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RET and NTRK1 proto-oncogenes in human diseases
Luisella Alberti1, Cristiana Carniti, Claudia Miranda
1Operative Unit Molecular Mechanisms of Tumor Growth and Progression, Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy.
Abstract:
RET and NTRK1 are receptor tyrosine kinase (RTK) proteins which play a role in the development and maturation of specific component of the nervous system. Their alterations have been associated to several human diseases, including some forms of cancer and developmental abnormalities. These features have contributed to the concept that one gene can be responsible for more than one disease. Moreover, both genes encoding for the two RTKs show genetic alterations that belong to either "gain of function" or "loss of function" class of mutations. In fact, receptor rearrangements or point mutations convert RET and NTRK1 in dominantly acting transforming genes leading to thyroid tumors, whereas inactivating mutations, associated with Hirschsprung's disease (HSCR) and congenital insensitivity to pain with anhidrosis (CIPA), impair RET and NTRK1 functions, respectively. In this review we have summarized the main features of the two receptors, their physiological and pathological roles. In addition, we attempted to identify the correlations between the different genetic alterations and the related pathogenetic mechanisms.
Insights
Receptor tyrosine kinases RET and NTRK1 are crucial for nervous system development. Their genetic alterations, including gain-of-function and loss-of-function mutations, are linked to diseases like cancer and Hirschsprung's disease.
Area of Science:
- Molecular Biology
- Genetics
- Developmental Biology
Background:
- RET and NTRK1 are receptor tyrosine kinases (RTKs) vital for nervous system development and maturation.
- Alterations in these RTKs are implicated in various human diseases, including cancers and developmental abnormalities.
Purpose of the Study:
- To review the key features of RET and NTRK1 receptors.
- To explore their physiological and pathological roles.
- To correlate specific genetic alterations with underlying pathogenetic mechanisms.
Main Methods:
- Literature review of scientific articles on RET and NTRK1.
- Analysis of genetic alterations (rearrangements, point mutations).
- Examination of functional consequences (gain-of-function, loss-of-function).
Main Results:
- Gain-of-function mutations in RET and NTRK1 can act as oncogenes, driving thyroid tumors.
- Loss-of-function mutations are associated with developmental disorders like Hirschsprung's disease (HSCR) and congenital insensitivity to pain with anhidrosis (CIPA).
Conclusions:
- RET and NTRK1 exhibit diverse roles in human health and disease.
- The type of genetic alteration (gain vs. loss of function) dictates the resulting pathology.
- Understanding these correlations is key to deciphering disease mechanisms.