The Function of Oligomerization-Incompetent RDS in Rods

Chakraborty, Dibyendu; Conley, Shannon M.; Fliesler, Steven J.; Naash, Muna I.

doi:10.1007/978-1-4419-1399-9_5

Cited by 7 publications

(8 citation statements)

References 23 publications

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“…Peripherin‐2 forms oligomeric complexes with other proteins, including the rod outer segment membrane protein‐1 (ROM‐1) and leucine‐rich repeat‐containing protein‐32/glycoprotein‐A repetitions predominant expressed in rods and is critical to the proper formation of the outer segment (Boon et al, 2008; Chakraborty, Conley, Fliesler et al, 2010; Chakraborty, Conley, Stuck et al, 2010; Conley et al, 2010; Ding et al, 2004, 2005; Duncan et al, 2011; van Lith‐Verhoeven et al, 2003; Loewen & Molday, 2000; Poetsch et al, 2001; Poloschek et al, 2010; Tam et al, 2004). The ability to review phenotype–genotype associations within a single rare disorder is advantageous for understanding the phenotypic range and properly categorizing causal genetic variation.…”

Section: Resultsmentioning

confidence: 99%

“…Each protein has four transmembrane domains and an intracellular domain (Charrin et al, 2014; Zimmerman et al, 2016). Peripherin‐2 localizes to the rims of cone lamellae and the rod disk of the photoreceptor outer segment in the adult retina (Chakraborty, Conley, Fliesler, & Naash, 2010; Conley, Stricker, & Naash, 2010; Loewen & Molday, 2000; Poetsch, Molday, & Molday, 2001; Tam, Moritz, & Papermaster, 2004). Peripherin‐2 forms intramolecular disulfide bonds at seven highly conserved cysteine residues within the D2 loop, forming covalently bonded homomultimeric complexes (Boon et al, 2008; Conley et al, 2010; Ding, Stricker, & Naash, 2005; Duncan et al, 2011; van Lith‐Verhoeven et al, 2003; Loewen & Molday, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Peripherin‐2 forms intramolecular disulfide bonds at seven highly conserved cysteine residues within the D2 loop, forming covalently bonded homomultimeric complexes (Boon et al, 2008; Conley et al, 2010; Ding, Stricker, & Naash, 2005; Duncan et al, 2011; van Lith‐Verhoeven et al, 2003; Loewen & Molday, 2000). These molecular interactions are essential to preserving structure and function of photoreceptor outer segments (Boon et al, 2008; Chakraborty, Conley, Fliesler et al, 2010; Chakraborty, Conley, Stuck, & Naash, 2010; Ding et al, 2004, 2005; Duncan et al, 2011; van Lith‐Verhoeven et al, 2003; Loewen & Molday, 2000; Tam et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Genotype–phenotype associations in a large PRPH2 ‐related retinopathy cohort

et al. 2020

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Molecular variant interpretation lacks disease gene‐specific cohorts for determining variant enrichment in disease versus healthy populations. To address the molecular etiology of retinal degeneration, specifically the PRPH2‐related retinopathies, we reviewed genotype and phenotype information obtained from 187 eyeGENE® participants from 161 families. Clinical details were provided by referring clinicians participating in the eyeGENE® Network. The cohort was sequenced for variants in PRPH2. Variant complementary DNA clusters and cohort frequency were compared to variants in public databases to help us to determine pathogenicity by current American College of Medical Genetics and Genomics/Association for Molecular Pathology interpretation criteria. The most frequent variant was c.828+3A>T, which affected 28 families (17.4%), and 25 of 79 (31.64%) variants were novel. The majority of missense variants clustered in the D2 intracellular loop of the peripherin‐2 protein, constituting a hotspot. Disease enrichment was noted for 23 (29.1%) of the variants. Hotspot and disease‐enrichment evidence modified variant classification for 16.5% of variants. The missense allele p.Arg172Trp was associated with a younger age of onset. To the best of our knowledge, this is the largest patient cohort review of PRPH2‐related retinopathy. Large disease gene‐specific cohorts permit gene modeling for hotspot and disease‐enrichment analysis, providing novel variant classification evidence, including for novel missense variants.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genotype–phenotype associations in a large PRPH2 ‐related retinopathy cohort

et al. 2020

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“…The cone-expressing C150S-RDS (COP-T) transgenic mice were generated and characterized previously (13,38). Briefly, the C150S mutation was introduced into the 1.6 kb full-length mouse Rds cDNA carrying the P341Q modification.…”

Section: Generation and Characterization Of C150s Transgenic Micementioning

confidence: 99%

Differences in RDS trafficking, assembly and function in cones versus rods: insights from studies of C150S-RDS

Chakraborty

Conley

Stuck

et al. 2010

Human Molecular Genetics

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Cysteine 150 of retinal degeneration slow protein (RDS) mediates the intermolecular disulfide bonding necessary for large RDS complex assembly and morphogenesis of the rim region of photoreceptor outer segments. Previously, we showed that cones have a different requirement for RDS than rods, but the nature of that difference was unclear. Here, we express oligomerization-incompetent RDS (C150S-RDS) in the conedominant nrl 2/2 mouse. Expression of C150S-RDS leads to dominant functional abnormalities, ultrastructural changes, biochemical anomalies and protein mislocalization in cones. These data suggest that RDS complexes in cones are more susceptible to disruption than those in rods, possibly due to structural or microenvironmental differences in the two cell types. Furthermore, our results suggest that RDS intermolecular disulfide bonding may be part of RDS inner-segment assembly in cones but not in rods. These data highlight significant differences in assembly, trafficking and function of RDS in rods versus cones.

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“…Animals that expressed only C150S RDS (no wild‐type RDS) were incapable of forming OSs, and the mutation caused a dominant‐negative degeneration in cones (i.e. even in the presence of wild‐type RDS) , underscoring the importance of this cysteine in RDS function and the differential role of RDS in rods versus cones.…”

Section: Introductionmentioning

confidence: 99%

Structural characterization of the second intra‐discal loop of the photoreceptor tetraspanin RDS

et al. 2012

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Vertebrate photoreceptors contain a unique tetraspanin protein known as 'retinal degeneration slow' (RDS). Mutations in the RDS gene have been identified in a variety of human retinal degenerative diseases, and more than 70% of these mutations are located in the second intra-discal (D2) loop, highlighting the importance of this region. Here we examined the conformational and thermal stability properties of the D2 loop of RDS, as well as interactions with ROM-1, a non-glycosylated homolog of RDS. The RDS D2 loop was expressed in Escherichia coli as a fusion protein with maltose binding protein (MBP). The fusion protein, referred to as MBP-D2, was purified to homogeneity. Circular dichroism spectroscopy showed that the wild-type (WT) D2 loop consists of approximately 21% a-helix, approximately 20% b-sheet and approximately 59% random coil. D2 loop fusion proteins carrying disease-causing mutations in RDS (e.g. R172W, C214S, N244H/K) were also examined, and conformational changes were observed (compared to wild-type D2). In particular, the C150S, C214S and N244H proteins showed significant reductions in a-helicity. However, the thermal stability of the mutants was unchanged compared to wild-type, and all the mutants were capable of interacting with ROM-1, indicating that this functional aspect of the isolated D2 loop remained intact in the mutants despite the observed conformational changes. An I-TASSER model of the RDS D2 loop predicted a structure consistent with the circular dichroism experiments and the structure of the conserved region of the D2 loop of other tetraspanin family members. These results provide significant insight into the mechanism of RDS complex formation and the disease process underlying RDS-associated retinal degeneration.

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The Function of Oligomerization-Incompetent RDS in Rods

Cited by 7 publications

References 23 publications

Genotype–phenotype associations in a large PRPH2 ‐related retinopathy cohort

Genotype–phenotype associations in a large PRPH2 ‐related retinopathy cohort

Differences in RDS trafficking, assembly and function in cones versus rods: insights from studies of C150S-RDS

Structural characterization of the second intra‐discal loop of the photoreceptor tetraspanin RDS

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