Purchase this article with an account.
Xue Chen, Xunlun Sheng, Wenjuan Zhuang, Biao Yan, Chen Zhao; GUCA1A mutation causes maculopathy in a five-generation family with a large spectrum of severity. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4512.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
To investigate the genetic basis and pathogenic mechanism for a five-generation family affected with variable maculopathies ranging from mild photoreceptor degeneration to central areolar choroidal dystrophy (CACD).
Clinical characterizations, whole exome sequencing and genome-wide linkage analysis were applied on the family. Zebrafish models were used to investigate the pathogenesis of GUCA1A mutations.
A novel mutation, GUCA1A p.R120L, was identified in the family and predicted to alter the tertiary structure of GCAP1, a photoreceptor-expressed protein encoded by the GUCA1A gene. The mutation was shown in zebrafish to cause significant disruptions in photoreceptors and retinal pigment epithelium (RPE), together with atrophies of retinal vessels and choroicapillaris. Those phenotypes could not be fully rescued by exogenous wild type GUCA1A, suggesting a likely gain-of-function mechanism for p.R120L. GUCA1A p.D100E, another mutation previously implicated in cone dystrophy, also impaired RPE and photoreceptors in zebrafish, but likely via a dominant negative effect.
We conclude that GUCA1A mutations could cause significant variability of maculopathies, including CACD, which represents a severe pattern of maculopathy. The diverse pathogenic modes of GUCA1A mutations may explain the phenotypic diversities.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
(A) Pedigree of family DC and haplotype reconstruction for the mapped region on chromosome 6 in family DC. (B-Q) Fundus photography, fundus autofluorescence (FAF), fundus fluorescein angiography (FFA), and optical coherence tomography (OCT) presentations for patients with different grades of maculopathy, including grade I (B-E), grade II (F-I), grade III (J-M), and grade IV (N-Q). (R-U) ERG presentations for patients representing different severities of maculopathy, including grade I (R), grade II (S), grade III (T), and grade IV (U).
(A-F) Morphological changes caused by GUCA1A p.R120L. Thickness of the RPE, shrinking, twisty and caduceus photoreceptor outer segments, and chorocapillary disruptions are found in the GUCA1Ap.R120L injected group. (G-T) Impairments in photoreceptors (G-J, N-P), RPE (K-M, Q), and ocular vasculature (R-T) induced by GUCA1A p.R120L in zebrafish. (U-Z) Photoreceptor (U-W) and RPE (X-Z) defects caused by GUCA1A p.D100E in zebrafish.
This PDF is available to Subscribers Only