Association of multiple endocrine neoplasia type 2 and Hirschsprung disease

Romeo, Giovanni; Ceccherini, Isabella; Celli, J.; Priolo, Manuela; Betsos, Nicola; Bonardi, Giulia; Seri, Marco; Yin, Ling; Lerone, Margherita; Jasonni, Vincenzo; Martucciello, G.

doi:10.1046/j.1365-2796.1998.00332.x

Cited by 70 publications

(42 citation statements)

References 20 publications

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“…In the RET 609 -or RET 620 -carrying patients, ENS development can be severely impaired (1,14,31,42). In an attempt to explain these puzzling observations, it has been proposed that the Ret 609 and Ret 620 mutants display a TK activity under the threshold required to promote neuroectodermic cell survival (49).…”

Section: Discussionmentioning

confidence: 99%

“…Germ line RET mutations at Cys 609 or Cys 620 were found in several families who develop HSCR in addition to MEN2A/FMTC (14,31,42). In an attempt to explore the molecular defects engendered by this type of mutation, Cys 609 3Trp or Cys 620 3Arg mutated RET cDNA was transfected into SK-N-MC cells.…”

Section: Fig 2 Retmentioning

confidence: 99%

“…Nevertheless, this concept does not fit the puzzling observa-tions that several families presenting HSCR harbor one RET mutation of the MEN2A type at Cys 609 (1) and that patients presenting a double HSCR/MEN2A phenotype carry a unique Cys 618 or Cys 620 mutation (14,39,42). In contrast, the Cys 634 mutations have never been associated with HSCR.…”

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confidence: 99%

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The Sensitivity of Activated Cys Ret Mutants to Glial Cell Line-Derived Neurotrophic Factor Is Mandatory To Rescue Neuroectodermic Cells from Apoptosis

Mograbi

Bocciardi

Bourget

et al. 2001

Molecular and Cellular Biology

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Hirschsprung's disease (HSCR), a frequent developmental defect of the enteric nervous system is due to lossof-function mutations of RET, a receptor tyrosine kinase essential for the mediation of glial cell-derived neurotrophic factor (GDNF)-induced cell survival. Instead, gain-of-function Cys mutations (e.g., Cys 609 , Cys 620 , and Cys 634 ) of the same gene are responsible for thyroid carcinoma (MEN2A/familial medullary thyroid carcinoma) by causing a covalent Ret dimerization, leading to ligand-independent activation of its tyrosine kinase. In this context, the association of Cys 609 -or Cys 620 -activating mutations with HSCR is still an unresolved paradox. To address this issue, we have compared these two mutants with the Cys 634 Ret variant, which has never been associated with HSCR, for their ability to rescue neuroectodermic cells (SK-N-MC cells) from apoptosis. We show here that despite their constitutively activated kinase, the mere expression of these three mutants does not allow cell rescue. Instead, we demonstrate that like the wild-type Ret, the Cys 634 Ret variant can trigger antiapoptotic pathways only in response to GDNF. In contrast, Cys 609 or Cys 620 mutations, which impair the terminal Ret glycosylation required for its insertion at the plasma membrane, abrogate GDNFinduced cell rescue. Taken together, these data support the idea that sensitivity to GDNF is the mandatory condition, even for constitutively activated Ret mutants, to rescue neuroectodermic cells from apoptosis. These findings may help clarify how a gain-of-function mutation can be associated with a developmental defect.The RET receptor tyrosine kinase (RTK) provides one of most interesting and documented models of human diseases caused by mutations within a single gene (for a review see reference 37). Its germ line mutations have been associated with Hirschsprung's disease (HSCR), a frequent defect (1 in 5,000 births) of development of the enteric nervous system (ENS) characterized by aganglionosis of the distal digestive tract. RET mutations are also involved in tumor formation: somatic RET chromosomal rearrangements are implicated in papillary thyroid carcinoma, and germ line RET mutations are responsible for the development of three inherited endocrine carcinomas: Familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia types 2A (MEN2A) and 2B (MEN2B).Detailed biochemical analysis of RET mutations in the MEN2A/FMTC and HSCR families has shown how different mutations can lead to such opposite diseases. Indeed, RET encodes an RTK, expressed in tissues derived from the neural crest such as ENS, thyroid, and adrenal medulla (34, 54).

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Section: Discussionmentioning

confidence: 99%

Section: Fig 2 Retmentioning

confidence: 99%

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The Sensitivity of Activated Cys Ret Mutants to Glial Cell Line-Derived Neurotrophic Factor Is Mandatory To Rescue Neuroectodermic Cells from Apoptosis

Mograbi

Bocciardi

Bourget

et al. 2001

Molecular and Cellular Biology

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“…Finally, additional exploration of the relationship between 2508C > T and HSCR disease in different populations and in families with contemporary occurrence of HSCR and MTC 20 will help to gain further insights into this complex disease.…”

Section: Figurementioning

confidence: 99%

A single-nucleotide polymorphic variant of the RET proto-oncogene is underrepresented in sporadic Hirschsprung disease

et al. 2000

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Hirschsprung disease (HSCR) is an inherited disorder characterised by absence of intrinsic ganglion cells in the distal gastrointestinal tract. Different susceptibility genes, involved in either the Ret-tyrosine kinase or the endothelin signalling pathways, contribute to HSCR phenotype. Interestingly, alterations of these genes are detected in only 30-50% of all HSCR patients, suggesting the involvement of modifier genes and/or additional genetic or environmental risk factors. In complex disorders common polymorphic variants can be associated with the disease phenotype, thus modifying the risk of recurrence. To investigate whether sequence variants of the RET proto-oncogene may be associated with the development of the HSCR phenotype, we analysed 92 Italian patients for the 2508C > T synonymous substitution in exon 14 (S836S) finding that the T allele is clearly less frequent than in control individuals (Fisher exact test P = 0.0002). On the other hand, this RET variant allele is overrepresented in patients affected with medullary thyroid carcinoma. Assuming a direct effect of this single-nucleotide polymorphism in predisposing to RET associated pathologies, we have performed functional tests which excluded any possible involvement of the C and T alleles in DNA-protein binding, transcript stability and RNA splicing and editing.

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“…Intestinal ganglioneuromatosis can lead to severe constipation and megacolon simulating Hirschsprung's disease (4-7). In fact, Hirschsprung's disease may also occur with MEN2B (8).…”

Section: Introductionmentioning

confidence: 99%

Early diagnosis of multiple endocrine neoplasia type 2B: a challenge for physicians

Camacho

Hoff

Lindsey

et al. 2008

Arq Bras Endocrinol Metab

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Background:The hereditary form of medullary thyroid carcinoma may occur isolated as a familial medullary thyroid carcinoma (FMTC) or as part of Multiple Endocrine Neoplasia 2A (MEN2A) and 2B (MEN2B). MEN2B is a rare syndrome, its phenotype may usually, but not always, be noted by the physician. In the infant none of the MEN2B characteristics are present, except by early gastrointestinal dysfunction caused by intestinal neuromas. When available, genetic analysis confi rms the diagnosis and guides pre-operative evaluation and extent of surgery. Here we report four cases of MEN2B in which the late diagnosis had a signifi cant impact in clinical evolution and, potentially, in overall survival. Case Report: We report four cases, 2 men and 2 women, with differences in their phenotypes and with a late diagnosis. The fi rst case has a history of severe gastrointestinal obstruction requiring a surgery intervention two days after his birth. The second told had nodules in the oral mucosa and constipation since childhood. The third case referred a history of constipation from birth until 5 months of life. The fourth has had a history of chronic constipation since childhood. Discussion: New concepts have emerged since the RET oncogene was identifi ed in 1993 as the responsible gene for hereditary medullary thyroid carcinoma. The majority of MEN2B individuals have M918T mutation in the exon 16 of RET, with a few cases having a mutation A883F or the association of V804M with E805K, Y806C or S904C mutations. The consensus classifi es the RET mutation in codon 918 as of highest risk and recommends total thyroidectomy and central lymph node dissection until 6 months after birth. A fast and precise diagnosis is essential to reach these goals. The identifi cation of early manifestations such as intestinal ganglioneuromatosis and oral mucosal neuromas should prompt the physician to initiate an investigation for multiple endocrine neoplasia type 2B. Conclusion: The diagnosis of MEN2B is very important to allow appropriate investigation of associated diseases and to allow counseling and appropriate screening of relatives for a RET mutation. Even patients with MEN2B, which often have typical physical features, may not be properly recognized and be followed as a sporadic case. Based on this, all suspicious cases of multiple endocrine neoplasia should undergo a molecular genetic test.

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Association of multiple endocrine neoplasia type 2 and Hirschsprung disease

Cited by 70 publications

References 20 publications

The Sensitivity of Activated Cys Ret Mutants to Glial Cell Line-Derived Neurotrophic Factor Is Mandatory To Rescue Neuroectodermic Cells from Apoptosis

The Sensitivity of Activated Cys Ret Mutants to Glial Cell Line-Derived Neurotrophic Factor Is Mandatory To Rescue Neuroectodermic Cells from Apoptosis

A single-nucleotide polymorphic variant of the RET proto-oncogene is underrepresented in sporadic Hirschsprung disease

Early diagnosis of multiple endocrine neoplasia type 2B: a challenge for physicians

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