Autosomal-Recessive Early-Onset Retinitis Pigmentosa Caused by a Mutation in PDE6G, the Gene Encoding the Gamma Subunit of Rod cGMP Phosphodiesterase

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Autosomal-Recessive Early-Onset Retinitis Pigmentosa Caused by a Mutation in PDE6G, the Gene Encoding the Gamma Subunit of Rod cGMP Phosphodiesterase Liron Dvir, Gassoub Srour, Rasmi Abu-Ras, Benjamin Miller, Stavit A. Shalev, Tamar Ben-Yosef The American Journal of Human Genetics Volume 87, Issue 2, Pages 258-264 (August 2010) DOI: 10.1016/j.ajhg.2010.06.016 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 Genetic Analysis in Family TB14 (A) Shown are the two sibships segregating the c.187+1G>T mutation of PDE6G. SNP analysis performed on each of the sibships demonstrates cosegregation of a 17q25.3-linked haplotype with arRP. Double lines indicate consanguineous unions. Filled symbols represent affected individuals, whereas clear symbols represent unaffected individuals. Mutation-bearing haplotypes are marked by black bars. The position of the SNPs, based on the Human Genome Browser working draft hg18, is indicated between parentheses. (B) Shown is chromosome 17 with the linkage intervals and the corresponding SNPs. FSCN2 and PDE6G reside within the region that is shared by all affected individuals. Also shown is the genomic structure of PDE6G. Coding exons are represented by black boxes. Noncoding exons are represented by white boxes. The location of the c.187+1G>T mutation is indicated. (C) Sequence chromatograms for the c.187+1G>T mutation of PDE6G in a noncarrier individual (WT), an individual heterozygous for the mutation (het), and an affected individual homozygous for the mutant allele (mut). The exon-intron boundary is marked. (D) A pedigree of the extended family TB14. Affected individuals are marked in black. Genotypes at the c.187+1 position are indicated. The American Journal of Human Genetics 2010 87, 258-264DOI: (10.1016/j.ajhg.2010.06.016) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 Minigene Constructs and Products Obtained in the In Vitro Splicing Assay (A) Shown is a schematic representation of the constructs, which include PDE6G exons 2 to 4 (represented by white boxes) flanked by 82–263 bp of intronic sequences (represented by straight lines). Vector-derived sequences are represented by a black box. Constructs harbor either the WT or the c.187+1G>T mutant allele at the donor splice site of intron 3. The locations of primers used for RT-PCR analysis are indicated by arrows (a forward primer located in exon 2 and a vector-derived reverse primer). Also shown are the obtained splicing products. Sizes of exonic and intronic fragments are indicated below them. (B) WT and mutant (mut) constructs were transfected into Y79 cells, followed by RNA extraction and RT-PCR analysis. No PCR products were obtained from cells transfected with the empty pCMV-script vector (vec). β-actin (ACTB) served as an internal control for RNA quality and quantity. M denotes size marker. The American Journal of Human Genetics 2010 87, 258-264DOI: (10.1016/j.ajhg.2010.06.016) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 3 Fundus Photographs and Optical Coherence Tomography in Affected Individuals from Family TB14 (A and C) Fundus photograph (A) and OCT (C) of individual III-19 at the age of 10 years, demonstrating normal blood vessels and optic disk, peripheral bone spicule-type pigment deposits, absence of a foveal reflex, and mild cystoid macular edema. (B and D) Fundus photograph (B) and OCT (D) of individual III-26 at the age of 16 years, demonstrating attenuation of retinal blood vessels, pale optic disk, tapetoretinal degeneration with unhealthy discoloration of the macula, absence of a foveal reflex, and severe cystoid macular edema. The American Journal of Human Genetics 2010 87, 258-264DOI: (10.1016/j.ajhg.2010.06.016) Copyright © 2010 The American Society of Human Genetics Terms and Conditions