APC or MUTYH mutations account for the majority of clinically well-characterized families with FAP and AFAP phenotype and patients with more than 30 adenomas.

Patients presenting familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP) or multiple colorectal adenomas (MCRAs) phenotype are clinically difficult to distinguish. We aimed to genetically characterize 107 clinically well-characterized patients with FAP-like phenotype, and stratified according to the recent guidelines for the clinical management of FAP: FAP, AFAP, MCRA (10-99 colorectal adenomas) without family history of colorectal cancer or few adenomas (FH), MCRA (10-99) with FH, MCRA (3-9) with FH. Overall, APC or MUTYH mutations were detected in 42/48 (88%), 14/20 (70%) and 10/38 (26%) of FAP, AFAP and MCRA patients, respectively. APC and MUTYH mutations accounted for 81% and 7% of FAP patients and for 30% and 40% of AFAP patients, respectively. Notably, MCRA patients did not present APC mutations. In 26% of these patients, an MUTYH mutation was identified and the detection rate increased with the number of adenomas, irrespectively of family history, being significantly higher in MCRA patients presenting more than 30 adenomas [7/12 (58%) vs 2/14 (14%), p = 0.023]. We validate the recently proposed guidelines in our patient's cohort and show that APC or MUTYH germline defects are responsible for the majority of clinically well-characterized patients with FAP and AFAP phenotype, and patients with more than 30 colorectal adenomas. The different mutation frequencies according to family history and to the number of adenomas underscore the importance of an adequate familial characterization, both clinically and by colonoscopy, in the management of FAP-like phenotypes. The phenotypes of the mutation-negative patients suggest distinct etiologies in these cases.

Autoradiographic localization of CRF1 and CRF2 binding sites in adult rat brain.

The regional distribution of corticotropin-releasing factor1 (CRF1) and CRF2 binding sites was assessed autoradiographically in adult rat brain. The differential pharmacological profiles of the CRF1 and CRF2 receptor subtypes were used for the discrimination of the CRF1 and CRF2 receptor subtypes in rat brain. Pharmacological characterization at the human CRF1 receptor subtype, expressed in baculovirus-infected Sf9 cells, showed high affinity binding (Ki < or = 10.0 nM) for the peptide agonists sauvagine, urotensin I, rat/human CRF, and ovine CRF. Pharmacological characterization at the rat CRF2 receptor subtype expressed in CHO cells showed a rank order affinity for the peptide agonists such that sauvagine, urotensin I and rat/human CRF showed high affinity binding whereas ovine CRF had a Ki value of 300 nM. Based on this differential binding affinity for ovine CRF, [125I]sauvagine binding in the presence of increasing concentrations of ovine CRF was used to discriminate CRF1 from CRF2 receptor subtypes in rat brain. The CRF1 receptor subtype was found to be localized to various regions of the cerebellum, as well as to several cortical areas. The CRF2 receptor subtype was shown to be localized to the lateral septal nucleus, entorhinal cortex, and to amygdaloid and hypothalamic regions. The present autoradiographic findings provide evidence that each subtype has a distinct regional distribution, thus strengthening the suggestion that CRF1 and CRF2 receptors serve different roles in mediating CRF function. Such data suggest that the development of CRF receptor subtype selective antagonists should help to delineate the role of CRF1 and CRF2 receptor subtypes in central nervous system function.