SMALL SEQUENCE VARIANTS IN RB1 GENE AND THEIR CORRELATION WITH THE FUNCTIONAL DOMAINS OF RETINOBLASTOMA PROTEIN

DIANA PARMA; NICOHOL TOVAR MATELO; FERRER MARCELA,; GILIBERTO FLORENCIA; SZIJAN IRENE

Mar del Plata

Congreso; SAIC SAI&FAIC SAFIS 2022 LXVII SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2022

SMALL SEQUENCE VARIANTS IN RB1 GENE AND THEIR CORRELATION WITH THE FUNCTIONAL DOMAINS OF RETINOBLASTOMA PROTEINDiana Parma1, Nicohol Tovar Matelo1, Marcela Ferrer2, Florencia Giliberto1, Irene Szijan11.Cátedra de Genética, INIGEM, UBA-CONICET Buenos Aires, Argentina. 2. Servicio de Genética, Hospital de Clínicas “José de San Martín” UBA Buenos Aires, Argentina.Retinoblastoma (RB) is the most frequent ocular pediatric tumor, it occurs by biallelic inactivation of the tumor suppressor RB1gene. RB may be hereditary or non-hereditary and the predisposition to RB is transmitted as an autosomal dominant trait with a 90% of penetrance. Alterations that inactivate RB1 may be gross rearrangements or small sequence variants. The small size changes include nucleotide substitutions and indels and they encompass 80% of all RB1 alterations. Nucleotide substitution, the most common variant, occurs by transient misalignment of one DNA strand. This alteration originates nonsense, missense or splice-site variants. Our aim was to study all the nucleotide substitutions and small indels annotated in the database http://rb1-lovd.d-lohmann.de to uncover the frequency of different variants, their correlation with the clinical presentation and their effect on the retinoblastoma protein (pRb) functional domains. The number of variants analyzed was 1748, 47% of them were nonsense, 14% missense, 31% splice-site and 7% small indels. The small germinal variants mainly gave rise to bilateral RB (72%-92%), while the somatic ones originated unilateral RB. The location of variations in pRb domains showed the highest frequency of them in the Pocket domain, a site of binding of the transcription factor E2F (58% for nonsense, 64% for missense, 50% for splice-site and 45% for small indels). The site more mutated of the consensus sequence for splicing was the first nucleotide of the donor, which is the driver of the splicing process. Moreover, the frequency of variants in the donor site vs acceptor site was 74% vs 26%. Conclusions: The highest percentage of variants was for the nonsense substitutions, followed by splice-site, missense and small indels. All germline variants occurred mostly in bilateral RB. The substitutions and small indels were mainly located in the Pocket domain, which is the major functional site for the regulatory process of pRb.