Biological Effects of the Dual Phenotypic Janus Mutation of ret Cosegregating with Both Multiple Endocrine Neoplasia Type 2 and Hirschsprung’s Disease

Arighi, Elena; Popsueva, Anna; Degl’Innocenti, Debora; Borrello, Maria Grazia; Carniti, Cristiana; Perälä, Nina; Pierotti, Marco A.; Sariola, Hannu

doi:10.1210/me.2003-0173

Cited by 60 publications

(40 citation statements)

References 33 publications

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“…Anderson) and the immunoprecipitates were characterized by Western blotting using specific antibodies for RET. In line with what was found in cell systems, [15][16][17]25 Western blot analysis in Ret C620R homozygous mice showed the prevailing expression of the Ret 140-kd isoform. (Figure 2B).…”

Section: Characterization Of the Ret C620r Micesupporting

confidence: 75%

“…Using cell systems such as NIH3T3 [15][16][17] or MadinDarby canine kidney (MDCK) cells 25 in which diverse RET constructs have been introduced, different groups have demonstrated that the expression of the 160-kd isoform of RET bearing the Cys620 mutation was very low compared with that of wild-type RET, suggesting that this mutation impairs the transport of RET to the plasma membrane. [15][16][17] The 140-kd product is endoglycosidase H-sensitive, suggesting that the 140-kd band corresponds to an incompletely glycosylated precursor of RET present in the endoplasmic reticulum whereas the 160-kd band is the mature RET protein, fully glycosylated and expressed at the cell surface.…”

Section: Characterization Of the Ret C620r Micementioning

confidence: 99%

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The RetC620R Mutation Affects Renal and Enteric Development in a Mouse Model of Hirschsprung's Disease

Carniti

Belluco

Riccardi

et al. 2006

The American Journal of Pathology

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In rare families RET tyrosine kinase receptor substitutions located in exon 10 (especially at positions 609, 618, and 620) can concomitantly cause the MEN 2A (multiple endocrine neoplasia type 2A) or FMTC (familial medullary thyroid carcinoma) cancer syndromes, and Hirschsprung's disease (HSCR). No animal model mimicking the co-existence of the MEN 2 pathology and HSCR is available, and the association of these activating mutations with a developmental defect still represents an unresolved problem. The aim of this work was to investigate the significance of the RET C620R substitution in the pathogenesis of both gain-and loss-of-function RET-associated diseases. We report the generation of a line of mice carrying the C620R mutation in the Ret gene. Although Ret C620R homozygotes display severe defects in kidney organogenesis and enteric nervous system development leading to perinatal lethality. Ret C620R heterozygotes recapitulate features characteristic of HSCR including hypoganglionosis of the gastrointestinal tract. Surprisingly, heterozygotes do not show any defects in the thyroid that might be attributable to a gain-offunction mutation. The Ret C620R allele is responsible for HSCR and affects the development of kidneys and the enteric nervous system (ENS). These mice represent an interesting model for studying new therapeutic approaches for the treatment of HSCR disease.

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Section: Characterization Of the Ret C620r Micesupporting

confidence: 75%

Section: Characterization Of the Ret C620r Micementioning

confidence: 99%

The RetC620R Mutation Affects Renal and Enteric Development in a Mouse Model of Hirschsprung's Disease

Carniti

Belluco

Riccardi

et al. 2006

The American Journal of Pathology

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“…MEN2A mutations such as C634R are responsive to GDNF, whereas Hirschsprung-MEN2A and Hirschsprung-FMTC mutations of RET (e.g. C620R) do not respond to GDNF [65]. Insensitivity to GDNF renders cells more prone to apoptosis, and these features are shared by all Hirschsprung-associated mutations of RET [66].…”

Section: Hirschsprung Combined With Men2mentioning

confidence: 99%

Current concepts in RET-related genetics, signaling and therapeutics

et al. 2006

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The receptor tyrosine kinase RET is expressed in cell lineages derived from the neural crest and has a key role in regulating cell proliferation, migration, differentiation and survival during embryogenesis. Germline and somatic mutations in RET that produce constitutively activated receptors cause the cancer syndrome multiple endocrine neoplasia type 2 and several endocrine and neural-crest-derived tumors, whereas mutations resulting in nonfunctional RET or lower expression of RET are found in individuals affected with Hirschsprung disease. This review focuses on the genetics and molecular mechanisms underlying the different inherited human neural-crest-related disorders in which RET dysfunction has a crucial role and discusses RET as a potential therapeutic target. IntroductionThe human gene RET is localized on chromosome 10 (10q11.2) and contains 21 exons [1]; alternative splicing generates three isoforms, which contain 51 (RET51), 43 (RET43) and 9 (RET9) amino acids in the carboxyl (C)-terminal tail [2]. RET51 and RET9 are the most prevalent and best-characterized isoforms in vivo; RET43 has not yet been characterized. The RET51 isoform shows the highest transforming and kinase activity in vitro [3], and several observations suggest that these isoforms have different tissue-specific effects during embryogenesis [4]. Monoisoformic RET9 mice are viable and normal, whereas the monoisoformic RET51 mice (which lack RET9) have kidney hypoplasia and lack enteric ganglia from the colon [4].RET (Figure 1) is the receptor for members of the glial cell-derived neurotrophic factor (GDNF) family of ligands (GFLs): namely GDNF, Neurturin, Persephin and Artemin [5]. To stimulate RET, these GFLs first need to form a complex with their glycosylphosphatidylinositol (GPI)-anchored co-receptor, a member of the GDNF receptor-a family (GFRa1-GFRa4), after which the GFL-GFRa complex activates RET [6,7]. The GFRs differ in their specificity for GFLs (Figure 1).

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“…Recombinant plasmids carrying RET9-WT (the short isoform of the proto-RET gene), RET51-WT (the long isoform of the proto-RET gene), RET9-C634R (containing an MEN2A causing mutation), and RET9-M918T (containing the main MEN2B causing mutation) are described elsewhere (Arighi et al 2004). Site-directed mutagenesis was performed, using an in vitro oligonucleotide mutagenesis system (QuikChange XL site-directed mutagenesis; Stratagene, La Jolla, CA, USA), on RET9-WT and RET51-WT cDNAs cloned in the eukaryotic expression vector pCDNA3 (Invitrogen), to obtain RET9-K666E, RET51-K666E, RET9-G691S and RET51-G691S constructs.…”

Section: Construction Of the Ret Mutantsmentioning

confidence: 99%

Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism

Borrello¹,

Aiello²,

Peissel³

et al. 2011

Endocrine-Related Cancer

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Activating mutations of RET, a gene encoding two isoforms of a tyrosine kinase receptor physiologically expressed in several neural crest-derived cell lineages, are associated with the inherited forms of medullary thyroid carcinoma (MTC). The identification and characterization of novel RET mutations involved in MTC is valuable, as RET gene testing plays a crucial role in the management of these patients. In an MTC patient, we have identified a germline c.1996AOG transition in heterozygosis leading to K666E substitution. In addition, the conservative S904S (c.2712COG) and the non-conservative functional G691S (c.2071GOA) polymorphisms have been identified. Through functional studies, we demonstrate for the first time that K666E is a gain-of-function mutation with oncogenic potential, based on its ability to transform NIH3T3 cells. It was not possible to define whether K666E is a de novo or inherited RET variant in the patient, as the family history was negative for MTC, and the carrier status of family members could not be tested. Our results, together with a recent report of co-segregation of the mutation in three MTC families, suggest that K666E is a causative MTC mutation. As we have shown that the same patient allele carries both K666E and G691S variants, the latter known to increase downstream RET signaling, a possible role for the G691S polymorphism has also been investigated. We have demonstrated that, although RET-G691S is not oncogenic per se, it enhances the transforming activity of the RET-K666E mutant, thus suggesting a modifier role for this functional polymorphism.

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Biological Effects of the Dual Phenotypic Janus Mutation of ret Cosegregating with Both Multiple Endocrine Neoplasia Type 2 and Hirschsprung’s Disease

Cited by 60 publications

References 33 publications

The RetC620R Mutation Affects Renal and Enteric Development in a Mouse Model of Hirschsprung's Disease

The RetC620R Mutation Affects Renal and Enteric Development in a Mouse Model of Hirschsprung's Disease

Current concepts in RET-related genetics, signaling and therapeutics

Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism

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