case_images: PMC3446876_01
case_images: Pedigree of the adRP family.. Squares and circles indicate males and females respectively, darkened symbols represent affected members, and slashed symbols denote that the subject is deceased. The arrow points to the proband. An asterisk indicates the subject underwent clinical and genetic analyses.
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case_images: The pedigree was consistent with autosomal dominant inheritance (Figure 1). Furthermore, these five mutations were selected for Sanger sequencing validation and segregation analysis on the available 14 members of the adRP family (Figure 1).
case_images: Fundus photography of the proband and a normal subject.. (A) Attenuation of retinal arterioles, bone-spicule pigmentation in the midperiphery, atrophy of the retinal pigment epithelium, waxy-pale discs, and enlarged optic cups in the fundus of the proband (B) Normal fundus.
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case_images: Funduscopic examinations revealed similar clinical manifestations among affected individuals, including waxy-pale discs, attenuation of retinal arterioles, bone-spicule pigmentation in the midperiphery, and atrophy of the retinal pigment epithelium (Figure 2). Ophthalmic examination of III:9 revealed a shallow anterior chamber and enlarged cup-to-disc ratio in both eyes (Figure 2).
case_images: The SNRNP200 sequencing results.. (Top) Sequencing data shows that a C to G transversion (arrow) resulted in the substitution of glutamine-885 by glutamic acid (Q885E) in affected individuals. (Bottom) The corresponding normal sequence (arrow) was found in unaffected family members and controls.
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case_images: Only one variant co-segregated with the disease phenotype in this family: a C to G transversion in exon 20 (c.2653C>G), resulting in the Q885E mutation in SNRNP200 (Figure 3).
case_images: Multiple sequence alignment of SNRNP200.. Sequence alignment of hBrr2 from eight species is shown. Q885E occurs at a highly conserved position in hBrr2 (arrow).
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case_images: We screened the SNRNP200 orthologs using the NCBI HomoloGene database (http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=homologene&dopt=MultipleAlignment&list_uids=5859) and revealed that Q885 is highly conserved in eight species (Figure 4).
case_images: Structure modeling of hBrr2(477-1174).. (A) Orthogonal ribbon plots of the model of hBrr2(477-1174). Three conserved residues (Q885, S1087 and R1090) that may interact with RNA base are shown as space-filling spheres, and colored as wheat, red and yellow respectively. (B) Orthogonal ribbon plots of the Hel308 DNA helicase (PDB ID: 2p6r). Cyan, Hel308; pink, DNA. Three DNA interacting residues R388, T596 and W599 in Hel308 which correlate to Q885, S1087 and R1090 in human respectively are shown as space-filling spheres, and colored in order as wheat, red and yellow. (C) A close view of the central pore in the model, highlighting the three conserved residues (Q885, S1087 and R1090). (D) A close view of the path of DNA strand through the central pore, highlighting the three related residues (R388, T596 and W599) implicated in DNA binding.
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case_images: From model it shows that hBrr2 (residues 477-1174) folds into five domains (RecA-like 1 and 2 domains, helical bundle, HLH and WH domains) and possesses a hole at the center of molecule (Figure 5A), similar to that of Hel308-DNA complex (Figure 5B). Three conserved amino acids across different species, highlighted as Q885, S1087 and R1090 of hBrr2 are shown as space-filling spheres (Figure 5A) in the model. In comparison, the 3 equivalent amino acids in Hel308, of which R388 equivalents to Q885 in human, T596 equivalents to S1087 in human and W599 equivalents to R1090 in human are shown as space-filling spheres (Figure 5B).