title: Mutation of IGFBP7 causes upregulation of BRAF/MEK/ERK pathway and familial retinal arterial macroaneurysms.
abstract: Insulin-like growth factor binding proteins (IGFBPs) play important physiological functions through the modulation of IGF signaling as well as IGF-independent mechanisms. Despite the established role of IGFs in development, a similar role for the seven known IGFBPs has not been established in humans. Here, we show that an autosomal-recessive syndrome that consists of progressive retinal arterial macroaneurysms and supravalvular pulmonic stenosis is caused by mutation of IGFBP7. Consistent with the recently established inhibitory role of IGFBP7 on BRAF signaling, the BRAF/MEK/ERK pathway is upregulated in these patients, which may explain why the cardiac phenotype overlaps with other disorders characterized by germline mutations in this pathway. The retinal phenotype appears to be mediated by a role in vascular endothelium, where IGFBP7 is highly expressed.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Leen
authors.initials: L
authors.lastname: Abu-Safieh
authors.forename: Emad B
authors.initials: EB
authors.lastname: Abboud
authors.forename: Hisham
authors.initials: H
authors.lastname: Alkuraya
authors.forename: Hanan
authors.initials: H
authors.lastname: Shamseldin
authors.forename: Shamsa
authors.initials: S
authors.lastname: Al-Enzi
authors.forename: Lama
authors.initials: L
authors.lastname: Al-Abdi
authors.forename: Mais
authors.initials: M
authors.lastname: Hashem
authors.forename: Dilek
authors.initials: D
authors.lastname: Colak
authors.forename: Abdullah
authors.initials: A
authors.lastname: Jarallah
authors.forename: Hala
authors.initials: H
authors.lastname: Ahmad
authors.forename: Steve
authors.initials: S
authors.lastname: Bobis
authors.forename: Georges
authors.initials: G
authors.lastname: Nemer
authors.forename: Fadi
authors.initials: F
authors.lastname: Bitar
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000293:Adolescent; D000328:Adult; D000783:Aneurysm / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics* / Q000378:metabolism; D005190:Family; D005260:Female; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics; D012161:Retinal Artery / Q000201:enzymology / Q000473:pathology*; D015854:Up-Regulation / Q000235:genetics; D055815:Young Adult
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; C102529:insulin-like growth factor binding protein-related protein 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases