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.
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.
Authors: Eliana Marisa Ramos; Miryam Carecchio; Roberta Lemos; Joana Ferreira; Andrea Legati; Renee Louise Sears; Sandy Chan Hsu; Celeste Panteghini; Luca Magistrelli; Ettore Salsano; Silvia Esposito; Franco Taroni; Anne-Claire Richard; Christine Tranchant; Mathieu Anheim; Xavier Ayrignac; Cyril Goizet; Marie Vidailhet; David Maltete; David Wallon; Thierry Frebourg; Lylyan Pimentel; Daniel H Geschwind; Olivier Vanakker; Douglas Galasko; Brent L Fogel; A Micheil Innes; Alison Ross; William B Dobyns; Diana Alcantara; Mark O'Driscoll; Didier Hannequin; Dominique Campion; João R Oliveira; Barbara Garavaglia; Giovanni Coppola; Gaël Nicolas Journal: Eur J Hum Genet Date: 2018-06-28 Impact factor: 4.246
Authors: Eliana Marisa Ramos; Alessandro Roca; Noravit Chumchim; Deepika Reddy Dokuru; Victoria Van Berlo; Giovanna De Michele; Maria Lieto; Enrico Tedeschi; Giuseppe De Michele; Giovanni Coppola Journal: Neurogenetics Date: 2019-03-21 Impact factor: 2.660
Authors: J B Ferreira; L Pimentel; M P Keasey; R R Lemos; L M Santos; M F Oliveira; S Santos; N Jensen; K Teixeira; L Pedersen; C R Rocha; M R Dias da Silva; J R M Oliveira Journal: J Mol Neurosci Date: 2014-06-27 Impact factor: 3.444