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Secondary Hypertension caused by Aldosterone-producing Adenomas caused by Somatic Mutations in ATP1A1 and ATP2B3

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, tagged , , , , , on February 21, 2013| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension

Nature Genetics

Published online 17 February 2013
Mutations affecting a pair of related enzyme-coding genes can contribute to the 

risk of benign glandular tumors 

called adenomas and secondary hypertension, a new 

Nature Genetics

 study suggests. An international team led by investigators in Germany performed

exome sequencing

on matched tumor and normal samples from nine individuals with forms of adenoma that enhance aldosterone hormone production. This leads to a type of so-called aldosteronism that can bump up blood pressure and cause other adverse symptoms.

When researchers sorted through the exome sequence data, they saw ties between aldosterone-producing adenoma and mutations in two ATPase genes — ATP1A1 and ATP2B3 — that participate in sodium/potassium and calcium signaling, respectively. Somatic ATP1A1 mutations turned up in more than 5 percent of 308 aldosterone-producing adenoma samples screened subsequently, the team noted, while 1.6 percent of those tumors contained ATP2B3 alterations.

“[T]hese findings expand the spectrum of somatic alterations leading to [aldosterone-producing adenomas] to two members of the P-type ATPase pump family, extend knowledge of the molecular mechanism leading to [aldosterone-producing adenoma],” the Ludwig Maximilian University of Munich researcher Martin Reincke, the study’s corresponding author, and colleagues wrote, “and indicate new potential therapeutic targets for the most frequent secondary form of arterial hypertension.”

SOURCE:

http://www.genomeweb.com//node/1194476?hq_e=el&hq_m=1505701&hq_l=6&hq_v=6fcaf1aef4

Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension

Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na+/K+ ATPase α subunit) and ATP2B3 (encoding a Ca2+ ATPase) genes in three and two of the nine APAs, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium and calcium ion homeostasis. Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium. Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3.

Mutation-positive cases showed

  • male dominance,
  • increased plasma aldosterone concentrations and
  • lower potassium concentrations compared with mutation-negative cases.

In summary, dominant somatic alterations in two members of the ATPase gene family result in autonomous aldosterone secretion.

Author information

Primary authors

  1. These authors contributed equally to this work.

    • Maria-Christina Zennaro &
    • Tim M Strom

Affiliations

  1. Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany.

    • Felix Beuschlein,
    • Andrea Osswald,
    • Urs D Lichtenauer,
    • Evelyn Fischer &
    • Martin Reincke

  2. Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche Scientifique (UMRS) 970, Paris Cardiovascular Research Center, Paris, France.

    • Sheerazed Boulkroun,
    • Laurence Amar,
    • Benoit Samson-Couterie,
    • Pierre-Francois Plouin,
    • Xavier Jeunemaitre &
    • Maria-Christina Zennaro

  3. Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

    • Sheerazed Boulkroun,
    • Laurence Amar,
    • Benoit Samson-Couterie,
    • Pierre-Francois Plouin,
    • Xavier Jeunemaitre &
    • Maria-Christina Zennaro

  4. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

    • Thomas Wieland,
    • Anett Walther,
    • Thomas Schwarzmayr,
    • Susanne Diener,
    • Elisabeth Graf,
    • Thomas Meitinger &
    • Tim M Strom

  5. Department of Biomedicine, Aarhus University, Aarhus, Denmark.

    • Hang N Nielsen,
    • Vivien R Schack &
    • Bente Vilsen

  6. Medizinische Zellbiologie, Universität Regensburg, Regensburg, Germany.

    • David Penton,
    • Philipp Tauber &
    • Richard Warth

  7. Assistance Publique–Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.

    • Laurence Amar,
    • Pierre-Francois Plouin,
    • Xavier Jeunemaitre &
    • Maria-Christina Zennaro

  8. Department of Medicine I, Endocrine and Diabetes Unit, University Hospital Würzburg, Würzburg, Germany.

    • Bruno Allolio

  9. Centre National de la Recherche Scientifique (CNRS), Institut des Hautes Etudes Scientifiques, Bures sur Yvette, France.

    • Arndt Benecke

  10. Clinical Endocrinology, Campus Mitte, University Hospital Charité, Berlin, Germany.

    • Marcus Quinkler

  11. Department of Medicine, University of Padova, Padova, Italy.

    • Francesco Fallo

  12. Endocrine Unit, Department of Medicine, University of Padova, Padova, Italy.

    • Franco Mantero

  13. Institute of Human Genetics, Technische Universität München, Munich, Germany.

    • Thomas Meitinger &
    • Tim M Strom

  14. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.

    • Thomas Meitinger

  15. Department of Medical Sciences, Division of Internal Medicine and Hypertension, University of Torino, Turin, Italy.

    • Paolo Mulatero

Contributions

S.B., H.N.N., U.D.L., D.P., V.R.S., A.W., P.T., S.D. and B.S.-C. performed the experiments. A.O., T.W., L.A., E.F., T.S., T.M.S., E.G. and A.B. performed statistical analysis and analyzed the data. B.A., M.Q., F.F., P.-F.P., F.M. and P.M. contributed materials. F.B., T.M., X.J., R.W., B.V., M.-C.Z., T.M.S. and M.R. jointly supervised research, conceived and designed the experiments, analyzed the data, contributed reagents, materials and/or analysis tools and wrote the manuscript.

SOURCE:

http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.2550.html

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What is Cancer?

Posted in Biological Networks, Gene Regulation and Evolution, Bone Disease and Musculoskeletal Disease, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Personalized and Precision Medicine & Genomic Research, tagged , , , , , , , , , , , , , , , on May 7, 2012| 1 Comment »

Curator: Venkat Karra, Ph.D.

Cancer is a broad group of various diseases involving unregulated cell growth. It is medically known as a malignant neoplasm. In cancer, cells divide and grow uncontrollably and invade nearby parts of the body. The cancer may also spread to more distant parts of the body through the lymphatic system or bloodstream, it is called metastasis. However, not all tumors are cancerous. Some tumors do not grow uncontrollably, do not invade neighboring tissues, and do not spread throughout the body which are called Benign tumors.

There are more than 100 types of Cancers. Follow the link to know more:

http://www.cancer.gov/cancertopics/types/alphalist

Classification of Cancers:

There are five broad groups that are used to classify cancer.

  1. Carcinomas: These are characterized by cells that cover internal and external parts of the body such as lung, breast, and colon cancer.
  2. Sarcomas:These are characterized by cells that are located in bone, cartilage, fat, connective tissue, muscle, and other supportive tissues.
  3. Lymphomas:These are cancers that begin in the lymph nodes and immune system tissues.
  4. Leukemias:These are cancers that begin in the bone marrow and often accumulate in the bloodstream.
  5. Adenomas:These are cancers that arise in the thyroid, the pituitary gland, the adrenal gland, and other glandular tissues.

Causes

  • Hereditary (about 5-10%)
  • Environmental (90-95% of cases) factors e.g.,
  • Tobacco (25-30%) – about 70% of the lung cancers are due to tobacco habit
  • Infections (15-20%)
  • Radiation (both ionizing and non-ionizing, up to 10%)
  • Obesity (30-35%) and
  • Pollutants,Sedentary life, poor diet etc. are likely to cause cancer.

These can directly damage genes or combine with existing genetic faults within cells to cause the disease.

Detection

Presence of certain signs and symptoms, screening tests including medical imaging etc. can be used.

Diagnosis

Cancer can be diagnosed by microscopic examination of a tissue sample called biopsy.

Visit Link for details: http://cancer.stanford.edu/information/cancerDiagnosis/

Treatment

Cancer is usually treated with chemotherapy, radiation therapy and surgery.

Survival

Survival depends greatly by the type and location of the cancer and the extent of disease at the start of treatment. The risk of developing cancer generally increases with age.

Young People with Cancer, visit the following link for details:

http://www.cancer.gov/cancertopics/coping/youngpeople/page6

For Types of Childhood Cancer, visit the following link:

http://www.cancer.gov/cancertopics/coping/youngpeople/page13

For common medical procedures, visit the following link:
http://www.cancer.gov/cancertopics/coping/youngpeople/page6

Signs and Symptoms

Initially there will be no signs and symptoms but only appearing as the mass that continues to grow or ulcerates. The findings that result depends on the type and location of the cancer. For example,

Mass effects from Lung Cancer – can cause blockage of the bronchus resulting in cough (coughing up blood if there is ulceration) or pneumonia.

Oesophageal Cancer – can cause narrowing of the esophagus making it difficult or painful to swallow.

Colorectal Cancer – may lead to changes in bowel habits and bleeding leading to anemia.

General symptoms may include:

  • Unintentional weight loss,
  • Fever,
  • Being excessively tired,
  • Changes to the skin,
  • Hodgkin disease,
  • Leukemias, and
  • Persistent fever due to Cancers of the liver or kidney.

Symptoms of metastasis include:

  • Enlarged lynph nodes which can be felt or sometimes seen under the skin and are typically hard),
  • Enlarged liver or spleen which can be felt in the abdomen,
  • Pain or fracture of affected bones, and
  • Neurological symptoms.

It is nearly impossible to prove what caused a cancer in any individual, because most cancers have multiple possible causes. For example, lung cancer could be due to tobacco habbit or could be a result of air pollution or radiation.

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