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*164761 RET PROTOONCOGENE; RET

table OF CONTENTS

Database Links

54 MEDLINE Citations 9 Protein Links 15 Nucleotide Links 1 Genome Link UniGene Cardiff Human Gene Mutation Database Gene Map GDB Jackson Labs Mouse Database

Gene Map Locus: 10q11.2

Note: pressing the Light Bulb symbol will find the citations in MEDLINE whose text most closely matches the text of the preceding OMIM paragraph, using the Entrez MEDLINE neighboring function.

 

TEXT


 

DESCRIPTION

Mutations in the RET gene are associated with the disorders multiple endocrine neoplasia, type IIA (MEN2A; 171400), multiple endocrine neoplasia, type IIB (MEN2B; 162300), Hirschsprung disease (HSCR; aganglionic megacolon; 142623), and medullary thyroid carcinoma (MTC; 155240).

RET (REarranged during Transfection), as its acronym suggests, was cloned as a chimeric oncogene during a classic NIH 3T3 transformation assay (Takahashi et al., 1985).

The RET protooncogene is one of the receptor tyrosine kinases, which are cell-surface molecules that transduce signals for cell growth and differentiation. The RET gene was defined as an oncogene by a classical transfection assay. Later it was shown (Grieco et al., 1990) that RET can undergo oncogenic activation in vivo and in vitro by cytogenetic rearrangement. Attie et al. (1995) studied the 20 exons of the RET gene by a combination of denaturing gradient gel electrophoresis and SSCP in 45 sporadic cases and 35 familial cases of Hirschsprung disease. They 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%). Mutations at the RET locus were scattered along the length of the gene and accounted for at least one-third of sporadic HSCR cases in this series. Among the mutations identified in sporadic cases (16/45), 7 proved to be de novo mutations. 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. 30 MEDLINE Neighbors

Bolk et al. (1996) stated that 16% of children with congenital central hypoventilation syndrome (CCHS; 209880) have Hirschsprung disease. Because RET mutations have been found in Hirschsprung disease, Bolk et al. (1996) used SSCP analysis to study mutations of the RET gene in 14 patients with CCHS. All detected nucleotide changes in the RET gene were classified as polymorphic variants. On the other hand, Amiel et al. (1998) found a mutation in the RET gene in 1 of 7 children with isolated CCHS. 30 MEDLINE Neighbors

Eng et al. (1995) screened 7 exons of the RET oncogene for mutations in 48 sporadic pheochromocytomas and found a RET mutation in exons 10, 11, and 16 in 5 of the 48. Of these, 1 was proven to be germline and 2 were proven to be somatic mutations. Mutations of the VHL gene were found in 4 of the 48 sporadic pheochromocytomas; these 4 included the 2 bilateral cases in the series, of which 1 was proven to be a germline mutation, and 2 others, of which 1 was proven to be somatic. 30 MEDLINE Neighbors

Pasini et al. (1995) cloned the entire RET genomic sequence in a contig of cosmids and established the position of the 20 exons of the RET gene with respect to a detailed restriction map based on 8 endonucleases. A new highly polymorphic CA repeat sequence was identified within intron 5. The estimated size of the gene is 55 kb. Intron 1 accounts for approximately 24 kb, while exons 2 to 20 are contained within a region of 31 kb. This overall gene structure of a large first intron with small exons interspersed at the 5-prime half and more clustered at the 3-prime half is reminiscent of that of PDGFRB (173410) and KIT (164920), genes that also encode tyrosine kinase receptors. No evidence of RET-related genes or RET pseudogenes in 10q11.2 or elsewhere in the genome was found. They could demonstrate that the orientation of the RET gene on 10q11.2 is 5-prime centromeric/3-prime telomeric. 30 MEDLINE Neighbors

Angrist et al. (1995) analyzed the RET gene in 80 HSCR probands by PCR and identified 8 putative mutations.

Iwashita et al. (1996) introduced 5 HSCR mutations into the extracellular domain of human RET cDNA. These mutations were introduced with or without a MEN2A mutation (cys634 to arg; 164761.0011). The 5 mutations in the RET extracellular domain inhibited the transport of the RET protein to the plasma membrane. Introduction of the extracellular domain RET mutation along with the MEN2A mutation led to significant reduction of the transforming activity of MEN2A-RET, for which cell surface expression is required. Iwashita et al. (1996) demonstrated that with the 5 HSCR extracellular domain RET mutations cell surface expression is low. The authors concluded that sufficient levels of RET expression on the cell surface are required for ganglia migration toward the distal portion of the colon or for full differentiation. 30 MEDLINE Neighbors

Using the approach of SSCP analysis established for all 20 exons of the RET gene, Seri et al. (1997) identified 7 additional mutations among 39 sporadic and familial cases of Hirschsprung disease (detection rate 18%). They considered that the relatively low efficiency of detecting mutations of RET in Hirschsprung patients cannot be accounted for by genetic heterogeneity, which is not supported by the results of linkage analysis in pedigrees analyzed to date. Almost 74% of the point mutations in their series, as well as in other patient series, were identified among long-segment patients, who represented only 25% of the patient population. Seri et al. (1997) found a C620R substitution in a patient affected with total colonic aganglionosis; the same mutation had been found in medullary thyroid carcinoma. An R313Q mutation (164761.0026) was identified in homozygous state in a child born of consanguineous parents and was associated with the most severe Hirschsprung phenotype, namely, a total colonic aganglionosis with small bowel involvement. 30 MEDLINE Neighbors

Familial adenomatous polyposis (FAP) is caused by germline mutations of the adenomatous polyposis coli (APC) gene, and it is associated with an increased risk of developing papillary thyroid carcinomas. A significant fraction of sporadic human papillary thyroid carcinomas have RET protooncogene rearrangements. These rearrangements generate chimeric transforming oncogenes designated RET/PTC. Cetta et al. (1998) used an immunohistochemical and RT-PCR approach to analyze for RET/PTC activation in papillary thyroid carcinomas in 2 FAP kindreds, both showing typical APC gene mutations. Kindred 1 had 7 members affected by FAP, and among these, 3 patients had papillary thyroid carcinomas. Kindred 2 had 2 patients, mother and daughter, who were affected by colonic polyposis; the daughter also had a papillary carcinoma. Cetta et al. (1998) found RET/PTC1 oncogene activation in 2 of 3 papillary carcinomas of FAP kindred 1 and in the papillary carcinoma of FAP kindred 2. These findings showed that loss of function of APC coexists with gain of function of RET in some papillary thyroid carcinomas, suggesting that RET/PTC1 oncogene activation could be a progression step in the development of FAP-associated thyroid tumors. 30 MEDLINE Neighbors

Shirahama et al. (1998) investigated the spectrum of RET mutations among Japanese patients by screening the RET gene in 71 patients with thyroid carcinoma. They found mutations in 33 of 34 MEN2A patients and in 5 of 6 FMTC families studied. The met918-to-thr mutation (164761.0013) was found in 4 patients with MEN2B and in 2 of the 22 patients with sporadic medullary thyroid carcinoma. A total of 5 germline mutations were found among the 22 sporadic cases studied, 4 of which were found to be de novo mutations. The authors commented that the high frequency of germline mutations among patients with sporadic medullary thyroid carcinoma has important implications for the clinical management of family members of any patient with this malignancy. 30 MEDLINE Neighbors

Decker et al. (1998) found that Hirschsprung disease cosegregated with MEN2A in 7 (16%) of 44 families ascertained through MEN2A. The predisposing RET mutations in all 7 families had previously been reported in MEN2A or FMTC and occurred in exon 10 at codons 609, 618, or 620: cys609-to-tyr (164761.0029), cys618-to-ser (164761.0008), cys620-to-arg (164761.0009), and cys620-to-trp (164761.0032). 30 MEDLINE Neighbors

Pelet et al. (1998) investigated the effect on RET function of 7 HSCR-related missense mutations by introducing them into either a 114-amino acid wildtype RET isoform (RET51) or a constitutively activated form of RET51 (RET-MEN2A). Pelet et al. (1998) reported that 1 mutation affecting the extracytoplasmic cadherin domain (arg231 to his; R231H) and 2 mutations located in the tyrosine kinase domain (lys907 to glu, K907E; or glu921 to lys, E921K) impaired the biologic activity of RET-MEN2A when tested in cultured fibroblast and pheochromocytoma cells. However, the mechanisms resulting in RET inactivation differed since the receptor bearing the R231H extracellular mutation results in an absent RET protein at the cell surface, while the E921K mutation located within the catalytic domain abolished its enzymatic activity. In contrast, 3 mutations mapping to the intracytoplasmic domain neither modified the transforming capacity of RET-MEN2A nor stimulated the catalytic activity of RET in a ligand-independent system (ser767 to arg, pro1039 to leu, met1064 to thr). Finally, the cys609-to-trp HSCR mutation exerted a dual effect on RET since it led to a decrease of the receptor at the cell surface and converted RET51 into a constitutively activated kinase due to the formation of disulfide-linked homodimers. The data demonstrated that allelic heterogeneity at the RET locus in HSCR is associated with various molecular mechanisms responsible for RET dysfunction. 30 MEDLINE Neighbors

Attie-Bitach et al. (1998) reported on in situ hybridization studies of the pattern of RET expression during early development of human embryos between 23 and 42 days. They showed that the RET gene is expressed in the developing kidney (nephric duct, mesonephric tubules, and ureteric bud), the presumptive enteric neuroblasts of the developing enteric nervous system, cranial ganglia (VII+VIII, IX, and X), and in the presumptive motor neurons of the spinal cord. Yet, despite the high level of RET gene expression in the kidney and in the motor neurons of the developing central nervous system, only rare cases with renal agenesis have been reported in Hirschsprung disease patients, and no clinical evidence of spinal cord involvement has been shown in patients carrying RET germline mutations (i.e., multiple endocrine neoplasia syndromes and Hirschsprung disease). 27 MEDLINE Neighbors

 


 

MAPPING

By fluorescence in situ hybridization, Ishizaka et al. (1989) assigned the RET oncogene to 10q11.2. Because of the location, they suggested that this might be a candidate gene for multiple endocrine neoplasia type IIA. Lairmore et al. (1993) developed a 1.5-Mb YAC contig containing 3 loci closely linked to the MEN2A locus. The orientation of the contig and order of the 3 markers were cen--RET--D10S94--D10S102--tel. A critical crossover event placed the MEN2A locus centromeric to D10S102. Lairmore et al. (1993) pointed out that no recombination events had been reported between MEN2A and either D10S94 or RET. Mulligan et al. (1993) and Donis-Keller et al. (1993) demonstrated mutations in the RET oncogene that are associated with MEN2A and medullary thyroid carcinoma. 30 MEDLINE Neighbors

 

 

REVIEWS

Eng (1996) reviewed the role of the RET protooncogene in multiple endocrine neoplasia type II and in Hirschsprung disease. Hoppener and Lips (1996) also reviewed RET gene mutations from the point of view of the molecular biology and the clinical aspects. Eng and Mulligan (1997) tabulated mutations of the RET gene in MEN2, the related sporadic tumors medullary thyroid carcinoma and pheochromocytoma, and familial and sporadic Hirschsprung disease. Germline mutations in 1 of 8 codons within RET cause the 3 subtypes of MEN2, namely, MEN2A, MEN2B, and familial medullary thyroid carcinoma. They stated that a somatic M918T mutation (164761.0013) accounts for the largest proportion of RET mutations detected in medullary thyroid carcinomas, most series showing a 30% to 50% range. It appeared that pheochromocytomas have a wider range of RET mutations. In contrast to MEN2, approximately 25% of patients with Hirschsprung disease have germline mutations scattered throughout the length of RET. 30 MEDLINE Neighbors

Fearon (1997) reviewed more than 20 different hereditary cancer syndromes that had been defined and attributed to specific germline mutations in various inherited cancer genes. In a useful diagram, he illustrated the roles of allelic variation ('1 gene - different syndromes') and genetic heterogeneity ('different genes - 1 syndrome') in inherited cancer syndromes. For example, some missense mutations, e.g., in codon 609 cause MEN2A and a familial medullary thyroid carcinoma; others, e.g., missense mutations in codon 918, cause MEN2B; yet other mutations cause Hirschsprung disease. 30 MEDLINE Neighbors


ALLELIC VARIANTS

 
 

.0001 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA [RET, CYS618GLY]

Mulligan et al. (1993) identified constitutional missense mutations of the RET gene in 20 of 23 apparently distinct MEN2A families, but not in 23 normal controls. One of these involved codon 364 in which a T-to-G transversion in basepair 1783 changed TGC (cys) to GGC (gly) (CYS364GLY). Cys364 is 1 of 27 cysteine residues in the RET extracellular domain that is conserved between man and mouse; the other 19 mutations were in another conserved cysteine residue, cys380. (The codon numbered 364 on the basis of the partial RET sequence published by Takahashi et al. (1988) was later referred to as codon 618 on the basis of the full-length RET sequence (Mulligan et al., 1994).) 30 MEDLINE Neighbors

 
 

.0002 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA [RET, GLU378ASP, LEU379VAL, CYS380ARG]

In a study of sequence variations in the RET gene in RNA from tumors in patients with MEN2A by the chemical cleavage mismatch (CCM) method, Mulligan et al. (1993) identified an unusual altered sequence in several: GAGCTGTGC was changed to GACGTGCGC resulting in the substitution of amino acids at codons 378, 379, and 380. All cases were heterozygous for the mutant allele. This unusual mutation was found in a total of 12 families. Cys380 is 1 of 27 cysteine residues in the RET extracellular domain that are conserved between man and mouse. Four other mutations of this codon were found among other MEN2A families. (The codon numbered 380 on the basis of the partial RET sequence published by Takahashi et al. (1988) is numbered codon 634 on the basis of the full-length RET sequence (Mulligan et al., 1994).) 30 MEDLINE Neighbors

 
 

.0003 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA, WITH CUTANEOUS LICHEN AMYLOIDOSIS [RET, CYS634GLY]

In affected members of 3 families with MEN2A, Mulligan et al. (1993) found a TGC-to-GGC transversion at basepair 1831 of codon 380 resulting in substitution of glycine for cysteine (CYS380GLY). (The codon numbered 380 on the basis of the partial RET sequence published by Takahashi et al. (1988) is numbered codon 634 on the basis of the full-length RET sequence (Mulligan et al., 1994).) Robinson et al. (1994) and Seri et al. (1997) likewise identified the C634G mutation in families with MEN2A associated with cutaneous lichen amyloidosis. 16 MEDLINE Neighbors

 
 

.0004 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA [RET, CYS634TYR]

In affected members of 2 families with MEN2A, Mulligan et al. (1993) found a TGC-to-TAC transition at basepair 1832 of codon 380 resulting in substitution of cysteine to tyrosine (CYS380TYR). (The codon numbered 380 on the basis of the partial RET sequence published by Takahashi et al. (1988) is numbered codon 634 on the basis of the full-length RET sequence (Mulligan et al., 1994).) 6 MEDLINE Neighbors

Ceccherini et al. (1994) found the cys634-to-tyr mutation in a family with MEN2A associated with primary localized cutaneous lichen amyloidosis (PLCA; 105250).

Santoro et al. (1995) showed that this mutation is a transforming gene in NIH 3T3 cells as a consequence of constitutive activation of the RET kinase. In MEN2A and familial medullary thyroid carcinoma, point mutations result in the substitution of 1 of the 5 cysteine residues in the extracellular domain of RET. This causes RET dimerization at steady state. 30 MEDLINE Neighbors

 
 

.0005 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA [RET, CYS634SER]

In affected members of 1 family with MEN2A, Mulligan et al. (1993) found a TGC-to-TCC transversion at basepair 1832 of codon 380 resulting in a cysteine-to-serine substitution (CYS380SER). (The codon numbered 380 on the basis of the partial RET sequence published by Takahashi et al. (1988) is numbered codon 634 on the basis of the full-length RET sequence (Mulligan et al., 1994).) 5 MEDLINE Neighbors

 
 

.0006 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA [RET, CYS634PHE]

MEDULLARY THYROID CARCINOMA, FAMILIAL
In a family with MEN2A, Mulligan et al. (1993) found that affected members had a TGC-to-TTC transversion of basepair 1832 resulting in a substitution of phenylalanine for cysteine-380 (CYS380PHE). (The codon numbered 380 on the basis of the partial RET sequence published by Takahashi et al. (1988) is numbered codon 634 on the basis of the full-length RET sequence (Mulligan et al., 1994).) 4 MEDLINE Neighbors

Xue et al. (1994) found the same cys634-to-phe mutation, caused by a TGC-to-TTC transversion at nucleotide 1832, in affected members of a family with medullary thyroid carcinoma.

 
 

.0007 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA [RET, CYS611TRP]

Donis-Keller et al. (1993) described a total of 5 point mutations in the RET gene in unrelated patients with MEN2A. All involved substitutions of cysteine residues. Exon 7 was the site of four of these and exon 8 the site of one. Using the numbering scheme of Mulligan et al. (1994), the 5 mutations were cys611-to-trp, cys618-to-ser, cys620-to-arg, cys620-to-tyr, and cys634-to-arg. The second of these mutations occurred in the same codon as the cys618-to-gly mutation (164761.0001). 30 MEDLINE Neighbors

 
 

.0008 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA [RET, CYS618SER]

MEDULLARY THYROID CARCINOMA, FAMILIAL
See 164761.0007. Xue et al. (1994) found a cys364-to-ser mutation (CYS364SER), caused by a TGC-to-TCC transversion in the RET gene, in affected members of a family with medullary thyroid carcinoma. Based on the full-length sequence of the RET gene, this mutation is cys618 to ser.

 
 

.0009 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA [RET, CYS620ARG]

See 164761.0007. Based on the partial sequence of the RET gene, this mutation was known as CYS366ARG.

 
 

.0010 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA [RET, CYS620TYR]

See 164761.0007. Based on the partial sequence of the RET gene, this mutation was known as CYS366TYR.

 
 

.0011 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA [RET, CYS634ARG]

See 164761.0007. This mutation had been denoted CYS380ARG based on the partial RET sequence published by Takahashi et al. (1988); based on the full-length sequence, the mutation is cys634 to arg. Mulligan et al. (1994) found that the cys634-to-arg mutation represented 54% of all disease mutations in MEN2A families and 65% of all changes in codon 634. It appears that the mutation occurred independently many times, since the families came from widely separated geographic areas and showed different haplotype associations. This mutation is due to change of codon 634 from TGC to CGC. Mulligan et al. (1994) found an unexpected correlation between the occurrence of the cys634-to-arg mutation in families with MEN2A and the probability that one or more family members would show parathyroid abnormality as part of the syndrome. By haplotype analysis in 30 apparently separate MEN2A families, Gardner et al. (1994) showed that the correlation is not explained by a single founder chromosome that carries both the cys634-to-arg mutation and a separate allele conferring susceptibility to parathyroid abnormality, but is probably due to the cys634-to-arg mutation itself. 30 MEDLINE Neighbors

Hofstra et al. (1996) found the cys634-to-arg mutation, due to a T-to-C transition at nucleotide 1900, in 2 presumably unrelated MEN2A families with associated skin amyloidosis. No RET mutation was found in familial cutaneous lichen amyloidosis (105250), a presumably distinct disorder.

 
 

.0012 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA [RET, CYS634TRP]

In 2 out of 57 families with MEN2A, Mulligan et al. (1994) found a C-to-G transversion in codon 634 (TGC), resulting in substitution of tryptophan for cysteine.

 
 

.0013 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB [RET, MET918THR]

MEDULLARY THYROID CARCINOMA, SPORADIC
In all 9 unrelated MEN2B patients studied, Hofstra et al. (1994) found a mutation in codon 918 of the RET gene, causing the substitution of a threonine for a methionine in the tyrosine kinase domain of the protein. They found the same mutation in 6 out of 18 sporadic medullary thyroid carcinomas. This conclusively demonstrates that MEN2A and MEN2B are related as allelic disorders; there is thus no justification for calling MEN2B MEN3. This identical point mutation in the catalytic core of the tyrosine kinase domain of RET was also found in association with both inherited and de novo MEN2B by Carlson et al. (1994) and Eng et al. (1994). The ATG-to-ACG mutation results in the substitution of threonine for methionine at codon 918 in the codon designation of Takahashi et al. (1988, 1989). Carlson et al. (1994) proposed that this amino acid replacement affects substrate interactions and results in oncogenic action by the RET protein. It is noteworthy that most mutations identified in cases of MEN2A and familial medullary thyroid carcinoma have been contained within the extracellular ligand-binding domain of the RET protooncogene and have resulted in nonconservative substitutions for 4 different cysteines. MEN2B has shown mainly noncysteine substitutions. 30 MEDLINE Neighbors

The existence of polymorphic markers tightly linked to MEN2B and the fact that the M918T mutation accounts for almost all cases of MEN2B enabled Carlson et al. (1994) to determine unequivocally whether mutations occurred on the maternal or paternal chromosome. Strikingly, all 25 of the mutations they analyzed occurred in the paternal allele. Therefore, MEN2B can be added to the list of neoplastic diseases, which already includes Wilms tumor, bilateral retinoblastoma, osteosarcoma, embryonal rhabdomyosarcoma, and neurofibromatosis type I, for which the relevant genetic alteration occurs either predominantly or exclusively on the paternally derived chromosome. Carlson et al. (1994) also observed a paternal age effect. 8 MEDLINE Neighbors

Santoro et al. (1995) demonstrated that this RET allele is a transforming gene in NIH 3T3 cells as a consequence of constitutive activation of the RET kinase. The mutation alters RET catalytic properties both quantitatively and qualitatively.

Eng et al. (1995) analyzed 71 sporadic medullary thyroid carcinomas (68 primary tumors and 3 cell lines) for mutations in RET exons 10, 11, and 16. They found that 23% of sporadic MTC had RET codon 918 mutations (located in exon 16), while only 3% had exon 10 mutations and none had mutations in exon 11. They found no exon 16 mutations in MTC from 14 MEN2A cases. Thus, exon 10 and 11 mutations, commonly found in familial MTC and MEN2A, rarely occur in sporadic MTC; somatic mutation of RET codon 918 appears to play a role in the tumorigenesis of a significant minority of sporadic MTC but not in MEN2A tumors. In addition to their biologic interest, these findings may have clinical application in determining whether a case presenting with isolated MTC is truly sporadic or is part of an inherited cancer syndrome. The codon 918 mutation was altered methionine (ATG) to threonine (ACG) in all instances in which germline DNA was available for analysis, it was found to be wildtype. This mutation was previously designated MET664THR. 30 MEDLINE Neighbors

In MEN2A, mutations affecting cysteine residues in the extracellular domain of the receptor tyrosine kinase cause constitutive activation of the tyrosine kinase by the formation of disulfide-bonded homodimers. In MEN2B, only the met918-to-thr mutation in the tyrosine kinase domain has been identified. This mutation does not lead to dimer formation, but has been shown both biologically and biochemically to cause ligand-independent activation of the RET protein, but to a lesser extent than MEN2A mutations. Bongarzone et al. (1998) showed that the activity of the MEN2B RET mutation could be increased by stable dimerization of the receptor. Dimerization was achieved experimentally by constructing a double mutant receptor with a MEN2A mutation (cys634 to arg; 164761.0011) in addition to the MEN2B mutation, and by chronic exposure of the cells expressing the met918-to-thr mutation of RET to the RET ligand glial cell line-derived neurotrophic factor (GDNF; 600837). In both cases, full activation of the RET-MEN2B mutant protein, measured by in vitro transfection assays and biochemical parameters, was seen. These results indicated that the MEN2B phenotype could be influenced by the tissue distribution or concentration of RET ligand(s). 30 MEDLINE Neighbors

 
 

.0014 HIRSCHSPRUNG DISEASE [RET, 1-BP DEL, G1120]

MEGACOLON, AGANGLIONIC
As reviewed in 142623, an autosomal dominant gene causing Hirschsprung disease was mapped to 10q11.2 by observations in a case of interstitial deletion of this region and by family linkage studies. The gene was subsequently localized to a 250-kb interval that contains the RET gene (Yin et al., 1993). Using flanking intronic sequences as primers to amplify 12 of the 20 exons of RET from genomic DNA of 27 Hirschsprung disease patients, Romeo et al. (1994) identified 1 frameshift and 3 missense mutations that totally disrupt or partially change the structure of the tyrosine kinase domain of the RET protein. The mutations in RET that cause multiple endocrine neoplasia are located in the extracellular cysteine-rich domain. On the other hand, a targeted mutation in the tyrosine kinase domain of the RET gene was found to produce intestinal aganglionosis and kidney agenesis in homozygous transgenic mice (Schuchardt et al., 1994). The frameshift mutation consisted of deletion of nucleotide 1120, a G, in exon 6 causing frameshift after the first 373 amino acids. One parent was a silent carrier of the mutation which caused early termination of translation at nucleotide 1355 where a new stop codon had arisen. 30 MEDLINE Neighbors

 
 

.0015 HIRSCHSPRUNG DISEASE [RET, SER765PRO]

In a sporadic case of Hirschsprung disease, Romeo et al. (1994) found a T-to-C transition at nucleotide 2293, causing substitution of proline for serine-765.

 
 

.0016 HIRSCHSPRUNG DISEASE [RET, ARG897GLN]

In a sporadic case of Hirschsprung disease, Romeo et al. (1994) found a G-to-A transition in nucleotide 2690 in exon 15 resulting in substitution of glutamine for arginine-897.

 
 

.0017 HIRSCHSPRUNG DISEASE [RET, ARG972GLY]

In a familial case of Hirschsprung disease, Romeo et al. (1994) found an A-to-G transition in nucleotide 2914 in exon 17 of the RET gene causing substitution of glycine for arginine-972.

 
 

.0018 HIRSCHSPRUNG DISEASE [RET, SER32LEU]

Edery et al. (1994) reported 4 missense mutations and 2 nonsense mutations in the RET gene causing Hirschsprung disease. One of them was a C-to-T transition in codon 32 of exon 2 leading to substitution of leucine for serine in the RET protein.

 
 

.0019 HIRSCHSPRUNG DISEASE [RET, PRO64LEU]

In a case of Hirschsprung disease, Edery et al. (1994) found a C-to-T transition in codon 64 of exon 2, leading to substitution of leucine for proline.

 
 

.0020 HIRSCHSPRUNG DISEASE [RET, GLU136TER]

In a patient with Hirschsprung disease, Edery et al. (1994) found a G-to-T transversion in codon 136 of exon 3, converting glu to a stop codon.

 
 

.0021 HIRSCHSPRUNG DISEASE [RET, ARG180TER]

In a patient with Hirschsprung disease, Edery et al. (1994) described a C-to-T transition in codon 180 of exon 3, converting arginine to a stop codon.

 
 

.0022 HIRSCHSPRUNG DISEASE [RET, ARG330GLN]

In a patient with Hirschsprung disease, Edery et al. (1994) found a G-to-A transition in codon 330 of exon 5, leading to substitution of glutamine for arginine.

 
 

.0023 HIRSCHSPRUNG DISEASE [RET, PHE393LEU]

In a patient with Hirschsprung disease, Edery et al. (1994) found a C-to-A transversion in codon 393 of exon 6, leading to substitution of leucine for phenylalanine in the RET protein.

 
 

.0024 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA [RET, CYS620PHE ]

In a family with MEN2A, Xue et al. (1994) found that affected members had a TGC-to-TTC transversion resulting in a substitution of phenylalanine for cysteine-366 (CYS366PHE). Based on the full-length sequence of the RET gene, this mutation is cys620 to phe.

 
 

.0025 MEDULLARY THYROID CARCINOMA, FAMILIAL [RET, CYS618ARG]

In a family with familial MTC, Xue et al. (1994) found that affected members had a TGC-to-CGC transversion resulting in a substitution of arginine for cysteine-364 (CYS364ARG). Based on the full-length sequence of the RET gene, this mutation is cys618 to arg.

 
 

.0026 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA, WITHOUT PHEOCHROMOCYTOMA [RET, 12-BP DUP]

Missense mutations in 5 cysteine codons encoded in exon 10 of the RET gene (codons 609, 611, 618, and 620) and exon 11 (codon 634) have been found in more than 92% of families with medullary thyroid carcinoma only (FMTC) or MEN2A (MTC and pheochromocytoma and/or hyperparathyroidism). The RET protooncogene encodes a receptor tyrosine kinase that is involved in the normal development of neural crest lineage. Glial cell-derived neurotrophic factor (GDNF; 600837), a member of the transforming growth factor (TGF)-beta superfamily, is a ligand for RET. Mutated RET (C634W; 164761.0012) transfected into NIH 3T3 cells confers the transformed phenotype, and the mutated receptors dimerize through intermolecular disulfide bridges and undergo autophosphorylation at tyrosine residues. Hoppner and Ritter (1997) noted that the mutation of a single cysteine residue into any other amino acid enables the formation of intermolecular disulfide bridges and changes the conformation to activate the intracellular tyrosine kinase domain without the presence of the ligand. This appears to be the crucial event in the stimulation of neoplastic growth. It appears that disappearance of any of the cysteine residues in the cysteine-rich domain is fundamental to the progression of MEN2A. Hoppner and Ritter (1997) described a novel class of germline mutation in a MEN2A family. Duplication of 12 bp in exon 11 created an additional cysteine codon in the cysteine-rich domain and resulted in a distinct clinical phenotype of the MEN2 syndrome. The duplication resulted in the insertion of 4 amino acids between codons 634 (cys) and 635 (arg), thus creating an additional cysteine residue. The family had 14 affected and 11 unaffected living members. Hypercalcemia was diagnosed in 8 patients and histologic evaluation revealed parathyroid hyperplasia in all 10 cases examined. No member of the family showed evidence of pheochromocytoma. The authors stated that this was the first documentation of a family without pheochromocytoma but with a high incidence of parathyroid disease. Approximately 85% of MEN2A families show a mutation of cysteine-634, and as a rule, the presence of both pheochromocytoma and parathyroidism is associated with mutation at that codon. 30 MEDLINE Neighbors

 
 

.0027 MEDULLARY THYROID CARCINOMA, FAMILIAL [RET, GLU768ASP]

In a large multigenerational family with multiple cases of medullary thyroid carcinoma or C-cell hyperplasia and 2 individuals with isolated adrenal medullary hyperplasia, Boccia et al. (1997) identified a glu768-to-asp mutation in exon 13 of the RET gene. The mutation segregated with the FMTC phenotype in this family but not with the adrenal medullary hyperplasia phenotype. The mutation had previously been described in 3 unrelated families with FMTC by Eng et al. (1995) and Bolino et al. (1995). 30 MEDLINE Neighbors

 
 

.0028 HIRSCHSPRUNG DISEASE [RET, ARG313GLN ]

COLONIC AGANGLIONOSIS, TOTAL, WITH SMALL BOWEL INVOLVEMENT
In a child born of consanguineous parents, Seri et al. (1997) found homozygosity for an A313Q mutation of the RET gene as the cause of the most severe Hirschsprung phenotype, namely, total colonic aganglionosis with small bowel involvement.

 
 

.0029 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA, WITH HIRSCHSPRUNG DISEASE [RET, CYS609TYR ]

Decker et al. (1998) found that Hirschsprung disease (HSCR1; 142623) cosegregated with MEN2A in 7 (16%) of 44 families ascertained through MEN2A. The predisposing RET mutations in all 7 families had previously been reported in MEN2A or FMTC and occurred in exon 10 at codons 609, 618, or 620: C609Y, C618S, C620R, and C620W. MEN2A families with RET exon 10 cys mutations had a subsequently greater risk of developing HSCR1 than those with the more common RET exon 11 cys634 or exon 14 mutations. These findings suggested that expression of HSCR1 in MEN2A may be particular to RET exon 10 cys mutations. It appeared that oncogenic activation of RET alone was insufficient to account for coexpression of the diseases. 30 MEDLINE Neighbors

 
 

.0032 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA, WITH HIRSCHSPRUNG DISEASE [CYS620TRP ]

See (164761.0029) and Decker et al. (1998).

 
 

.0033 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA [RET, LEU790PHE ]

MEDULLARY THYROID CARCINOMA, FAMILIAL
Berndt et al. (1998) studied 181 German families with MEN2A or FMTC for mutations in the RET protooncogene. In 8 families with MEN2A or FMTC, no mutation could be detected in the cysteine-rich domain encoded in exons 10 and 11. DNA sequencing of exons 13 to 15 revealed rare noncysteine mutations in 3 families (codons 631, 768, and 844). In contrast to these rare events, heterozygous missense mutations in exon 13, codons 790 and 791, were found in 5 families (4 with MTC only; 1 family with MTC and pheochromocytoma) and 11 patients with apparently sporadic tumors. Two different leu790-to-phe mutations (TTG to TTT, TTG to TTC) and 1 tyr791-to-phe mutation (TAT to TTT) (164761.0034) were found. They concluded that codons 790 and 791 of the RET protooncogene represent a new hotspot for mutations causing MEN2A/FMTC and that 100% of the German MEN2A/FMTC families could be characterized by a mutation in the RET protooncogene. 30 MEDLINE Neighbors

 
 

.0034 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA [RET, TYR791PHE ]

MEDULLARY THYROID CARCINOMA, FAMILIAL
See (164761.0033) and Berndt et al. (1998).

 
 

.0035 HIRSCHSPRUNG DISEASE [RET, ARG231HIS ]

Doray et al. (1998) suggested digenic inheritance for severe aganglionosis extending up to the small intestine in 4 of 8 sibs in a nonconsanguineous French family. Both parents were normal. The father and the 4 affected children were double heterozygotes for an arg231-to-his (R231H) mutation in the RET gene and an ala96-to-ser (A96S) mutation in the neurturin gene (602018.0001). It appeared that the NRTN mutation was not sufficient to result in HSCR by itself, but could interact with other susceptibility loci. The RET mutation had previously been shown by Pelet et al. (1998) to be significant in HSCR as it resulted in haploinsufficiency via a significant reduction of the RET protein at the cell surface, as demonstrated in vitro. 30 MEDLINE Neighbors

 
 

.0036 HIRSCHSPRUNG DISEASE [RET, ARG982CYS ]

Svensson et al. (1998) described a family with missense mutations in both the RET gene (arg982 to cys; R982C) and the EDNRB gene (gly57 to ser; 131244.0005). In this family, 3 of 5 members had both mutations, but only 1, a boy, had the Hirschsprung disease phenotype.


 

SEE ALSO

Eng et al. (1995) ; Eng et al. (1995) ; Ikeda et al. (1990) ; Pachnis et al. (1993) ; Pierotti et al. (1992) ; Rodrigues and Park (1993) ; Santoro et al. (1992) ; van Heyningen (1994)

 

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