title: Mutations in IMPG1 cause vitelliform macular dystrophies.
abstract: Vitelliform macular dystrophies (VMD) are inherited retinal dystrophies characterized by yellow, round deposits visible upon fundus examination and encountered in individuals with juvenile Best macular dystrophy (BMD) or adult-onset vitelliform macular dystrophy (AVMD). Although many BMD and some AVMD cases harbor mutations in BEST1 or PRPH2, the underlying genetic cause remains unknown for many affected individuals. In a large family with autosomal-dominant VMD, gene mapping and whole-exome sequencing led to the identification of a c.713T>G (p.Leu238Arg) IMPG1 mutation, which was subsequently found in two other families with autosomal-dominant VMD and the same phenotype. IMPG1 encodes the SPACR protein, a component of the rod and cone photoreceptor extracellular matrix domains. Structural modeling indicates that the p.Leu238Arg substitution destabilizes the conserved SEA1 domain of SPACR. Screening of 144 probands who had various forms of macular dystrophy revealed three other IMPG1 mutations. Two individuals from one family affected by autosomal-recessive VMD were homozygous for the splice-site mutation c.807+1G>T, and two from another family were compound heterozygous for the mutations c.461T>C (p.Leu154Pro) and c.1519C>T (p.Arg507(∗)). Most cases had a normal or moderately decreased electrooculogram Arden ratio. We conclude that IMPG1 mutations cause both autosomal-dominant and -recessive forms of VMD, thus indicating that impairment of the interphotoreceptor matrix might be a general cause of VMD.
authors.affiliation: INSERM U1051, Institute for Neurosciences of Montpellier, Université Montpellier 1, Montpellier, France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Manes
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meunier
authors.forename: Almudena
authors.initials: A
authors.lastname: Avila-Fernández
authors.forename: Sandro
authors.initials: S
authors.lastname: Banfi
authors.forename: Guylène
authors.initials: G
authors.lastname: Le Meur
authors.forename: Xavier
authors.initials: X
authors.lastname: Zanlonghi
authors.forename: Marta
authors.initials: M
authors.lastname: Corton
authors.forename: Francesca
authors.initials: F
authors.lastname: Simonelli
authors.forename: Philippe
authors.initials: P
authors.lastname: Brabet
authors.forename: Gilles
authors.initials: G
authors.lastname: Labesse
authors.forename: Isabelle
authors.initials: I
authors.lastname: Audo
authors.forename: Saddek
authors.initials: S
authors.lastname: Mohand-Said
authors.forename: Christina
authors.initials: C
authors.lastname: Zeitz
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.forename: Michel
authors.initials: M
authors.lastname: Weber
authors.forename: Hélène
authors.initials: H
authors.lastname: Dollfus
authors.forename: Claire-Marie
authors.initials: CM
authors.lastname: Dhaenens
authors.forename: Delphine
authors.initials: D
authors.lastname: Allorge
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.forename: Susanne
authors.initials: S
authors.lastname: Kohl
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: Joe G
authors.initials: JG
authors.lastname: Hollyfield
authors.forename: Audrey
authors.initials: A
authors.lastname: Sénéchal
authors.forename: Maxime
authors.initials: M
authors.lastname: Hebrard
authors.forename: Béatrice
authors.initials: B
authors.lastname: Bocquet
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso García
authors.forename: Christian P
authors.initials: CP
authors.lastname: Hamel
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002877:Chromosomes, Human / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000235:genetics*; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005654:Fundus Oculi; D020022:Genetic Predisposition to Disease; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011509:Proteoglycans / Q000737:chemistry / Q000235:genetics*; D057826:Vitelliform Macular Dystrophy / Q000235:genetics*; D055815:Young Adult
chemical_list: D016326:Extracellular Matrix Proteins; D005136:Eye Proteins; C486428:IMPG1 protein, human; D011509:Proteoglycans