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Masahide Takahashi - One of the best experts on this subject based on the ideXlab platform.

  • Cys611Ser mutation in RET Proto-Oncogene in a kindred with medullary thyroid carcinoma and Hirschsprung's disease
    European Journal of Human Genetics, 2003
    Co-Authors: Mikiko Nishikawa, Hiroomi Funahashi, Tsuneo Imai, Yoshiki Murakumo, Kumi Kawai, Masahiro Nagaya, Akimasa Nakao, Masahide Takahashi
    Abstract:

    Germline mutations in the RET Proto-Oncogene are responsible for the development of human hereditary diseases, including multiple endocrine neoplasia (MEN) type 2A and 2B, familial medullary thyroid carcinoma (FMTC), and Hirschsprung's disease (HSCR). It has been reported that some families developed both MEN 2A/FMTC and HSCR, in which a mutation in a cysteine residue at codon 609, 618, or 620 in the RET gene was present. Here we report a novel RET mutation detected in a Japanese family with medullary thyroid carcinoma and HSCR. A germline mutation in cysteine 611 of the RET gene was identified in this family, which introduced an amino-acid change from cysteine to serine. By biological and biochemical analyses of mutant RET proteins, we previously predicted the potentiality that amino-acid substitution for cysteine 611 as well as cysteines 609, 618, and 620 would promote the development of MEN 2A/FMTC and HSCR. This clinical case substantiates our suggestion for the mechanism of the development of both the diseases.

  • The role of the RET Proto-Oncogene in human disease.
    Nagoya Journal of Medical Science, 1997
    Co-Authors: Masahide Takahashi
    Abstract:

    : The RET Proto-Oncogene encodes a receptor tyrosine kinase with a cadherin-like motif in the extracellular domain. Recently, it turned out that RET is the causative gene for the development of multiple endocrine neoplasia (MEN) type 2A and type 2B and Hirschsprung's disease. MEN 2A and MEN 2B mutations represent activating changes of RET whereas Hirschsprung mutations inactivate RET. In addition, another activating change of RET was found in papillary thyroid carcinoma, particularly in those cancers which developed in children from areas contaminated by the Chernobyl accident. This review summarizes the role of RET in the development of human disease.

  • RET: Proto-Oncogene activated by recombination (vertebrates)
    The Protein Kinase FactsBook, 1995
    Co-Authors: Masahide Takahashi
    Abstract:

    The RET Proto-Oncogene encodes a transmembrane PTK and is activated to an oncogene by recombination with other cellular sequences. Rearrangement of the RET gene was found in 11%–33% of thyroid papillary carcinomas from European and American patients, while the frequency of rearrangement was low (

  • A single missense mutation in codon 918 of the RET Proto-Oncogene in sporadic medullary thyroid carcinomas.
    Endocrine Journal, 1995
    Co-Authors: Shigeto Maeda, Masahide Takahashi, Hiroyuki Namba, Noboru Takamura, Ken Tanigawa, Shiroh Noguchi, Shigenobu Nagataki, Takashi Kanematsu, Shunichi Yamashita
    Abstract:

    The RET Proto-Oncogene is expressed in human medullary thyroid carcinoma and pheochromocytoma.Recently germline mutations of the RET Proto-Oncogene were reported in four syndromes (MEN 2A, MEN 2B, familial medullary thyroid carcinoma and Hirschprung's disease) and somatic mutation was also found in sporadic medullary thyroid carcinoma. To determine the incidence of RET mutations in medullary thyroid carcinoma in Japan, we investigated 14 medullary thyroid carcinomas (comprising 1 case of MEN 2A, 1 case of MEN 2B, 2 cases of familial medullary thyroid carcinoma and 10 cases of sporadic). Tumors from all cases were screened by PCR-SSCP on exons 10 and 11. DNA sequencing on these exons was performed for the hereditary medullary thyroid carcinoma cases. The PCR products of exon 16 from tumor DNA were analyzed by means of Fok1 restriction enzyme digestion analysis and mutations confirmed by DNA sequencing. We found no structural abnormalities in either exon 10 or exon 11 in any of the cases examined, but in four of 10 sporadic cases we detected a common point mutation at codon 918 (ATG to ACG) in exon 16, where methionine was replaced with threonine. Our results support the theory that a point mutation of exon 16 of the RET Proto-Oncogene may be related to the oncogenesis of sporadic medullary thyroid carcinomas. However, further studies on the entire RET Proto-Oncogene are needed to clarify the relationship between its expression and thyroid tumorigenesis.

  • GERM LINE MUTATIONS OF THE RET Proto-Oncogene IN JAPANESE PATIENTS WITH MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A AND TYPE 2B
    Japanese Journal of Cancer Research, 1994
    Co-Authors: Shoichi Maruyama, Giovanni Romeo, Isabella Ceccherini, Toshihide Iwashita, Hiroomi Funahashi, Mutsushi Matsuyama, Tsuneo Imai, Seiichi Matsuo, Masahide Takahashi
    Abstract:

    : We investigated mutations of the RET Proto-Oncogene in Japanese patients with multiple endocrine neoplasia (MEN) type 2A and type 2B. DNAs from pheochromocytomas and/or medullary thyroid carcinomas (MTCs) of five MEN 2A and three MEN 2B patients were amplified by a polymerase chain reaction (PCR) and analyzed. Tumors of four MEN 2A patients had missense mutations in Cys 634 in the extracellular domain of the RET Proto-Oncogene. The same mutations were detected in normal tissues of the patients, indicating that the mutations had arisen in the germ line. Using a reverse transcriptase(RT)-PCR, both normal and mutant transcripts of the RET Proto-Oncogene were detected in a tumor of one patient with MEN 2A mutation. In addition, three MEN 2B patients examined had the same point mutation (ATG-->ACG) at codon 918 in the tyrosine kinase domain of the RET Proto-Oncogene. Since all mutations identified in this study generated new restriction enzyme sites or eliminated a restriction site, the mutant alleles of affected family members could be readily detected without sequencing.

Lois M. Mulligan - One of the best experts on this subject based on the ideXlab platform.

  • Multiple mRNA isoforms of the human RET Proto-Oncogene generated by alternate splicing.
    Oncogene, 1995
    Co-Authors: Maria J. Lorenzo, Lois M. Mulligan, Timothy J. Stonehouse, Catherine S. Healey, Bruce Aj Ponder, Darrin P. Smith
    Abstract:

    : The RET Proto-Oncogene encodes a receptor tyrosine kinase. We and others have recently shown that distinct germline mutations of the RET Proto-Oncogene account for the majority of cases of the dominantly inherited multiple endocrine neoplasia (MEN) type 2 syndromes, and can cause a dominantly inherited form of Hirschsprung disease, a disorder of development of the autonomic innervation of the gut. RET is also oncogenically activated in some sporadic thyroid and adrenal tumours. Here we report the characterisation of multiple mRNA isoforms of RET generated by alternate splicing. Two isoforms are predicted to encode membrane-spanning receptors with a truncated extracellular ligand-binding domain. A third isoform is predicted to encode a soluble, secRETed form of the receptor. These mRNA isoforms are expressed in both normal and tumour tissues.

  • A novel polymorphism in the coding sequence of the human RET Proto-Oncogene
    Human Genetics, 1994
    Co-Authors: Patrick Edery, T Attié, Lois M. Mulligan, Anna Pelet, Brace A. J. Ponder, Arnold Munnich, Stanislas Lyonnet
    Abstract:

    A novel polymorphism in the coding sequence of the human RET Proto-Oncogene is described. The RET Proto-Oncogene maps to chromosome 10q11.2, and is involved in multiple endocrine neoplasia (MEN 2A, MEN 2B), familial medullary thyroid carcinoma and Hirschsprung's disease.

  • point mutation within the tyrosine kinase domain of the RET proto oncogene in multiple endocrine neoplasia type 2b and related sporadic tumours
    Human Molecular Genetics, 1994
    Co-Authors: Darrin P. Smith, Lois M. Mulligan, Catherine S. Healey, E Gardner, M A Ponder, Maria A Nagal, G F W Scheumann, Charies E Jackson, Alan Tunnacllffe, Bruce Aj Ponder
    Abstract:

    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

  • specific mutations of the RET proto oncogene are related to disease phenotype in men 2a and fmtc
    Nature Genetics, 1994
    Co-Authors: Lois M. Mulligan, Catherine S. Healey, John B J Kwok, E Gardner, M A Ponder, Charies E Jackson, David G Clayton, Andrea Frilling, Hendrik Lehnert, Hartmut P H Neumann
    Abstract:

    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.

  • germ line mutations of the RET proto oncogene in multiple endocrine neoplasia type 2a
    Nature, 1993
    Co-Authors: Lois M. Mulligan, Catherine S. Healey, John B J Kwok, Mark J Elsdon, E Gardner, Donald R Love, Sara E Mole, Julie Moore, Laura Papi, M A Ponder
    Abstract:

    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 phaeochromocytomal. The MEN2A gene has recently been localized by a combination of genetic and physical mapping techniques to a 480-kilobase region in chromosome 10qll.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 thyroid4. 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.

M A Ponder - One of the best experts on this subject based on the ideXlab platform.

  • point mutation within the tyrosine kinase domain of the RET proto oncogene in multiple endocrine neoplasia type 2b and related sporadic tumours
    Human Molecular Genetics, 1994
    Co-Authors: Darrin P. Smith, Lois M. Mulligan, Catherine S. Healey, E Gardner, M A Ponder, Maria A Nagal, G F W Scheumann, Charies E Jackson, Alan Tunnacllffe, Bruce Aj Ponder
    Abstract:

    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

  • specific mutations of the RET proto oncogene are related to disease phenotype in men 2a and fmtc
    Nature Genetics, 1994
    Co-Authors: Lois M. Mulligan, Catherine S. Healey, John B J Kwok, E Gardner, M A Ponder, Charies E Jackson, David G Clayton, Andrea Frilling, Hendrik Lehnert, Hartmut P H Neumann
    Abstract:

    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.

  • germ line mutations of the RET proto oncogene in multiple endocrine neoplasia type 2a
    Nature, 1993
    Co-Authors: Lois M. Mulligan, Catherine S. Healey, John B J Kwok, Mark J Elsdon, E Gardner, Donald R Love, Sara E Mole, Julie Moore, Laura Papi, M A Ponder
    Abstract:

    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 phaeochromocytomal. The MEN2A gene has recently been localized by a combination of genetic and physical mapping techniques to a 480-kilobase region in chromosome 10qll.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 thyroid4. 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.

Catherine S. Healey - One of the best experts on this subject based on the ideXlab platform.

  • Multiple mRNA isoforms of the human RET Proto-Oncogene generated by alternate splicing.
    Oncogene, 1995
    Co-Authors: Maria J. Lorenzo, Lois M. Mulligan, Timothy J. Stonehouse, Catherine S. Healey, Bruce Aj Ponder, Darrin P. Smith
    Abstract:

    : The RET Proto-Oncogene encodes a receptor tyrosine kinase. We and others have recently shown that distinct germline mutations of the RET Proto-Oncogene account for the majority of cases of the dominantly inherited multiple endocrine neoplasia (MEN) type 2 syndromes, and can cause a dominantly inherited form of Hirschsprung disease, a disorder of development of the autonomic innervation of the gut. RET is also oncogenically activated in some sporadic thyroid and adrenal tumours. Here we report the characterisation of multiple mRNA isoforms of RET generated by alternate splicing. Two isoforms are predicted to encode membrane-spanning receptors with a truncated extracellular ligand-binding domain. A third isoform is predicted to encode a soluble, secRETed form of the receptor. These mRNA isoforms are expressed in both normal and tumour tissues.

  • point mutation within the tyrosine kinase domain of the RET proto oncogene in multiple endocrine neoplasia type 2b and related sporadic tumours
    Human Molecular Genetics, 1994
    Co-Authors: Darrin P. Smith, Lois M. Mulligan, Catherine S. Healey, E Gardner, M A Ponder, Maria A Nagal, G F W Scheumann, Charies E Jackson, Alan Tunnacllffe, Bruce Aj Ponder
    Abstract:

    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

  • specific mutations of the RET proto oncogene are related to disease phenotype in men 2a and fmtc
    Nature Genetics, 1994
    Co-Authors: Lois M. Mulligan, Catherine S. Healey, John B J Kwok, E Gardner, M A Ponder, Charies E Jackson, David G Clayton, Andrea Frilling, Hendrik Lehnert, Hartmut P H Neumann
    Abstract:

    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.

  • germ line mutations of the RET proto oncogene in multiple endocrine neoplasia type 2a
    Nature, 1993
    Co-Authors: Lois M. Mulligan, Catherine S. Healey, John B J Kwok, Mark J Elsdon, E Gardner, Donald R Love, Sara E Mole, Julie Moore, Laura Papi, M A Ponder
    Abstract:

    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 phaeochromocytomal. The MEN2A gene has recently been localized by a combination of genetic and physical mapping techniques to a 480-kilobase region in chromosome 10qll.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 thyroid4. 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.

Isabella Ceccherini - One of the best experts on this subject based on the ideXlab platform.

  • cDNA sequence and genomic structure of the rat RET Proto-Oncogene.
    Dna Sequence, 2009
    Co-Authors: Ivana Matera, Manuel De Miguel-rodríguez, José M. Fernández-santos, Giuseppe Santamaria, Aldamaria Puliti, Roberto Ravazzolo, Giovanni Romeo, Hugo Galera-davidson, Isabella Ceccherini
    Abstract:

    The RET Proto-Oncogene, a member of the Receptor Tyrosine Kinase family, plays a crucial role during the development of the excRETory system and the enteric nervous system, as demonstrated by in vivo animal studies and by its involvement in the pathogenesis of several human neurocristopathies like Hirschsprung disease and Multiple Endocrine Neoplasia type 2. Using a multistep RT-PCR approach we have isolated and sequenced the cDNA of the whole rat RET Proto-Oncogene, reporting the deduced amino acid sequence in comparison with the human and mouse counterparts. Moreover, two different isoforms (RET9 and RET51) have been confirmed in the rat, while a third RET isoform demonstrated in human (RET43) has not resulted to be conserved in this species. Finally, we have determined the genomic structure of the rat RET Proto-Oncogene comparing the exon-intron boundaries and intron sizes with the known structure of the human homologous gene. Our findings will facilitate the molecular study of appropriate rat models o...

  • An intronic nucleotide variant of the RET Proto-Oncogene causes Hirschsprung disease by interfering with RNA splicing
    Gene Function & Disease, 2000
    Co-Authors: Paola Griseri, Roberto Ravazzolo, Giovanni Romeo, Michele Mishto, Manuela Priolo, B Pesce, Ben C. J. Hamel, Isabella Ceccherini
    Abstract:

    The RET Proto-Oncogene is expressed during embryogenesis in neural-crest derived cells and is involved in different human neurocristopathies such as Multiple Endocrine Neoplasia type 2 (MEN2) syndromes and Hirschsprung disease (HSCR or congenital megacolon). While MEN2 are inherited cancer syndromes due to constitutive activation of the RET receptor, HSCR pathogenesis is caused by loss of function of the RET product. We have analyzed the RET Proto-Oncogene in a family showing a peculiar recurrence of neurocristopathies: a mother with ganglioneuroblastoma and a daughter with long segment aganglionosis. In the HSCR patient no mutation in the RET gene was detected, except for a C>T substitution in intron 12. Functional evidences that such an intronic mutation introduces a novel splice donor site which is recognized and actively used during RNA splicing are provided. Moreover, a polymorphic RET variant, found overrepresented in sporadic medullary carcinomas, was detected in the mother. The association of HSCR with ganglioneuroblastoma in close relatives could be more than coincidental and further investigation into genes driving neural crest differentiation will help to explain the occurrence of different neurocristopathies within the same pedigree.

  • Somatic in frame deletions not involving juxtamembranous cysteine residues strongly activate the RET Proto-Oncogene.
    Oncogene, 1997
    Co-Authors: Isabella Ceccherini, Ivana Matera, Giuseppe Santamaria, Barbara Pasini, Furio Pacini, Maria Gullo, Italia Bongarzone, Cristina Romei, Piera Mondellini, Lucio Scopsi
    Abstract:

    Somatic in frame deletions not involving juxtamembranous cysteine residues strongly activate the RET Proto-Oncogene

  • GERM LINE MUTATIONS OF THE RET Proto-Oncogene IN JAPANESE PATIENTS WITH MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A AND TYPE 2B
    Japanese Journal of Cancer Research, 1994
    Co-Authors: Shoichi Maruyama, Giovanni Romeo, Isabella Ceccherini, Toshihide Iwashita, Hiroomi Funahashi, Mutsushi Matsuyama, Tsuneo Imai, Seiichi Matsuo, Masahide Takahashi
    Abstract:

    : We investigated mutations of the RET Proto-Oncogene in Japanese patients with multiple endocrine neoplasia (MEN) type 2A and type 2B. DNAs from pheochromocytomas and/or medullary thyroid carcinomas (MTCs) of five MEN 2A and three MEN 2B patients were amplified by a polymerase chain reaction (PCR) and analyzed. Tumors of four MEN 2A patients had missense mutations in Cys 634 in the extracellular domain of the RET Proto-Oncogene. The same mutations were detected in normal tissues of the patients, indicating that the mutations had arisen in the germ line. Using a reverse transcriptase(RT)-PCR, both normal and mutant transcripts of the RET Proto-Oncogene were detected in a tumor of one patient with MEN 2A mutation. In addition, three MEN 2B patients examined had the same point mutation (ATG-->ACG) at codon 918 in the tyrosine kinase domain of the RET Proto-Oncogene. Since all mutations identified in this study generated new restriction enzyme sites or eliminated a restriction site, the mutant alleles of affected family members could be readily detected without sequencing.

  • Exclusion of the RET Proto-Oncogene as candidate for total colonic aganglionsis in the spotting lethal (sl) rat strain
    American Journal of Human Genetics, 1994
    Co-Authors: Isabella Ceccherini, Ivana Matera, Marcella Devoto
    Abstract:

    Causative germline mutations and deletions of the RET Proto-Oncogene have been demonstrated in a number of Hirschsprung disease (HSCR) patients showing either short- or long-segment intestinal aganglionosis, including both sporadic and familial cases with an autosomal dominant mode of inheritance. The spotting lethal (sl) rats show autosomal recessive recurrence of total colonic aganglionosis which resembles the long-segment HSCR type in humans with 100% mortality of the homozygotes at 4-5 weeks of age. Heterozygotes were backcrossed with DA rats and the F2 offspring was used to test the possible cosegregation of the aganglionosis and the RET Proto-Oncogene. A genomic DNA fragment of the rat RET gene was amplified using degenerated oligonucleotides, subcloned and sequenced. The coding portion of this DNA fragment (300bp) shares 93% and 81% of its amino acids with the murine and human RET Proto-Oncogene, respectively. An A{yields}G transition in the third nucleotide of the alanine codon corresponding to amino acid Glu90 of the human RET gene was identified in the sl but not in the wild type DA strain. This mutation creates a Bsp 1286I restriction site. Restriction analysis performed on 57 affected rats (mutated homozygotes) of the F2 generation revealed independent segregation between the rat colonic aganglionosismore » gene and RET, thus allowing the exclusion of the latter Proto-Oncogene as candidate for the mutation present in the sl rat strain. Several different candidate rat chromosomal regions are being analyzed in order to proceed with the mapping of the genetic defect in the sl rats.« less