"Next Generation Sequencing" helps researching a rare hormonal disease

Billions of genes can be examined simultaneously with "Next Generation Sequencing". The method helped researchers identify a gene mutation causing a rare hormone disease. Such precision medicine could develop tailor-made therapies and avoid side effects.

Genetic causes of aromatase deficiency were investigated

Thanks to "Next Generation Sequencing", billions of genes can be examined simultaneously. With this pioneering method, researchers at the University of Berne and the Berne Inselspital University Hospital (in German: Inselspital, Universitätsspital Bern) have now been able to identify a gene mutation that leads to a rare hormone disease. This is an example of how precision medicine may be used in the future to develop tailor-made therapies and avoid side effects.

An international team of researchers led by Amit Pandey and Christa Flück from the Department for BioMedical Research (DBMR) at the University of Berne and the Department of Pediatric Endocrinology at the University Children's Hospital Berne (in German: Abteilung für pädiatrische Endokrinologie der Universitätskinderklinik Bern) has investigated the genetic causes of aromatase deficiency, a rare metabolic disorder. This congenital disease prevents the production of estrogens. In girls, an aromatase deficiency leads to masculinization already in the fetus and later to a lack of puberty development. In boys, among other things, large growth can occur due to a lack of growth arrest. This is caused by a defect in the gene that forms the aromatase enzyme.

The researchers identified a previously unknown mechanism that prevents the production of estrogen - even if the aromatase enzyme responsible is present. The results are based on a collaboration between the Bern group and Spanish researchers and have now been published in the Journal of Clinical Endocrinology and Metabolism (JCEM). This publication is the most recent from the group around Amit Pandey, who, thanks to their precision medical approach and international networking, has achieved several breakthroughs in the field of sex hormone disorders, including how fetal masculinization occurs in the womb.

A jigsaw puzzle is put together

"Aromatase deficiency can be treated with hormone replacement therapy. However, this therapy has side effects. That's why we wanted to know which part of the genetic code was altered in the patients in order to target the right place for future therapies," says Amit Pandey, further explaining that "modern DNA sequencing helped us do this." Pandey had been made aware of a special case by Spanish geneticists: one patient showed symptoms of aromatase deficiency, but no defects were found in the sequencing of the gene responsible for aromatase. However, by using the "Next Generation Sequencing" technology, which simultaneously examines billions of parts of the genetic code, the researchers identified a defect in another gene. This gene forms a specific enzyme, cytochrome P450 oxidoreductase (POR).

This is where Amit Pandey's group came in: his laboratory for pediatric endocrinology is a leader in the field of metabolic disorders caused by mutations of this POR gene. Through his many years of research into the POR gene, Pandey knew that aromatase depends on the energy supply by the POR enzyme to produce estrogens. "We had the methods to find out exactly how a change in POR now affects estrogen production," explains Pandey.

Shaheena Parween and his group were able to genetically modify the POR gene to match the defect found in the patient and recreated the production of the patient's POR enzyme in Escherichia coli bacteria. The researchers from Berne were able to show that POR, produced with the patient's genetic defect, had lost most of its ability to support estrogen production. "As a result, even with a correct aromatase enzyme, the patient could no longer produce sufficient estrogens," explains Pandey. Knowing the exact mechanism that leads to aromatase deficiency allows physicians to accurately control current estrogen replacement therapies. This also opens up possibilities for new therapeutic approaches. "Our study demonstrated the powerful diagnostic capabilities of modern sequencing technologies," says Pandey.

Support for research in Africa and India

The Berne team expanded its studies by examining more patients with aromatase deficiency from Africa and India and identifying the exact causes of the genetic defects responsible for the loss of estrogen production. The collaboration with the researchers from Berne enabled the use of advanced diagnostic and testing technologies that are not available in local hospitals. "This underlines the role of international cooperation in the diagnosis and treatment of rare metabolic disorders," emphasizes Pandey.

Bern as an ideal location

"All humans have very similar genes, but can still have up to a million or more differences in their genetic code, even between a daughter and her mother. So if we find out exactly what causes a disease, then precise diagnoses can be made and new targeted therapies developed," says Pandey. "Modern sequencing technologies are advancing precision medicine - making it possible to develop tailor-made treatments for patients according to their genetic make-up," Pandey adds. In the field of rare metabolic diseases, in particular, Pandey said that the medical location of Berne is ideally positioned with the two new foundations of the Berne Center for Precision Medicine (BCPM) at the University of Berne and the Center for Rare Diseases at the Inselspital.

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