Descripción del proyecto
Análisis genético exhaustivo de la diabetes monogénica
La diabetes del adulto de inicio juvenil, una forma de diabetes monogénica, es una enfermedad mendeliana que hace referencia a cualquiera de las distintas formas hereditarias de diabetes mellitus provocadas por mutaciones en un gen autosómico dominante que interrumpen la producción de insulina. Los análisis genéticos no logran detectar mutaciones causales en más de la mitad de las enfermedades mendelianas conocidas, lo que pone de relieve la necesidad urgente de determinar el papel de las mutaciones no codificantes en esta enfermedad. El objetivo del proyecto financiado con fondos europeos DecodeDiabetes es desarrollar una estrategia para el análisis genético de las variaciones reguladoras en las enfermedades mendelianas. El proyecto creó recursos epigenómicos para interpretar el genoma regulador en el páncreas embrionario y en islotes pancreáticos adultos. Es más, los investigadores recopilaron una gran cohorte internacional de pacientes con un fenotipo compatible con la diabetes monogénica y con una mayor probabilidad de presentar mutaciones no codificantes. Estos recursos, utilizados en combinación con tecnologías innovadoras, permitirán descubrir mutaciones no codificantes causales.
Objetivo
Whole genome sequencing is quickly becoming a routine clinical instrument. However, our ability to decipher DNA variants is still largely limited to protein-coding exons, which comprise 1% of the genome. Most known Mendelian mutations are in exons, yet genetic testing still fails to show causal coding mutations in more than 50% of well-characterized Mendelian disorders. This defines a pressing need to interpret noncoding genome sequences, and to establish the role of noncoding mutations in Mendelian disease.
A recent case study harnessed whole genome sequencing, epigenomics, and functional genomics to show that mutations in an enhancer cause most cases of neonatal diabetes due to pancreas agenesis. This example raises major questions: (i) what is the overall impact of penetrant regulatory mutations in human diabetes? (ii) do regulatory mutations cause distinct forms of diabetes? (iii) more generally, can we develop a strategy to systematically tackle regulatory variation in Mendelian disease?
The current project will address these questions with unique resources. First, we have created epigenomic and functional perturbation resources to interpret the regulatory genome in embryonic pancreas and adult pancreatic islets. Second, we have collected an unprecedented international cohort of patients with a phenotype consistent with monogenic diabetes, yet lacking mutations in known gene culprits after genetic testing, and therefore with increased likelihood of harboring noncoding mutations. Third, we have developed a prototype platform to sequence regulatory mutations in a large number of patients.
These resources will be combined with innovative strategies to uncover causal enhancer mutations underlying Mendelian diabetes. If successful, this project will expand the diagnostic spectrum of diabetes, it will discover new genetic regulators of diabetes-relevant networks, and will provide a framework to understand regulatory variation in Mendelian disease.
Ámbito científico
Not validated
Not validated
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
08003 Barcelona
España