Researchers show how mutations in dark genome cause pancreatic malformations: Mutations in EnhP is most clear-cut example to date of how disruptions in non-protein coding DNA elements cause disease

Researchers at the Centre for Genomic Regulation (CRG) have identified a DNA sequence that is crucial for pancreatic differentiation and function — and for the first time — describe how it works.

Patients with mutations in a DNA sequence — which they coin EnhP — develop pancreas malformations. It is the most clear-cut example to date of an inherited disease that is caused by mutations that do not disrupt the DNA sequence of a gene.

Disorders?caused by mutations in a single DNA sequence, for example Huntington disease or sickle cell anaemia, are known as monogenic diseases. In the vast majority of cases, such mutations disrupt a protein-coding gene. In this case, the mutations in EnhP disrupt a single “enhancer” instead of a single gene.

Our genomes contain hundreds of thousands of DNA elements that are thought to act as enhancers. These enhancer DNA sequences act as switches to turn on the transcription of their target genes in the right tissues.

According to the authors of the study, published today in Developmental Cell, EnhP is by no means the only enhancer defect to cause disease. Mutations in enhancers may be the cause of a monogenic disease in many patients in which laboratory tests have failed to disclose causal gene mutations.

Understanding the role of enhancers in disease could change how we practice medicine. “Clinical genetics is shifting from a focus on sequencing protein-coding genes to sequencing whole genomes. It is now theoretically possible to discover disease-causing mutations that lie outside of traditional areas of the genome, although it is still challenging to discern which parts of the genome are truly vulnerable to mutations,” explains Dr. Jorge Ferrer, senior author of the study, Coordinator of the Medical Genomics Transversal Programme at the CRG and Group Leader at CIBERDEM.

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