Abstract
Activating mutations of the RET proto-oncogene are associated with inherited syndromes, multiple endocrine neoplasia (MEN2A/2B) and with familial and sporadic medullary thyroid cancer (MTC). Single base pair missense mutations in the extracellular Cys-rich domain are responsible for most MEN2A and familial MTC (FMTC) cases. Rarely, somatic deletions and germline duplications have been described in sporadic MTC and in FMTC. We report the detection and functional studies of a deletion/insertion in exon 11 (c.2646delGinsTTCT) associated with FMTC. This in-frame complex rearrangement leads to an Asn to Lys change (Lys666Asn) and to a Ser insertion. The mutation was found in the proband, who was diagnosed with metastatic MTC at 41 years, and in her son, who presented diffuse C-cells hyperplasia at 4 years of age. The mutation displayed a transforming activity stronger than Ret wild type (Ret-WT) at the focus formation assay and functional analyses after transient and stable transfection revealed an increased autophosphorylation, indicating the constitutive activation of the receptor. The transforming activity may be favoured by an increased stabilization of the fully mature form of the mutant receptor. Dimerization assay demonstrated that the activation mechanism of the complex mutation is not mediated by stable dimer formation. Computational analysis predicted non-conservative alterations in the mutant protein consistent with a possible modification of the conformation of the receptor. In conclusion, the first molecular studies on a complex germline RET mutation lying in the juxtamembrane region of the receptor are reported. Functional analyses showed that alterations at this level too can lead to a ligand independent Ret activation.
| Original language | English |
|---|---|
| Pages (from-to) | 945-953 |
| Number of pages | 9 |
| Journal | Endocrine-Related Cancer |
| Volume | 13 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Sep 2006 |
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ASJC Scopus subject areas
- Endocrinology
- Oncology
- Cancer Research
- Endocrinology, Diabetes and Metabolism
Cite this
An in-frame complex germline mutation in the juxtamembrane intracellular domain causing RET activation in familial medullary thyroid carcinoma. / Cordella, Daniela; Muzza, Marina; Alberti, Luisella; Colombo, Paolo; Travaglini, Pietro; Beck-Peccoz, Paolo; Fugazzola, Laura; Persani, Luca.
In: Endocrine-Related Cancer, Vol. 13, No. 3, 09.2006, p. 945-953.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - An in-frame complex germline mutation in the juxtamembrane intracellular domain causing RET activation in familial medullary thyroid carcinoma
AU - Cordella, Daniela
AU - Muzza, Marina
AU - Alberti, Luisella
AU - Colombo, Paolo
AU - Travaglini, Pietro
AU - Beck-Peccoz, Paolo
AU - Fugazzola, Laura
AU - Persani, Luca
PY - 2006/9
Y1 - 2006/9
N2 - Activating mutations of the RET proto-oncogene are associated with inherited syndromes, multiple endocrine neoplasia (MEN2A/2B) and with familial and sporadic medullary thyroid cancer (MTC). Single base pair missense mutations in the extracellular Cys-rich domain are responsible for most MEN2A and familial MTC (FMTC) cases. Rarely, somatic deletions and germline duplications have been described in sporadic MTC and in FMTC. We report the detection and functional studies of a deletion/insertion in exon 11 (c.2646delGinsTTCT) associated with FMTC. This in-frame complex rearrangement leads to an Asn to Lys change (Lys666Asn) and to a Ser insertion. The mutation was found in the proband, who was diagnosed with metastatic MTC at 41 years, and in her son, who presented diffuse C-cells hyperplasia at 4 years of age. The mutation displayed a transforming activity stronger than Ret wild type (Ret-WT) at the focus formation assay and functional analyses after transient and stable transfection revealed an increased autophosphorylation, indicating the constitutive activation of the receptor. The transforming activity may be favoured by an increased stabilization of the fully mature form of the mutant receptor. Dimerization assay demonstrated that the activation mechanism of the complex mutation is not mediated by stable dimer formation. Computational analysis predicted non-conservative alterations in the mutant protein consistent with a possible modification of the conformation of the receptor. In conclusion, the first molecular studies on a complex germline RET mutation lying in the juxtamembrane region of the receptor are reported. Functional analyses showed that alterations at this level too can lead to a ligand independent Ret activation.
AB - Activating mutations of the RET proto-oncogene are associated with inherited syndromes, multiple endocrine neoplasia (MEN2A/2B) and with familial and sporadic medullary thyroid cancer (MTC). Single base pair missense mutations in the extracellular Cys-rich domain are responsible for most MEN2A and familial MTC (FMTC) cases. Rarely, somatic deletions and germline duplications have been described in sporadic MTC and in FMTC. We report the detection and functional studies of a deletion/insertion in exon 11 (c.2646delGinsTTCT) associated with FMTC. This in-frame complex rearrangement leads to an Asn to Lys change (Lys666Asn) and to a Ser insertion. The mutation was found in the proband, who was diagnosed with metastatic MTC at 41 years, and in her son, who presented diffuse C-cells hyperplasia at 4 years of age. The mutation displayed a transforming activity stronger than Ret wild type (Ret-WT) at the focus formation assay and functional analyses after transient and stable transfection revealed an increased autophosphorylation, indicating the constitutive activation of the receptor. The transforming activity may be favoured by an increased stabilization of the fully mature form of the mutant receptor. Dimerization assay demonstrated that the activation mechanism of the complex mutation is not mediated by stable dimer formation. Computational analysis predicted non-conservative alterations in the mutant protein consistent with a possible modification of the conformation of the receptor. In conclusion, the first molecular studies on a complex germline RET mutation lying in the juxtamembrane region of the receptor are reported. Functional analyses showed that alterations at this level too can lead to a ligand independent Ret activation.
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UR - http://www.scopus.com/inward/citedby.url?scp=33751103971&partnerID=8YFLogxK
U2 - 10.1677/erc.1.01144
DO - 10.1677/erc.1.01144
M3 - Article
C2 - 16954442
AN - SCOPUS:33751103971
VL - 13
SP - 945
EP - 953
JO - Endocrine-Related Cancer
JF - Endocrine-Related Cancer
SN - 1351-0088
IS - 3
ER -