A T to C mutation in the polypyrimidine tract of the exon 9 splicing site of the RB1 gene responsible for low penetrance hereditary retinoblastoma

The N Terminus of the Retinoblastoma Protein Inhibits DNA Replication via a Bipartite Mechanism Disrupted in Partially Penetrant Retinoblastomas

“…An intact N-terminal domain of Rb is required for tumor suppression in transgenic mice (7), and N-terminal loss-of-function inframe exon deletions are associated with partially penetrant retinoblastoma (8,(10)(11)(12)(13)(14). Since C-terminal loss-of-function mutations in Rb produce nearly full penetrant disease, growthregulatory defects arising from N-terminal in-frame exon deletions of Rb are arguably distinct in function from C-terminal deficiencies.…”

“…Inframe deletions and mutations have also been found in Rb exons 6 and 8 in prostate cancers and astrocytomas, respectively (15, 16). Furthermore, in contrast to pocket mutations, N-terminal inframe deletions in Rb generally display partial penetrance for the development of retinoblastoma (6,8,(11)(12)(13)(14). For example, transgenic mice expressing Rb proteins with N-terminal in-frame deletions produce a partial-penetrance phenotype for tumor development (7).…”

“…These lesions leave an intact C-terminal pocket and generate stable forms of Rb that bind E2F transcription factors and localize to the nucleus in a fashion similar to that of wild-type Rb (wt-Rb) (6)(7)(8)(9)(10). Several in-frame RbN exon deletions in familial retinoblastomas have been reported, including individual losses of exon 4 (Ex4), Ex5, Ex7, or Ex9 (11)(12)(13)(14). Inframe deletions and mutations have also been found in Rb exons 6 and 8 in prostate cancers and astrocytomas, respectively (15,16).…”

SCARB1 Gene Variants Are Associated With the Phenotype of Combined High High-Density Lipoprotein Cholesterol and High Lipoprotein (a)

“…The c.631-14T>G base change in subject 4 is located within a polypyrimidine sequence, which may affect mRNA splicing. 34 The base change in subjects 2 and 3 is located just after the ATG initiation codon and was previously found to be important for efficient protein translation. 35 The base change in subjects 8 and 9 is predicted to impair function of the translated protein.…”

“…The mutations in subjects 4 and 5, potentially affecting intron splicing 34 and altering DNA methylation pattern, 37 were tested by making wild-type and mutant types of minigenes containing exons 4 through 6 of SCARB1. Splicing of the SCARB1 minigenes was examined by reverse transcriptase PCR after transfection of 293 cells.…”