The RET gene and its associated diseases

Protein kinases can be classified in two main classes serine/threonine and tyrosine kinases. They show auto-phosphorylation in response to stimuli (ligands) and can thereby phosphorylate substrate proteins. For many protein kinases the signalling pathways and also the ligands or stimuli which activate them, are still unknown. The RET proto-oncogene encodes a receptor tyrosine kinase involved in the normal development and the neoplastic growth of neural crest cell lineages. The ligand of the receptor is as yet unidentified. During embryogenesis RET expression is high in neuroectodermal tissues, suggesting a function of RET in the proliferation, the migration and the differentiation of these cell types. In adult tissues the gene is hardly expressed. Expression is high in several tumor types derived from neural crest cells. Transfection studies with DNA from different tumors revealed focal proliferation due to the presence of different DNA sequences that, however, shared a common part called RET. The original RET gene turned out to be rearranged in such a way that the sequences coding for the extracellular part of its protein product were replaced by sequences from elsewhere, resulting in a rearranged protein with a constitutive tyrosine kinase activity. The same rearrangement occurs in papillary thyroid carcinoma (PTC). Protein kinases can be involved in various ways in neoplastic syndromes and tumors, and in non-neoplastic hereditary diseases. This also holds true for RET. After the genes involved in both MEN 2A and MEN 2B and in HSCR had been mapped to the centromeric region of chromosome 10 by linkage analysis, mutations of RET, a gene present in this very region, were found responsible for the development of these diseases. MEN 2A and MEN 2B are associated with specific mutations in the RET gene resulting in an activation of the protein translated, whereas HSCR is associated with mutations resulting in a functional loss of the translated protein.

Congenital Short Bowel Syndrome: from clinical and genetic diagnosis to the molecular mechanisms involved in intestinal elongation

AbstractCongenital Short Bowel Syndrome (CSBS) is a rare gastrointestinal disorder in which the mean length of the small intestine is substantially reduced when compared to its normal counterpart. Families with several affected members have been described and CSBS has been suggested to have a genetic basis. Recently, our group found mutations in CLMP as the cause of the recessive form of CSBS, and mutations in FLNA as the cause of the X-linked form of the disease. These findings have improved the quality of genetic counselling for CSBS patients and made prenatal diagnostics possible. Moreover, they provided a reliable starting point to further investigate the pathogenesis of CSBS, and to better understand the development of the small intestine. In this review, we present our current knowledge on CSBS and discuss hypotheses on how the recent genetic findings can help understand the cause of CSBS

Mutations in SCG10 Are Not Involved in Hirschsprung Disease

Hirschsprung disease (HSCR) is a congenital malformation characterized by the absence of enteric neurons in the distal part of the colon. Several genes have been implicated in the development of this disease that together account for 20% of all cases, implying that other genes are involved. Since HSCR is frequently associated with other congenital malformations, the functional characterization of the proteins encoded by the genes involved in these syndromes can provide insights into the protein-network involved in HSCR development. Recently, we found that KBP, encoded by the gene involved in a HSCR- associated syndrome called Goldberg-Shprintzen syndrome, interacts with SCG10, a stathmin-like protein. To determine if SCG10 is involved in the etiology of HSCR, we determined SCG10 expression levels during development and screened 85 HSCR patients for SCG10 mutations. We showed that SCG10 expression increases during development but no germline mutation was found in any of these patients. In conclusion, this study shows that SCG10 is not directly implicated in HSCR development. However, an indirect involvement of SCG10 cannot be ruled out as this can be due to a secondary effect caused by its direct interactors