Mutations in C8orf37, Encoding a Ciliary Protein, are Associated with Autosomal- Recessive Retinal Dystrophies with Early Macular Involvement Alejandro.

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Mutations in C8orf37, Encoding a Ciliary Protein, are Associated with Autosomal- Recessive Retinal Dystrophies with Early Macular Involvement Alejandro Estrada-Cuzcano, Kornelia Neveling, Susanne Kohl, Eyal Banin, Ygal Rotenstreich, Dror Sharon, Tzipora C. Falik-Zaccai, Stephanie Hipp, Ronald Roepman, Bernd Wissinger, Stef J.F. Letteboer, Dorus A. Mans, Ellen A.W. Blokland, Michael P. Kwint, Sabine J. Gijsen, Ramon A.C. van Huet, Rob W.J. Collin, H. Scheffer, Joris A. Veltman, Eberhart Zrenner, Anneke I. den Hollander, B. Jeroen Klevering, Frans P.M. Cremers The American Journal of Human Genetics Volume 90, Issue 1, Pages 102-109 (January 2012) DOI: 10.1016/j.ajhg.2011.11.015 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees with C8orf37 Mutations and Partial Alignment of C8orf37 Orthologs (A) Schematic representation of the four consanguineous families in which homozygous C8orf37 variants were identified. The respective mutations (M1–M4) are indicated above the pedigrees. In family 1, a protein-truncating mutation (p.Leu166∗) was identified; in family 2, the c.156−2A>G variant affects one of the canonical nucleotides of a splice-acceptor site. Affected individuals in families 3 and 4 carry C8orf37 missense mutations that are located in close proximity (see B). The + symbol represents wild-type. Diamond-shaped symbols represent male(s) or female(s); the numbers in the symbols indicate the numbers of individuals. Blackened symbols represent affected individuals. Symbols with slashes depict deceased individuals. (B) Evolutionary conservation of the part of the C8orf37 polypeptide that contains the missense mutations p.Arg177Trp and p.Gln182Arg, which are identified in families 3 and 4, respectively. The alignment was performed via ClustalW2 with the following protein sequences: human (NP_808880.1), rat (NP_001007747.1), mouse (NP_680281.3), chicken (Xp_418346.2), frog (XP_002931575.1), sea urchin (XP_001194284), Phytophtora (XP_002904228.1), and Chlamydomonas (XP_001697126.1). Amino acid residues that are identical in all sequences are white on a black background, whereas amino acids that are similar but not identical are black on a light gray background. Nonconservative changes are indicated in black on a white background. The American Journal of Human Genetics 2012 90, 102-109DOI: (10.1016/j.ajhg.2011.11.015) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Homozygous Region in Individual IV:1 of Family 1, C8orf37 Exon-Intron Structure, and Sequence Variant (A) The 31.6 Mb homozygous region encompassing the flanking SNPs and C8orf37 on part of chromosome 8q in IV:1 of family 1. (B) Genomic structure of C8orf37, which consists of six exons, all of which are protein coding. (C) Next-generation sequence traces for the reads covering the C8orf37 c.497T>A variant (minus strand), which results in a premature stop codon (p.Leu166∗). Twenty five reads, all of which show the c.497T>A change (visible in antisense direction as c.497A>T), encompass cDNA nucleotide 497. The visibility of this mutation is hampered in the five reads at the bottom, probably because of the mononucleotide stretches around the mutation. These stretches most likely lead to either sequencing or mapping problems when the Roche 454 sequencing technology is used. The homozygosity of this variant was confirmed by traditional Sanger sequencing (see D). The abbreviation wt represents the wild-type anti-sense sequence. (D) Sanger sequencing confirmation of the c.497T>A variant in individual IV:1 of family 1. The American Journal of Human Genetics 2012 90, 102-109DOI: (10.1016/j.ajhg.2011.11.015) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 mRNA and Protein-Expression Characteristics of C8orf37 (A) mRNA expression of C8orf37 in adult human tissues is the highest in the heart and the brain, followed by the retinae. The y axis shows the relative expression of C8orf37 in comparison to the lowest expression detected in the liver. For liver expression, the ΔΔCt value was set at 0, resulting in an arbitrary expression of 1.33,34 The x axis shows the adult human tissues that were tested for C8orf37 expression. (B–D) Immunohistochemical staining of ciliated hTERT-RPE1 cells with antibodies against human C8orf37 (in green), and (in red) the ciliary markers GT335 (antipolyglutamylated tubulin) (B), antiacetylated α-tubulin (C), and anti-γ-tubulin (D) revealed that endogenous C8orf37 localizes to the base of the primary cilia. Nuclei were stained with DAPI (in blue). Insets show selected magnifications. (E–G) Immunohistochemical staining in mouse retinal sections (P30). The most intense labeling for C8orf37 (in green) was noted at the base of the photoreceptor connecting cilia which partially colocalized with (in red) the connecting cilium markers GT335 (antipolyglutamylated tubulin) (E), antiacetylated α-tubulin (F), and anti-γ-tubulin (G). C8orf37 also stains structures that extend from the base of the cilium toward the inner segments, suggestive of ciliary rootlets. Abbreviations are as follows: CC, connecting cilia; IS, photoreceptor inner segments; and OS, photoreceptor outer segments. The scale bars represent the following: (B–D), 20 μm and (E–G), 10 μm. The American Journal of Human Genetics 2012 90, 102-109DOI: (10.1016/j.ajhg.2011.11.015) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 4 Fundus Photograph and Optical Coherence Tomography of the Left Eye of Individual V:2 of Family 2 at age 27 The upper panel of the fundus photograph shows atrophy with a beaten-bronze aspect at the center of the macula. The optic disc shows temporal pallor, and there is a gliosis over the posterior pole. The retinal arterioles are mildly attenuated. The optical coherence tomography in the lower panel shows a section of the central retina that includes the fovea; the retina is atrophic and much thinner than a normal retina. The American Journal of Human Genetics 2012 90, 102-109DOI: (10.1016/j.ajhg.2011.11.015) Copyright © 2012 The American Society of Human Genetics Terms and Conditions