title: Col4a1 mutation generates vascular abnormalities correlated with neuronal damage in a mouse model of HANAC syndrome.
abstract: The HANAC syndrome is caused by mutations in the gene coding for collagen4a1, a major component of blood vessel basement membranes. Ocular symptoms include an increase in blood vessel tortuosity and occasional hemorrhages. To examine how vascular defects can affect neuronal function, we analyzed the retinal phenotype of a HANAC mouse model. Heterozygous mutant mice displayed both a thinning of the basement membrane in retinal blood vessels and in Bruch's membrane resulting in vascular leakage. Homozygous mice had additional vascular changes, including greater vessel coverage and tortuosity. This greater tortuosity was associated to higher expression levels of vascular endothelial growth factor (VEGF). These major changes to the blood vessels were correlated with photoreceptor dysfunction and degeneration. The neuronal damage was associated with reactive gliosis in astrocytes and Müller glial cells, and by the migration of microglial cells into the outer retina. This study illustrates how vascular changes can trigger neuronal degeneration in a new model of HANAC syndrome that can be used to further study dysfunctions of neurovascular coupling.
  
  
  CONCLUSIONS
  This study provides a phenotypic analysis of a novel mouse model of HANAC syndrome focusing on the retinal aspect. It recapitulates most of the aspects of the human disease and is therefore a great tool to study and to address this condition.
authors.affiliation: INSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, France.
authors.forename: Alix
authors.initials: A
authors.lastname: Trouillet
authors.affiliation: INSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, France.
authors.forename: Henri
authors.initials: H
authors.lastname: Lorach
authors.affiliation: INSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Dubus
authors.affiliation: Fovea Sanofi, Paris, France.
authors.forename: Brahim
authors.initials: B
authors.lastname: El Mathari
authors.affiliation: INSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, France.
authors.forename: Ivana
authors.initials: I
authors.lastname: Ivkovic
authors.affiliation: INSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Dégardin
authors.affiliation: INSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Simonutti
authors.affiliation: INSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, France; CHNO des Quinze-Vingts, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Paques
authors.affiliation: INSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Guillonneau
authors.affiliation: INSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Sennlaub
authors.affiliation: INSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, France; CHNO des Quinze-Vingts, Paris, France; Fondation Ophtalmologique Adolphe de Rothschild, Paris, France; Academie des Sciences, Paris, France.
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: AP HP, Department of Nephrology, Tenon Hospital, Paris, France; INSERM, U1155, Paris F-75020, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS_1155, Paris F-75020, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Ronco
authors.affiliation: AP HP, Department of Nephrology, Tenon Hospital, Paris, France; INSERM, U1155, Paris F-75020, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS_1155, Paris F-75020, France. Electronic address: emmanuelle.plaisier@tnn.aphp.fr.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Plaisier
authors.affiliation: INSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, France. Electronic address: serge.picaud@inserm.fr.
authors.forename: Serge
authors.initials: S
authors.lastname: Picaud
mesh_terms: D000818:Animals; D024141:Collagen Type IV / Q000235:genetics*; D004195:Disease Models, Animal; D008822:Mice, Transgenic; D009120:Muscle Cramp / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D011928:Raynaud Disease / Q000235:genetics*; D012160:Retina / Q000378:metabolism; D012171:Retinal Vessels / Q000002:abnormalities* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C000619517:Col4a1 protein, mouse; D024141:Collagen Type IV; D042461:Vascular Endothelial Growth Factor A
keywords: Collagen; Mouse model; Retinal damage; Vascular permeability