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Crystal structure of the globular domain of C1QTNF5: Implications for late-onset retinal macular degeneration.

ABSTRACT: Autosomal dominant late-onset retinal macular degeneration (L-ORMD) is caused by a single S163R mutation in the C1q and tumor necrosis factor-related protein 5 (C1QTNF5) gene. The C1QTNF5 gene encodes a secreted and membrane-associated protein involved in adhesion of retinal pigmented epithelial cells (RPE) to Bruch's membrane. The crystal structure of the trimeric globular domain of human C1QTNF5 at 1.34Å resolution reveals unique features of this novel C1q family member. It lacks a Ca²?-binding site, displays a remarkable non-uniform distribution of surface electrostatic potentials and possesses a unique sequence (F???F???G???G???W???P???) that forms a hydrophobic plateau surrounded by Lys and Arg residues with a solvent cavity underneath. S??? forms a hydrogen bond with F??? in a hydrophobic area extending to the hydrophobic plateau. The pathogenic mutation S163R disrupts this hydrogen bonding and positively charges these hydrophobic areas. Thus, our analysis provides insights into the structural basis of the L-ORMD disease mechanism.

SUBMITTER: Tu X

PROVIDER: S-EPMC3496058 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Crystal structure of the globular domain of C1QTNF5: Implications for late-onset retinal macular degeneration.

Tu Xiongying X Palczewski Krzysztof K

Journal of structural biology 20120807 3

Autosomal dominant late-onset retinal macular degeneration (L-ORMD) is caused by a single S163R mutation in the C1q and tumor necrosis factor-related protein 5 (C1QTNF5) gene. The C1QTNF5 gene encodes a secreted and membrane-associated protein involved in adhesion of retinal pigmented epithelial cells (RPE) to Bruch's membrane. The crystal structure of the trimeric globular domain of human C1QTNF5 at 1.34Å resolution reveals unique features of this novel C1q family member. It lacks a Ca²⁺-bindin ...[more]

PMID: 22892318

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Project description:PurposeThe purpose of this study was to present our findings on the natural history of late-onset retinal degeneration (LORD) in patients with molecularly confirmed C1QTNF5 heterozygous pathogenic variants and assess suitability of retinal structure parameters for disease monitoring.MethodsSixteen patients with C1QTNF5-LORD were retrospectively identified from Moorfields Eye Hospital, UK. Fundus autofluorescence (FAF), optical coherence tomography (OCT) scans, and best-corrected visual acuity (BCVA) were collected. Area of atrophy (AA) was manually drawn in FAF images. Ellipsoid zone (EZ) width and foveal retinal thickness of the whole retina and outer retina were extracted from OCT scans. Age-related changes were tested with linear-mixed models.ResultsPatients had median age of 62.3 years (interquartile range [IQR] = 58.8-65.4 years) at baseline, and median follow-up of 5.1 years (IQR = 2.6-7.6 years). AA, EZ width, and retinal thickness parameters remained unchanged until age 50 years, but showed significant change with age thereafter (all P < 0.0001). AA and EZ width progressed rapidly (dynamic range normalized rates = 4.3-4.5%/year) from age 53.9 and 50.8 years (estimated inflection points), respectively. Retinal thickness parameters showed slower progression rates (range = 1.6-2.5%/year) from age 60 to 62.3. BCVA (median = 0.3 LogMAR, IQR = 0.0-1.0 at baseline) showed a rapid decline (3.3%) from age 70 years. Findings from patients with earlier disease showed FAF atrophy manifests in the temporal retina initially, and then progresses nasally.ConclusionsPatients with LORD remained asymptomatic until age 50 years, before suffering rapid outer retinal degeneration. EZ width and AA showed rapid progression and high interocular correlation, representing promising outcome metrics. Clinical measures also capturing the temporal retina may be preferable, enabling earlier detection and better disease monitoring.Translational relevanceArea of atrophy in FAF images and OCT-measured EZ width represent promising outcome metrics for disease monitoring in patients with C1QTNF5-LORD.

Dataset Information

Crystal structure of the globular domain of C1QTNF5: Implications for late-onset retinal macular degeneration.

Publications

Crystal structure of the globular domain of C1QTNF5: Implications for late-onset retinal macular degeneration.

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