Maternal inheritance associated with higher mutant RB1 expression than paternal inheritance

Retinoblastoma (Rb), the most common pediatric intra-ocular malignancy, results from inactivation of both alleles of the RB1 tumor suppressor gene. The second allele is most commonly lost, as demonstrated by loss of heterozygosity studies. RB1 germline carriers usually develop bilateral tumors, but some Rb families display low penetrance and variable expressivity. In order to decipher the underlying mechanisms causing this phenomenon, authors [see below] studied 23 non-related low penetrance pedigrees segregating the common c.1981C>T/p.Arg661Trp mutation and other low-penetrance mutations.

In families segregating the c.1981C>T mutation, authors demonstrated a correlation between the gender of the transmitting carrier and penetrance, as evidenced by Fisher’s exact test: the probability of being unaffected is 90.3%, versus 32.5%, when the mutation is inherited from the mother versus the father, respectively (P = 7e–07). Interestingly, similar correlations were observed in families segregating other low-penetrance alleles. Consequently, authors investigated the putative involvement of an imprinted modifier gene in low-penetrance Rb. First, they ruled out a MED4-driven mechanism (by MED4 methylation and expression analyses). They then focused on the differentially methylated CpG85 island located in intron 2 of RB1 that shows parent-of-origin-specific DNA methylation; this differential methylation promotes expression of the maternal c.1981C>T allele.

Authors propose that the maternally inherited c.1981C>T allele, encoding the Arg661Trp mutation, retains sufficient tumor suppressor activity to prevent the development of retinoblastoma. In contrast, when the mutation is paternally transmitted, the low residual activity would mimic a null mutation and, subsequently, lead to retinoblastoma. This implies that the c.1981C>T mutation is not deleterious per se, but rather needs to be destabilized in order to reach pRb haploinsufficiency and initiate tumorigenesis. The authors suggest that this phenomenon might be a general mechanism to explain phenotypic differences in low-penetrance Rb families.

 PLoS Genet  2o16;  12: e1005888

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