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Abstract
Objectives: To identify a new idiopathic basal ganglia calcification (IBGC)-causing gene.
Methods: In a 3-generation family with no SLC20A2 mutation, we performed whole exome sequencing in 2 affected first cousins, once removed. Nonsynonymous coding variants, splice acceptor and donor site variants, and frameshift coding indels (NS/SS/I) were filtered against dbSNP131, the HapMap Project, 1000 Genomes Project, and our in-house database including 72 exomes.
Results: Seventeen genes were affected by identical unknown NS/SS/I variations in the 2 patients. After screening the relatives, the p.Leu658Pro substitution within the PDGFRB gene remained the sole unknown mutation segregating with the disease in the family. This variation, which is predicted to be highly damaging, was present in 13 of 13 affected subjects and absent in 8 relatives without calcifications. Sequencing PDGFRB of 19 other unrelated IBGC cases allowed us to detect another potentially pathogenic substitution within PDGFRB, p.Arg987Trp, also predicted to be highly damaging. PDGFRB encodes a protein involved in angiogenesis and in the regulation of inorganic phosphate (Pi) transport in vascular smooth muscle cells via Pit-1, a Pi transporter encoded by SLC20A1.
Conclusion: Mutations of PDGFRB further support the involvement of this biological pathway in IBGC pathophysiology.
GLOSSARY
- IBGC=
- idiopathic basal ganglia calcification;
- NS/SS/I=
- nonsynonymous coding variants, splice acceptor and donor site variants, and frameshift coding indels;
- PDGF=
- platelet-derived growth factor;
- PDGFR=
- platelet-derived growth factor receptor;
- Pi=
- inorganic phosphate;
- Pit=
- inorganic phosphate transporter;
- vSMC=
- vascular smooth muscle cell
Footnotes
↵* These authors contributed equally to this work.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Supplemental data at www.neurology.org
- Received May 12, 2012.
- Accepted August 22, 2012.
- © 2013 American Academy of Neurology
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