Mutations in IMPG1 Cause Vitelliform Macular Dystrophies

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Mutations in IMPG1 Cause Vitelliform Macular Dystrophies Gaël Manes, Isabelle Meunier, Almudena Avila-Fernández, Sandro Banfi, Guylène Le Meur, Xavier Zanlonghi, Marta Corton, Francesca Simonelli, Philippe Brabet, Gilles Labesse, Isabelle Audo, Saddek Mohand-Said, Christina Zeitz, José-Alain Sahel, Michel Weber, Hélène Dollfus, Claire-Marie Dhaenens, Delphine Allorge, Elfride De Baere, Robert K. Koenekoop, Susanne Kohl, Frans P.M. Cremers, Joe G. Hollyfield, Audrey Sénéchal, Maxime Hebrard, Béatrice Bocquet, Carmen Ayuso García, Christian P. Hamel The American Journal of Human Genetics Volume 93, Issue 3, Pages 571-578 (September 2013) DOI: 10.1016/j.ajhg.2013.07.018 Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of the Families Affected by Autosomal-Dominant Vitelliform Macular Dystrophy (A–C) Pedigrees, alleles of the microsatellite markers surrounding IMPG1, and the IMPG1 c.713T>G (p.Leu238Arg) mutation are shown in families MTP327 (A), MTP1290 (B), and MD0531 (C). The haplotype common to the three families is shown in black. (D) Electropherograms showing the normal control sequence and the affected sequence (from individual IV:2 of family MTP327) surrounding the c.713T>G mutation. The American Journal of Human Genetics 2013 93, 571-578DOI: (10.1016/j.ajhg.2013.07.018) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 2 Fundus Pictures Showing the Vitelliform Macular Dystrophy Phenotypes Caused by IMPG1 Mutations Codes for family names and member numbers refer to the family trees from Figures 1 and 4. Color pictures are fundus photographs, and black and white pictures (B, D, and H) are autofluorescence fundus imaging. Among the three families with the heterozygous, dominantly inherited missense change p.Leu238Arg, in family MTP327 (A) a macular, round vitelliform deposit containing highly autofluorescent material is found (B), whereas in family MTP1290 multifocal vitelliform deposits are encountered (C) also with autofluorescent material (D), and in family MD0531 macular (E) and multifocal (F) vitelliform deposits are found in distinct individuals. In the two families with recessive inheritance, a similar macular vitelliform deposit was found. In family NAL69, a small round macular deposit (G, insert: retinal scan showing the foveal dome-shaping accumulation of vitelliform material), which was autofluorescent (H), was seen. In family NA1863 there were additional multifocal vitelliform deposits in the two affected individuals (I and J); the heterozygous asymptomatic parents showed only tiny vitelliform spots outside the macula (K and L). The American Journal of Human Genetics 2013 93, 571-578DOI: (10.1016/j.ajhg.2013.07.018) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 3 Chromosomal Localization of IMPG1, Protein-Domain Organization of SPACR, and Position of Detected Mutations (A) The 95.2 Mb mapped disease locus in chromosomal region 6p12.1–q24.3 for family MTP327 is located between the SNPs rs1076701 and rs6910680. IMPG1, ELOVL4, and MCDR1 within the region and PRPH2/RDS outside the region are indicated. The position of D6S456 and D6S1589 markers shared by the three families with the p.Leu238Arg substitution is shown between dotted lines. (B and C) Schematic representation of the exon-intron structure of IMPG1. Shown are (B) the location of the splice-site mutations found in this study and (C) the domain structure of its encoded SPACR protein, including the signal peptide, the N-terminal SEA1 and C-terminal SEA2 domains, the mucin-like domain (dotted line), the autoproteolytic site (∗), and the EGF-like domain. The missense and nonsense changes found in this study are indicated, as is the previously described change p.Leu579Pro in the BCAMD condition. The American Journal of Human Genetics 2013 93, 571-578DOI: (10.1016/j.ajhg.2013.07.018) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 4 Pedigrees of Families Showing Autosomal-Recessive Inheritance and of a Family with a Simplex Case of Vitelliform Macular Dystrophy Families NAL69, NA1863, and NAX1, affected by vitelliform macular dystrophies. A double horizontal line indicates consanguinity in family NA1863. The American Journal of Human Genetics 2013 93, 571-578DOI: (10.1016/j.ajhg.2013.07.018) Copyright © 2013 The American Society of Human Genetics Terms and Conditions