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Mutations in gene cause brain calcifications in humans and mice

Press release   •   Aug 05, 2013 07:20 BST

Why many diseases lead to calcifications in the brain is not known. New insights into the genetic causes of familial idiopathic basal ganglia calcification (FIBGC), also referred to as Fahr’s disease, pinpoint brain pericytes and a defective blood-brain barrier (BBB) as likely culprits in brain calcification. The findings were recently published in the journal Nature Genetics.

An international collaboration involving researchers from Switzerland, Germany, Brazil, Spain, France, Serbia, Canada, Iran, USA and Sweden now report that loss-of-function mutations in the gene encoding platelet-derived growth factor-B (PDGF-B), a growth factor important for blood vessel development and BBB maturation, cause FIBGC in humans as well as a similar disease in mice.

The widespread use of non-invasive imaging techniques, such as computerized tomography in modern medicine, has identified ectopic brain calcification (formation of bone-like tissue) as the single most common radiological finding. Most calcifications are thought to represent nonspecific age-related changes; however, they also often accompany neurodegenerative diseases such as Parkinson’s, and Alzheimer’s. In addition, brain calcifications are encountered in diverse conditions such as trauma, infection and even certain brain tumors.
In some instances, the tendency to develop brain calcifications is inherited. FIBGC is an example of an inherited disease, where a single copy of the mutant gene is sufficient to cause brain calcifications. Patients with FIBGC suffer from Parkinson-like movement disorders, migraine, psychosis, as well as dementia and seizures.

FIBGC is a monogenic disease, which means that mutations in a single gene cause the disease. During the past year, loss-of-function mutations in two other genes have been linked to FIBCG. These genes encode inorganic phosphate co-transporter SLC20A2 and PDGF receptor-beta (PDGF-Rb). The new study identifies six different mutations in the PDGF-B gene as underlying causes of FIBGC in six families of different ancestry. Strikingly, PDGF-B is the main ligand for PDGF-Rb.

Importantly, the new study also shows that mice with loss-of-function mutations in the PDGF-B gene develop a condition resembling FIBGC. As in humans, the size and number of brain calcifications progress with age. PDGF-B and PDGF-Rb play a critical role in pericyte recruitment to developing blood vessels. Pericytes are cells that surround and support the outer wall of blood vessels. The researchers’previous work has demonstrated that pericytes are very important for the development and maintenance of the BBB. The BBB renders all blood vessels in the brain virtually impermeable to blood-borne molecules, which is important to ensure proper neuronal functioning. Mouse models that have greatly reduced pericyte numbers in the brain also have a defective BBB, thus allowing plasma proteins to freely enter into the brain.

“We show that the extent of brain calcifications in various PDGFB mouse mutants correlates with pericyte-deficiency and blood-brain barrier defects. Moreover, we show that the expression of endothelial PDGFB is protective against brain calcification”, says Dr. Annika Keller, researcher at Uppsala University and Zürich University.

The future work of the research group will now be directed towards understanding how PDGFB-deficiency, pericyte loss and an impaired blood-brain barrier leads to brain calcification.

“Understanding these mechanisms may lead to the development of effective therapy to treat FIBGC, and may also shed light on other conditions with brain calcification”, says Dr. Annika Keller.

Read the full article "“Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice” by Oliveira et al, on Nature Genetics website. 

For more information, please contact Annika Keller, phone: +41 44 255 9845, e-mail:, or Christer Betsholtz, phone: +46 18 471 4816, e-mail:

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