Whole genome sequencing reveals novel mutations causing autosomal dominant inherited macular degeneration

Borooah, Shyamanga; Stanton, Chloe; Marsh, Joseph A.; Carss, Keren; Waseem, Naushin; Biswas, Pooja; Agorogiannis, Georgios; Raymond, Lucy; Arno, Gavin; Webster, Andrew R.

doi:10.1080/13816810.2018.1546406

Cited by 13 publications

(13 citation statements)

References 25 publications

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“…A heterozygous missense mutation, S163R, in the CTRP5 protein was originally shown to segregate with L‐ORD in several families (Ayyagari et al, ; Hayward et al, ). More recently, three additional mutations in the C1q domain of CTRP5 were identified in patients with L‐ORD (Borooah et al, ; Stanton et al, ). Despite the identification of these mutations, little is known about the mechanism underlying L‐ORD pathology.…”

Section: Introductionmentioning

confidence: 99%

Late‐onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1

et al. 2019

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Late‐onset retinal degeneration (L‐ORD) is an autosomal dominant macular degeneration characterized by the formation of sub‐retinal pigment epithelium (RPE) deposits and neuroretinal atrophy. L‐ORD results from mutations in the C1q‐tumor necrosis factor‐5 protein (CTRP5), encoded by the CTRP5/C1QTNF5 gene. To understand the mechanism underlying L‐ORD pathology, we used a human cDNA library yeast two‐hybrid screen to identify interacting partners of CTRP5. Additionally, we analyzed the Bruch's membrane/choroid (BM‐Ch) from wild‐type (Wt), heterozygous S163R Ctrp5 mutation knock‐in (Ctrp5S163R/wt), and homozygous knock‐in (Ctrp5S163R/S163R) mice using mass spectrometry. Both approaches showed an association between CTRP5 and HTRA1 via its C‐terminal PDZ‐binding motif, stimulation of the HTRA1 protease activity by CTRP5, and CTRP5 serving as an HTRA1 substrate. The S163R‐CTRP5 protein also binds to HTRA1 but is resistant to HTRA1‐mediated cleavage. Immunohistochemistry and proteomic analysis showed significant accumulation of CTRP5 and HTRA1 in BM‐Ch of Ctrp5S163R/S163R and Ctrp5S163R/wt mice compared with Wt. Additional extracellular matrix (ECM) components that are HTRA1 substrates also accumulated in these mice. These results implicate HTRA1 and its interaction with CTRP5 in L‐ORD pathology.

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Section: Introductionmentioning

confidence: 99%

Late‐onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1

et al. 2019

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“…Findings from the clinical and basic science work associated with these mutations will be discussed further below. 29 , 30 …”

Section: Historical Landmarksmentioning

confidence: 99%

Late-Onset Retinal Degeneration: Clinical Perspectives

Lando¹,

Borooah²

2022

OPTH

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Late-onset retinal degeneration (L-ORD) is a type of retinal dystrophy marked by nyctalopia and subretinal pigment epithelium deposits, which eventually promote retinal atrophy with final visual compromise. L-ORD may also present with changes in the anterior segment, notably long anterior zonules and iris atrophy, distinguishing it from other inherited eye conditions. Although it can clinically simulate age-related macular degeneration, L-ORD has a different course of progression and prognosis, requiring adequate diagnosis for patient counseling. This review summarizes the main clinical, genetic, pathophysiological, diagnostic, and therapeutic aspects of L-ORD to help ophthalmologists identify and manage this rare ocular disease.

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“…This family showed variability in the presentation of visual symptoms as previously described for LORD (Figure 2). 105,106 The patient RPN-640 is one of the youngest patients showing clinical symptoms with mutations in this gene.…”

Section: Phenotypic Intrafamilial Variabilitymentioning

confidence: 99%

Expanding the Clinical and Molecular Heterogeneity of Nonsyndromic Inherited Retinal Dystrophies

Rodríguez-Muñoz

Aller

Jaijo

et al. 2020

The Journal of Molecular Diagnostics

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Whole genome sequencing reveals novel mutations causing autosomal dominant inherited macular degeneration

Cited by 13 publications

References 25 publications

Late‐onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1

Late‐onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1

Late-Onset Retinal Degeneration: Clinical Perspectives

Expanding the Clinical and Molecular Heterogeneity of Nonsyndromic Inherited Retinal Dystrophies

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