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RB1 gene mutation up-date, a meta-analysis based on 932 reported mutations available in a searchable database.

ABSTRACT: BACKGROUND: Retinoblastoma, a prototype of hereditary cancer, is the most common intraocular tumour in children and potential cause of blindness from therapeutic eye ablation, second tumours in germ line carrier's survivors, and even death when left untreated. The molecular scanning of RB1 in search of germ line mutations lead to the publication of more than 900 mutations whose knowledge is important for genetic counselling and the characterization of phenotypic-genotypic relationships. RESULTS: A searchable database (RBGMdb) has been constructed with 932 published RB1 mutations. The spectrum of these mutations has been analyzed with the following results: 1) the retinoblastoma protein is frequently inactivated by deletions and nonsense mutations while missense mutations are the main inactivating event in most genetic diseases. 2) Near 40% of RB1 gene mutations are recurrent and gather in sixteen hot points, including twelve nonsense, two missense and three splicing mutations. The remainder mutations are scattered along RB1, being most frequent in exons 9, 10, 14, 17, 18, 20, and 23. 3) The analysis of RB1 mutations by country of origin of the patients identifies two groups in which the incidence of nonsense and splicing mutations show differences extremely significant, and suggest the involvement of predisposing ethnic backgrounds. 4) A significant association between late age at diagnosis and splicing mutations in bilateral retinoblastoma patients suggests the occurrence of a delayed-onset genotype. 5) Most of the reported mutations in low-penetrance families fall in three groups: a) Mutations in regulatory sequences at the promoter resulting in low expression of a normal Rb; b) Missense and in-frame deletions affecting non-essential sequence motifs which result in a partial inactivation of Rb functions; c) Splicing mutations leading to the reduction of normal mRNA splicing or to alternative splicing involving either true oncogenic or defective (weak) alleles. CONCLUSION: The analysis of RB1 gene mutations logged in the RBGMdb has shown relevant phenotype-genotype relationships and provided working hypothesis to ascertain mechanisms linking certain mutations to ethnicity, delayed onset of the disease and low-penetrance. Gene profiling of tumors will help to clarify the genetic background linked to ethnicity and variable expressivity or delayed onset phenotypes.

SUBMITTER: Valverde JR

PROVIDER: S-EPMC1298292 | biostudies-literature | 2005

REPOSITORIES: biostudies-literature

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RB1 gene mutation up-date, a meta-analysis based on 932 reported mutations available in a searchable database.

Valverde José R JR Alonso Javier J Palacios Itziar I Pestaña Angel A

BMC genetics 20051104

<h4>Background</h4>Retinoblastoma, a prototype of hereditary cancer, is the most common intraocular tumour in children and potential cause of blindness from therapeutic eye ablation, second tumours in germ line carrier's survivors, and even death when left untreated. The molecular scanning of RB1 in search of germ line mutations lead to the publication of more than 900 mutations whose knowledge is important for genetic counselling and the characterization of phenotypic-genotypic relationships.<h ...[more]

PMID: 16269091

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Project description:BackgroundMedical school curricula strives to teach as much material as can be retained in a limited amount of time. A common "gold standard" resource used building curricula are medical objectives suggested by national societies. Unfortunately these objectives suffer from several functional limitations such as limited accessibility to society members, non-searchable formats (such as nested tables or pdf images), and inability to compare and search across societal objectives for redundancy or gaps. The shift towards integrated curriculums in medical school also highlights the need to access suggested content across classical discipline categories.Main bodyWe have codified recommendations from national societies in the United States for medical school objectives in a common tabular format and developed an open access database which can be searched across disciplines and societies. A front end website that allows for searching objectives by keyword while filtering on society or discipline was created. The objectives returned from the initial search can be subsearched by a second term. There is a large range in the format, age, breadth, quantity, and quality of objectives from different societies. Some unique disciplines have overlapping suggested content though most of the content does seem "binnable" by discipline. The choice of metadata for objectives from each given society was also very inconsistent.ConclusionA free and searchable database of medical content to deliver during medical school has been developed with over 13,000 objectives from 18 societies and 22 disciplines at http://data.medobjectives.marian.edu/ . The normalization of the different disciplines' objectives into a common database allows a platform to standardize objectives moving forward. Future work could include adding user accounts to access the database, submission of new objectives, voting up and down suggested objectives, and adding "answers" mapped to objectives. Keyword tagging could allow import of content (e.g. PowerPoints) and outputting of suggested objectives, which would also allow comparison of curriculum across medical schools.

Dataset Information

RB1 gene mutation up-date, a meta-analysis based on 932 reported mutations available in a searchable database.

Publications

RB1 gene mutation up-date, a meta-analysis based on 932 reported mutations available in a searchable database.

Similar Datasets

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