title: Bi-allelic variants inCOL3A1encoding the ligand to GPR56 are associated with cobblestone-like cortical malformation, white matter changes and cerebellar cysts.
abstract: Collagens are one of the major constituents of the pial membrane, which plays a crucial role in neuronal migration and cortical lamination during brain development. Type III procollagen, the chains of which are encoded byCOL3A1, is the ligand of the G protein-coupled receptor 56 (GPR56), also known as adhesion G protein-coupled receptor G1. Bi-allelic mutations inGPR56give rise to cobblestone-like malformation, white matter changes and cerebellar dysplasia. This report shows that bi-allelic mutations inCOL3A1are associated with a similar phenotype.
  
  
  
  Exome analysis was performed in a family consisting of two affected and two non-affected siblings. Brain imaging studies of this family and of two previously reported individuals with bi-allelic mutations inCOL3A1were reviewed. Functional assays were performed on dermal fibroblasts.
  
  
  
  Exome analysis revealed a novel homozygous variant c.145C>G (p.Pro49Ala) in exon 2 ofCOL3A1. Brain MRI in the affected siblings as well as in the two previously reported individuals with bi-allelicCOL3A1mutations showed a brain phenotype similar to that associated with mutations inGPR56.
  
  
  
  Homozygous or compound heterozygous mutations inCOL3A1are associated with cobblestone-like malformation in all three families reported to date. The variability of the phenotype across patients suggests that genetic alterations in distinct domains of type III procollagen can lead to different outcomes. The presence of cobblestone-like malformation in patients with bi-allelicCOL3A1mutations emphasises the critical role of the type III collagen-GPR56 axis and the pial membrane in the regulation of brain development and cortical lamination.
authors.affiliation: Neurogenetics Research Group, Research Cluster Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel, Brussels, Belgium.|Center for Medical Genetics, UZ Brussel, Brussels, Belgium.
authors.forename: Laura
authors.initials: L
authors.lastname: Vandervore
authors.affiliation: Neurogenetics Research Group, Research Cluster Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel, Brussels, Belgium.|Center for Medical Genetics, UZ Brussel, Brussels, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Stouffs
authors.affiliation: Neurogenetics Research Group, Research Cluster Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel, Brussels, Belgium.|Center for Medical Genetics, UZ Brussel, Brussels, Belgium.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Tanyalçin
authors.affiliation: Department of Radiology, UZ Brussel, Brussels, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Vanderhasselt
authors.affiliation: Department of Pediatric Neurology, AZ Delta, Roeselare, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Roelens
authors.affiliation: Department of Clinical Genetics, Guy's Hospital, London, UK.
authors.forename: Muriel
authors.initials: M
authors.lastname: Holder-Espinasse
authors.affiliation: Division of Child and Adolescent Health, Department of Medical Genetics, University Hospital of North Norway, Tromsø, Norway.
authors.forename: Agnete
authors.initials: A
authors.lastname: Jørgensen
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Melanie G
authors.initials: MG
authors.lastname: Pepin
authors.affiliation: Service de Génétique Clinique, Hôpital J. de Flandre, Lille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Petit
authors.affiliation: Unité de Génétique Médicale, Nîmes University Hospital,CHU Carémeau, Nîmes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Khau Van Kien
authors.affiliation: Institut Imagine, Université Paris Descartes - Sorbonne Paris Cités, Paris, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
authors.affiliation: Neurogenetics Research Group, Research Cluster Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel, Brussels, Belgium.|Center for Medical Genetics, UZ Brussel, Brussels, Belgium.
authors.forename: Willy
authors.initials: W
authors.lastname: Lissens
authors.affiliation: Neurogenetics Research Group, Research Cluster Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel, Brussels, Belgium.|Center for Medical Genetics, UZ Brussel, Brussels, Belgium.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gheldof
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.|Department of Medicine (Medical Genetics), University of Washington, Seattle, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Byers
authors.affiliation: Neurogenetics Research Group, Research Cluster Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel, Brussels, Belgium.|Department of Pediatrics, Pediatric Neurology Unit, UZ Brussel, Brussels, Belgium.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Jansen
mesh_terms: D000328:Adult; D000483:Alleles; D002478:Cells, Cultured; D002526:Cerebellar Diseases / Q000235:genetics / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D024061:Collagen Type III / Q000235:genetics*; D003560:Cysts / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D008024:Ligands; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D054220:Malformations of Cortical Development / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D066127:White Matter / Q000473:pathology*; D055815:Young Adult
chemical_list: C118925:ADGRG1 protein, human; C439971:COL3A1 protein, human; D024061:Collagen Type III; D008024:Ligands; D043562:Receptors, G-Protein-Coupled
keywords: COL3A1; Cobblestone-like malformation; GPR56; vascular Ehlers-Danlos syndrome