ABSTRACT
Germline mutations in BUB1 and BUB3 have been reported to increase the risk of developing colorectal cancer (CRC) at young age, in presence of variegated aneuploidy and reminiscent dysmorphic traits of mosaic variegated aneuploidy syndrome. We performed a mutational analysis of BUB1 and BUB3 in 456 uncharacterized mismatch repair-proficient hereditary non-polyposis CRC families and 88 polyposis cases. Four novel or rare germline variants, one splice-site and three missense, were identified in four families. Neither variegated aneuploidy nor dysmorphic traits were observed in carriers. Evident functional effects in the heterozygous form were observed for c.1965-1G>A, but not for c.2296G>A (p.E766K), in spite of the positive co-segregation in the family. BUB1 c.2473C>T (p.P825S) and BUB3 c.77C>T (p.T26I) remained as variants of uncertain significance. As of today, the rarity of functionally relevant mutations identified in familial and/or early onset series does not support the inclusion of BUB1 and BUB3 testing in routine genetic diagnostics of familial CRC.
Subject(s)
Adenomatous Polyposis Coli/genetics , Cell Cycle Proteins/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Germ-Line Mutation , Poly-ADP-Ribose Binding Proteins/genetics , Protein Serine-Threonine Kinases/genetics , Spindle Apparatus/genetics , Cell Cycle Proteins/chemistry , Humans , Models, Molecular , Pedigree , Poly-ADP-Ribose Binding Proteins/chemistry , Protein Conformation , Protein Serine-Threonine Kinases/chemistryABSTRACT
Glycogen shortage during fasting coincides with dramatic changes in hepatic adenine nucleotide levels. The aim of this work was to study the relevance of liver glycogen in the regulation of the hepatic energy state during food deprivation. To this end, we examined the response of mice with sustained increased liver glycogen content to prolonged fasting. In order to increase hepatic glycogen content, we generated mice that overexpress protein targeting to glycogen (PTG) in the liver (PTGOE mice). Control and PTGOE mice were fed ad libitum or fasted for 36 h. Upon fasting, PTGOE mice retained significant hepatic glycogen stores and maintained hepatic energy status. Furthermore, we show that liver glycogen controls insulin sensitivity, gluconeogenesis, lipid metabolism, and ketogenesis upon nutrient deprivation.