->Trp mutation at codon 609 which had not been previously observed. In three families, both HSCR and MEN 2A were associated with a single Cys-->Arg mutation at either codon 618 or 620 of RET. In the fifth family, FMTC and HSCR were present but we could not determine whether HSCR arose from mutation of the RET locus. We suggest that specific mutations in cysteine codons 618 and 620 result in MEN 2A or FMTC, but can also predispose to HSCR with low penetrance.

Base Sequence↗
PubMed1994

Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours.

The susceptibility loci for the three multiple endocrine neoplasia (MEN) type 2 syndromes have been mapped to the region of chromosome 10q11.2 containing the RET proto-oncogene, which codes for a receptor tyrosine kinase. The majority of MEN 2A and familial medullary thyroid carcinoma results from missense mutations within one of five cysteine codons in the extracellular domain of the RET proto-oncogene. We now report a missense mutation, resulting in the substitution of a threonine for a methionine at codon 918 in the tyrosine kinase catalytic domain, in the germline of 26 of 28 apparently distinct families with MEN 2B. DNA from five of 13 apparently sporadic MTC and one of 12 apparently sporadic phaeochromocytomas harboured a similar mutation, but the corresponding germline DNA was wildtype in each case.

Adenoma↗
PubMed1994

Direct, non-radioactive detection of mutations in multiple endocrine neoplasia type 2A families.

We have designed PCR primers that permit the rapid non-isotopic detection of mutations in codon 634 of the RET proto-oncogene, the causative mutations in over 80% of MEN 2A and 50% of FMTC families. In this paper we report the investigation of eleven MEN 2A families referred to the East Anglian Regional Genetics Service. Nine of these families carry codon 634 mutations. We were able to confirm the diagnosis of MEN 2A in twenty six affected individuals and to determine the carrier status of forty one individuals thought to be at risk of developing the disease. Of those at risk, thirty one patients lacked the familial mutation and ten were presymptomatic carriers of MEN 2A. In five cases the direct test proved that patients who had been treated by thyroidectomy but who lacked confirmed cancer, did not carry the familial mutation, removing the perceived risk of MEN 2A from their children. This group included one patient who had been diagnosed as having mild C-cell hyperplasia, confirming that in MEN 2A families C-cell hyperplasia can result from causes other than the presence of the MEN 2A mutation.

Base Sequence↗