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L M Mulligan

Publications and source records attributed to L M Mulligan.

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

Hirschsprung's disease associated with a deletion of chromosome 10 (q11.2q21.2): a further link with the neurocristopathies?

We report a patient with total colonic aganglionosis in association with a deletion of part of the long arm of chromosome 10: (del(10)(q11.2q21.2)). This deletion includes the ret proto-oncogene, which has recently been implicated in multiple endocrine neoplasia type 2A (MEN 2A). The possible links between Hirschsprung's disease and the neurocristopathies and the aetiological role of abnormalities of neural crest development in these conditions are discussed.

Cephalometry↗
PubMed1994

Long segment and short segment familial Hirschsprung's disease: variable clinical expression at the RET locus.

Hirschsprung's disease (aganglionic megacolon, HSCR) is a frequent condition of unknown origin (1/5000 live births) resulting in intestinal obstruction in neonates and severe constipation in infants and adults. In the majority of cases (80%), the aganglionic tract involves the rectum and the sigmoid colon only (short segment HSCR), while in 20% of cases it extends toward the proximal end of the colon (long segment HSCR). In a previous study, we mapped a gene for long segment familial HSCR to the proximal long arm of chromosome 10 (10q11.2). Further linkage analyses in familial HSCR have suggested tight linkage of the disease gene to the RET protoncogene mapped to chromosome 10q11.2. Recently, nonsense and missense mutations of RET have been identified in HSCR patients. However, the question of whether mutations of the RET gene account for both long segment and short segment familial HSCR remained unanswered. We have performed genetic linkage analyses in 11 long segment HSCR families and eight short segment HSCR families using microsatellite DNA markers of chromosome 10q. In both anatomical forms, tight pairwise linkage with no recombinant events was observed between the RET proto-oncogene locus and the disease locus (Zmax = 2.16 and Zmax = 5.38 for short segment and long segment HSCR respectively at 0 = 0%) Multipoint linkage analyses performed in the two groups showed that the maximum likelihood estimate was at the RET locus. Moreover, we show that point mutations of the RET proto-oncogene occur either in long segment or in short segment HSCR families and we provide evidence for incomplete penetrance of the disease causing mutation. These data suggest that the two anatomical forms of familial HSCR, which have been separated on the basis of clinical and genetic criteria, may be regarded as the variable clinical expression of mutations at the RET locus.

Chromosome Mapping↗
PubMed1994

Clinical value of direct DNA analysis of the RET proto-oncogene in families with multiple endocrine neoplasia type 2A.

BACKGROUND: The multiple endocrine neoplasia type 2A gene is the RET proto-oncogene located on the long arm of chromosome 10, and many mutations within this gene have been reported. METHODS: Peripheral blood DNA was analyzed from 95 members of twelve families with multiple endocrine neoplasia type 2A and known mutations in codon 634 (of exon 11) of the RET proto-oncogene. This region was amplified by the polymerase chain reaction, followed by digestion with Cfo I, which detects restriction sites created by the most common TGC- > CGC mutation and by a TGC- > TGG mutation or with Rsa I, which detects a restriction site created by a TGC- > TAC mutation. RESULTS: Diagnoses were confirmed in 39 patients; 15 of 56 at-risk persons were gene carriers and 41 were noncarriers. The noncarriers included seven persons who had previously undergone thyroidectomies for suspected C-cell hyperplasia but were negative for the RET mutation present in affected members of their families. CONCLUSIONS: Identification of the specific gene alterations within families permits direct DNA diagnosis of at-risk family members. The 41 noncarriers will not require further testing nor need to be concerned about transmitting multiple endocrine neoplasia type 2A to their descendants. The normal DNA findings in seven of these persons emphasize the importance of DNA studies in patients with C-cell hyperplasia but no medullary thyroid cancer at operation.

DNA↗
PubMed1994

[Mutations of RET proto-oncogene in Hirschsprung 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. 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 on nonsense and missense mutations in the extracellular domain of the RET protein (exons 2, 3, 5 and 6) in 6 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.

Codon, Nonsense↗
PubMed1993

Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.

Multiple endocrine neoplasia type 2A (MEN 2A) is a dominantly inherited cancer syndrome that affects tissues derived from neural ectoderm. It is characterized by medullary thyroid carcinoma (MTC) and phaeochromocytoma. The MEN2A gene has recently been localized by a combination of genetic and physical mapping techniques to a 480-kilobase region in chromosome 10q11.2 (refs 2,3). The DNA segment encompasses the RET proto-oncogene, a receptor tyrosine kinase gene expressed in MTC and phaeochromocytoma and at lower levels in normal human thyroid. This suggested RET as a candidate for the MEN2A gene. We have identified missense mutations of the RET proto-oncogene in 20 of 23 apparently distinct MEN 2A families, but not in 23 normal controls. Further, 19 of these 20 mutations affect the same conserved cysteine residue at the boundary of the RET extracellular and transmembrane domains.

Amino Acid Sequence↗
PubMed1993

Genetic events in tumour initiation and progression in multiple endocrine neoplasia type 2.

Multiple endocrine neoplasia type 2 (MEN 2) is a familial cancer syndrome arising from mutation at a locus or loci in chromosome region 10p11.2-q11.2. The disease is characterized by medullary thyroid carcinoma (MTC) and pheochromocytoma (Pheo). To assess the genetic events in tumour initiation and progression in this disease, we have compiled an allelotype for MTC and Pheo tumours using polymorphic marker loci from each chromosome arm. Using a panel of 58 tumours, we found frequent allele losses on chromosome arms 1p (42%), 3p (30%), 3q (38%), 11p (11%), 13q (10%), 17p (8%), and 22q (29%). Loss of heterozygosity (LOH) for loci on chromosome 10 was detected in a single tumour where one whole chromosome copy was lost. We used a panel of polymorphic markers for each of chromosomes 1, 3, 11, and 17 to define a shortest region of overlap for these regions. The most frequent allele losses were on chromosome 1, spanning the entire short arm of the chromosome but not loci on 1q. LOH on chromosome 3 encompassed a minimal common region of 3q12-qter. The regions of allelic deletion on chromosome 11 (11pter-p13), 17 (17pter-p11.2), and 13 (13q) encompass known tumour suppressor loci (WTI, TP53, RBI) which must therefore be candidates for genes contributing to MTC and Pheo development. Our data suggest allele loss on chromosome 11, 13, or 17 occurs predominantly in tumours with losses on chromosome 3, potentially reflecting the accumulation of genetic change in tumour progression. These events may be associated with more advanced disease in MTC. We suggest that at least 7 genes contribute to tumour development in MEN 2, including an initiating locus on chromosome 10 and loci on chromosomes 1, 3, 11, 13, 17, and 22 which have a progressional role in these tumours.

Adrenal Gland Neoplasms↗
PubMed1993

Genetic linkage studies map the multiple endocrine neoplasia type 2 loci to a small interval on chromosome 10q11.2.

We have carried out genetic linkage analyses using fifteen polymorphic loci in the pericentromeric region of chromosome 10 in families with the inherited cancer syndromes multiple endocrine neoplasia (MEN) type 2A or 2B. A highly polymorphic microsatellite from the locus D10S141 in q11.2 was found to be recombinant with respect to the disease locus in two individuals and defines a new proximal flanking marker for both MEN2A and 2B. An additional recombination provides evidence that the locus D10S94, also in q11.2, is the closet distal flanking marker for MEN2A. This localises the MEN2A gene to a small region of 10q11.2 flanked by the loci D10S141 and D10S94, which are separated by a sex-averaged genetic distance of 0.55 cM. The MEN2B gene maps to a larger region, flanked by D10S141 and RBP3.

Chromosome Mapping↗
PubMed1993

Structural analysis of the human ret proto-oncogene using exon trapping.

A genomic contig of the human ret protooncogene was created with four overlapping cosmid clones isolated from two libraries. After southern analysis with portions of the ret cDNA, eight cosmid fragments were analysed in detail for the presence of ret exons using exon trapping. PCR products corresponding to spliced exons were isolated and subcloned. Exon boundaries were delineated by comparison of the PCR product sequence and the published ret cDNA sequence. The exons were initially positioned on a genomic map defined by BamHI, EcoRI and HindIII restriction sites. The positions of the exons were then refined by amplifying genomic DNA using primer pairs derived from one or more exons along the ret gene, the length of the PCR product indicating the approximate genomic distance between the exon sequences. The ret proto-oncogene is composed of at least 20 exons, ranging in size from 60 bp to 287 bp, distributed along 30 kb of genomic DNA. The extracellular domain is encoded by 10 exons and the cytoplasmic domain by 9 exons. The transmembrane domain is encoded by a single exon.

Base Sequence↗
PubMed1992

Loss of NF1 alleles in phaeochromocytomas from patients with type I neurofibromatosis.

Type I neurofibromatosis (NF1) is a common autosomal dominant disorder that affects tissues derived from the neural crest. The manifestations are varied, comprising generalised disorders of growth and development as well as an increased risk of benign and malignant tumours including phaeochromocytomas and neurofibrosarcomas. The NF1 locus has been mapped to chromosome bands 17q11-12, and recently the NF1 gene has been cloned. Deletions identified in the constitutional genotype of some patients have suggested that the NF1 phenotype may arise from loss of function mutations of the NF1 gene, consistent with the hypothesis that it is a tumour suppressor gene. To date, however, analysis of NF1 tumours has not revealed the frequent allele losses encompassing the NF1 locus, implying loss of the wild-type NF1 allele, which would support this hypothesis. We report allele losses with markers flanking the NF1 region in each of 7 NF1 phaeochromocytomas. In each of the 3 tumours for which this could be determined, the loss involved the wild-type chromosome. These results provide strong evidence that, in cells of the adrenal medulla at least, the NFI gene may act as a tumour suppressor.

Adrenal Gland Neoplasms↗
PubMed1992

Complementary physical and genetic techniques map the vinculin (VCL) gene on chromosome 10q.

Vinculin is a cytoskeletal protein component of adherens type cell junctions. The gene had been mapped to 10q11.2-qter. We have used a combination of physical and genetic mapping techniques to refine this localization. Hybridization of the vinculin cDNA probe, HV1, to a human-rodent somatic hybrid panel initially suggested a position of either 10q11.2 or 10q22.1-10q23. Genetic recombination mapping in three-generation families with multiple endocrine neoplasia type 2 (MEN2) indicated a position distal to D10S22 (10q21.1) in 10q22.1-10q23. This was confirmed by hybridization of the vinculin cDNA to flow-sorted translocation derivative chromosomes containing the q21-qter portion of chromosome 10. We conclude that the vinculin locus maps in 10q22.1-q23, distal to D10S22.

Animals↗
PubMed1990

Mechanisms of p53 loss in human sarcomas.

An important role for the p53 gene in neoplastic transformation in vitro and in vivo has been imputed by functional studies and identification of tumor-acquired gene defects or alterations in its expression. To study the generality and mechanisms of p53 alteration in human cancer, we examined 241 tumors of several types for structural aberrations of the locus. Alterations of the gene or its RNA or protein products consistent with loss of function by either recessive or dominant mechanisms were identified among this set uniquely in rhabdomyosarcomas and osteosarcomas. The alterations of p53 in rhabdomyosarcoma tumors included cases with complete deletion of both p53 alleles, complete deletions of one allele with or without point mutation of the remaining allele, and absence of detectable RNA. Similarly, we detected homozygous deletion and lack of expression of p53 RNA or aberrant expression of p53 protein in osteosarcomas. These observations provide strong support for the inclusion of the p53 locus in the group of loci whose functional inactivation by either dominant or recessive modes plays a significant role in human cancer.

Animals↗
PubMed1990

Genetic mapping of two new DNA markers in Xq26-q28 relative to the fragile-X syndrome locus.

We have characterized and genetically mapped two new DNA markers (DXS311 and DXS312) with respect to 10 existing loci in Xq26----Xq28 in a set of 15 families in which the fragile-X [fra(X)] syndrome was segregating. Two-point and multipoint linkage analyses were performed taking into account the incomplete penetrance of the fra(X) mutation. The most likely order on the basis of these data is centromere-DXS79-DXS10-DXS311-DXS86-(F9-DXS99 )-(DXS98-DXS312)-fra(X)-DXS52- DXS15-F8C-telomere. DXS98 and one of the new loci, DXS312, were found to be the proximal markers closest to the fra(X) locus. The order F9-(DXS98-DXS312)-fra(X) was found to be 5.9 x 10(4) times more likely than the order (DXS98-DXS312)-F9-fra(X).

Chromosome Mapping↗