Families with Incomplete Penetrance and Milder Expressivity

In about 10% of families with retinoblastoma, penetrance is incomplete (''low-penetrance retinoblastoma''). In some of these families, less than one in five mutation carriers is affected. Usually, incomplete penetrance is accompanied by milder expressivity, i.e., affected mutation carriers have retinoblastoma in one eye only. The spectrum of mutations in families with incomplete penetrance and mild expressivity is distinct from that of families with complete penetrance and includes:

• Promoter mutations. Predisposing RB1 gene mutations have been identified in motifs that bind transcriptions factors. The most likely result of such mutations is a reduced level of structurally normal transcript.[20]

• Missense and small in-frame mutations. These mutations result in substitution, deletion, or insertion of one or few amino acids that are part of the A/B pocket of the pRB. Functional studies have shown that mutant pRB expressed from these alleles shows only a partial loss of normal function.[21]

• Gross in-frame deletions. Deletions of exon 4[22] and of exons 24-25[23] have been found in extended pedigrees. These mutations result in an in-frame loss of 40 and 58 amino acids that are not part of the A/B pocket.

• Mutations that result in leaky splice defects. Splice mutations that affect splice signals in exons or less conserved intronic splice signals can be associated with milder expressivity and incomplete penetrance. One reasonable explanation is that the effect of these mutations on splicing is ''leaky,'' and therefore apart of the mutant transcript is processed into a normally spliced mRNA.[24] This would result in higher levels of normal transcript compared to cells heterozygous for null mutations.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

Get My Free Ebook

Post a comment