Next-generation sequencing to provide precision medicine for rare
metabolic disorders

Date:
June 30, 2020
Source:
University of Bern
Summary:
Advances in next-generation-sequencing technology that allow
researchers to look at billions of pieces of genetic information are
changing the way a disease is diagnosed. Correct identification of
changes in the human genetic code responsible for rare metabolic
disorders provides scientists and physicians with fact-based
guidelines for the treatment.



FULL STORY ========================================================================== Advances in next-generation-sequencing technology that allow researchers
to look at billions of pieces of genetic information are changing the
way a disease is diagnosed. Correct identification of changes in the
human genetic code responsible for rare metabolic disorders provides
scientists and physicians with fact-based guidelines for the treatment.


==========================================================================
An international team of scientists from Switzerland Spain, has studied
the genetic basis of aromatase deficiency, a rare metabolic disorder that prevents the production of estrogens in humans, according to new research
in JCEM (Journal of Clinical Endocrinology and Metabolism). The latest
studies on aromatase deficiency in humans come from the group of Amit
V. Pandey and Christa E. Flu"ck at the Department for BioMedical Research, University of Bern, and Pediatric Endocrinology, University Children's
Hospital Bern, done in collaboration with Laura Audi' at Hospital
Vall d'Hebron, Autonomous University of Barcelona, Spain. Scientists
found the answers by analysis of the DNA map of patients with aromatase deficiency and comparing those with DNA of the broader human population
from different ethnic groups.

"Supplementation with steroids can target multiple different pathways,
so we wanted to know which part of genetic code was changed in patients
in order to target therapies to the appropriate place," writes Dr. Amit
Pandey, University of Bern and Inselspital, University Hospital Bern,
with coauthors. "We knew we had cases of genetic disorders leading to
aromatase deficiency, but we needed to find the exact cause of disease,
and modern DNA sequencing helped us find it." Bern expertise helps
solving a special case Collaborating with genetics specialists at the
Vall d'Hebron Hospital in Barcelona (Laura Audi, Nu'ria Camats and
Mo'nica Ferna'ndez-Cancio) and Hospital Universitario La Paz, Madrid
(Sara Benito-Sanz), Pandey focused on a patient with aromatase deficiency identified by Dr. Juan-Pedro Lo'pez-Siguero at Hospital Carlos Haya, Universidad de Ma'laga, Spain. What caused the attention of geneticists
in Barcelona and Madrid was the observation that patient has symptoms
of aromatase deficiency, but, when the gene for aromatase (CYP19A1)
was sequenced, no defects were found.

Through the use of next-generation sequencing technology that
simultaneously looks at billions of pieces of genetic code, Spanish
scientists identified an error in the gene for cytochrome P450
oxidoreductase (POR). Laboratory of Pediatric Endocrinology in Bern, Switzerland, is a world leader in metabolic disorders caused by mutations
in POR The Swiss and Spanish teams joined forces and set out to find
how the aromatase deficiency was being caused by a defect in the POR
gene. Amit Pandey has been studying the POR gene for many years and knew
that aromatase activity to produce estrogens requires energy supply from
POR and had the systems in place to measure the impact of changes in
POR on estrogen production. Dr. Shaheena Parween, in the laboratory of
Amit Pandey, was able to genetically modify the POR gene to duplicate the defect found in the patient and used E.coli bacteria in the laboratory to produce a copy of POR enzyme matching the genetic sequence of the patient.



========================================================================== Scientists in Bern could show that POR made with the genetic code of the patient had lost most of its ability to provide energy to the aromatase
enzyme.

Therefore, even with a correct aromatase enzyme, the patient could not
produce sufficient estrogens. Learning the exact metabolic step where
the aromatase deficiency was originating from, allows the physicians to
guide the therapy very precisely and prevent side effects associated with steroid supplementation. The study demonstrated the powerful diagnostic
ability of next-generation sequencing technologies.

Supporting research in Africa and India The Bern team extended their
studies by looking at more patients with aromatase deficiency from Africa
and India and identified the exact causes of genetic defects responsible
for the loss of estrogen production. These findings have been reported
in JES (Journal of the Endocrine Society), and recently been discussed in
PNAS (Proceedings of the National Academy of Sciences of the United States
of America). Collaboration with the scientists in Bern, Switzerland,
allowed the use of advanced diagnostic and assay technologies not
available in local hospitals, which highlights the role of international collaborations in the diagnosis and therapy of rare metabolic disorders.

Variations of POR common in specific populations The research team
of Pandey and Flu"ck is also studying genetic mutations in POR that
cause other diseases, such as congenital adrenal hyperplasia, a common inherited disorder that affects a large number of people each year. Pandey highlights the value of translational medicine in his research. From
his previous work, Pandey knew that the POR gene in humans has lots of variations, and some populations carry specific mutations to a greater
extent than others.



==========================================================================
The Laboratory of Gianfranco Gilardi and Giovanna Di Nardo at the
University of Torino, Italy, had studied a common variation of aromatase
that was predominant in the south-east Asian population. The scientists
in Bern and Turin teamed up to check what if the same individual has
an alternative form of both the POR and aromatase genes. By preparing
the variations of POR and aromatase proteins based on genetic changes
observed in the South-east Asian population, scientists could show that
a compounding effect can be found when there is a change in POR and
aromatase genes at the same time. These findings have been reported in
JSBMB (Journal of Steroid Biochemistry and Molecular Biology).

The power of genomics for Precision Medicine Some of the variations in
the POR gene are quite common in specific populations, so Pandey advises looking at changes in the POR gene whenever a defect in other genes
that are dependent on POR is identified. With the power of whole-genome sequencing at our disposal, it is time to move on from the theories
of monogenic disorders as individual patients in the world are not the
same in their genetic composition, says Pandey. "All humans have very
similar genes, but still may 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 therapies can be
used that are tailored for individual patients," Pandey said. "We are
now seeing the power of genomics tailored for use in Precision Medicine, allowing the design of specific treatments for a patient according to
their genetic makeup." Precision medicine will be a vital component
of the NextGen Precision Health Initiative by helping to accelerate
medical breakthroughs for both patients in Switzerland and beyond. A
center of rare diseases has recently been established at Inselspital, University Hospital Bern, to focus on diagnosis and research on rare
metabolic disorders.

These studies were funded by the Swiss National Science Foundation,
Novartis Foundation for Medical Biological Research, Switzerland, Burgergemeinde, Bern, Switzerland , Fondo de Investigacio'n Sanitaria,
ISCIII, Spain, and CRT Foundation, Italy.


========================================================================== Story Source: Materials provided by University_of_Bern. Note: Content
may be edited for style and length.


========================================================================== Journal References:
1. Amit V Pandey, Laura Audi', Christa E Flu"ck, Norio Kagawa, Sameer S
Udhane, Juan-Pedro Lo'pez-Siguero, Maria Natalia Rojas Velazquez,
Nu'ria Camats, Sara Benito-Sanz, Mo'nica Ferna'ndez-Cancio,
Shaheena Parween.

Molecular Basis of CYP19A1 Deficiency in a 46,XX Patient With
R550W Mutation in POR: Expanding the PORD Phenotype. The Journal
of Clinical Endocrinology & Metabolism, 2020; 105 (4): e1272 DOI:
10.1210/clinem/ dgaa076
2. Christa E. Flu"ck, Shaheena Parween, Maria Natalia Rojas Velazquez,
Amit
V. Pandey. Inhibition of placental CYP19A1 activity remains as
a valid hypothesis for 46,XX virilization in P450 oxidoreductase
deficiency.

Proceedings of the National Academy of Sciences, 2020; 202003154
DOI: 10.1073/pnas.2003154117
3. Shaheena Parween, Giovanna DiNardo, Francesca Baj, Chao Zhang,
Gianfranco
Gilardi, Amit V. Pandey. Differential effects of variations
in human P450 oxidoreductase on the aromatase activity of
CYP19A1 polymorphisms R264C and R264H. The Journal of Steroid
Biochemistry and Molecular Biology, 2020; 196: 105507 DOI:
10.1016/j.jsbmb.2019.105507
4. Christa E Flu"ck, Amit V Pandey, Aurel Perren, Mafalda Trippel,
Efstathios Katharopoulos, Annie Pulickal, Kay-Sara Sauter, Asmahane
Ladjouze, Valiyaparambil Pavithran Praveen. Novel CYP19A1 Mutations
Extend the Genotype-Phenotype Correlation and Reveal the Impact
on Ovarian Function. Journal of the Endocrine Society, 2020; 4
(4) DOI: 10.1210/jendso/bvaa030 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200630131720.htm

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