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Mutations in IMPG1 cause vitelliform macular dystrophies.

ABSTRACT: Vitelliform macular dystrophies (VMD) are inherited retinal dystrophies characterized by yellow, round deposits visible upon fundus examination and encountered in individuals with juvenile Best macular dystrophy (BMD) or adult-onset vitelliform macular dystrophy (AVMD). Although many BMD and some AVMD cases harbor mutations in BEST1 or PRPH2, the underlying genetic cause remains unknown for many affected individuals. In a large family with autosomal-dominant VMD, gene mapping and whole-exome sequencing led to the identification of a c.713T>G (p.Leu238Arg) IMPG1 mutation, which was subsequently found in two other families with autosomal-dominant VMD and the same phenotype. IMPG1 encodes the SPACR protein, a component of the rod and cone photoreceptor extracellular matrix domains. Structural modeling indicates that the p.Leu238Arg substitution destabilizes the conserved SEA1 domain of SPACR. Screening of 144 probands who had various forms of macular dystrophy revealed three other IMPG1 mutations. Two individuals from one family affected by autosomal-recessive VMD were homozygous for the splice-site mutation c.807+1G>T, and two from another family were compound heterozygous for the mutations c.461T>C (p.Leu154Pro) and c.1519C>T (p.Arg507(?)). Most cases had a normal or moderately decreased electrooculogram Arden ratio. We conclude that IMPG1 mutations cause both autosomal-dominant and -recessive forms of VMD, thus indicating that impairment of the interphotoreceptor matrix might be a general cause of VMD.

SUBMITTER: Manes G

PROVIDER: S-EPMC3769927 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Mutations in IMPG1 cause vitelliform macular dystrophies.

Manes Gaël G Meunier Isabelle I Avila-Fernández Almudena A Banfi Sandro S Le Meur Guylène G Zanlonghi Xavier X Corton Marta M Simonelli Francesca F Brabet Philippe P Labesse Gilles G Audo Isabelle I Mohand-Said Saddek S Zeitz Christina C Sahel José-Alain JA Weber Michel M Dollfus Hélène H Dhaenens Claire-Marie CM Allorge Delphine D De Baere Elfride E Koenekoop Robert K RK Kohl Susanne S Cremers Frans P M FP Hollyfield Joe G JG Sénéchal Audrey A Hebrard Maxime M Bocquet Béatrice B Ayuso García Carmen C Hamel Christian P CP

American journal of human genetics 20130829 3

Vitelliform macular dystrophies (VMD) are inherited retinal dystrophies characterized by yellow, round deposits visible upon fundus examination and encountered in individuals with juvenile Best macular dystrophy (BMD) or adult-onset vitelliform macular dystrophy (AVMD). Although many BMD and some AVMD cases harbor mutations in BEST1 or PRPH2, the underlying genetic cause remains unknown for many affected individuals. In a large family with autosomal-dominant VMD, gene mapping and whole-exome seq ...[more]

PMID: 23993198

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Project description:PURPOSE: To analyze functional and clinical data of Best vitelliform macular dystrophy (VMD) patients with mutations in the BEST1 gene. METHODS: Best VMD patients with BEST1 mutations were evaluated prospectively regarding age, age of onset, best-corrected visual acuity (BCVA), fundus autofluorescence, fluorescein angiography, optical coherence tomography, and electro-oculography. Mutations in BEST1 were established by direct sequencing. RESULTS: Forty-six eyes of 23 patients (10 male, 13 female) were included in the study. We identified nine different BEST1 mutations (3/9 novel), in ten unrelated families. The age of patients ranged between 3 and 75 years; age of onset varied between 2 and 67 years. BCVA ranged between 20/20 and 20/200. On the basis of fundus biomicroscopy with direct illumination, using one widely accepted classification, the macular lesions could be counted as follows: 1. no lesion (normal fovea): eight eyes, five patients carrying a mutation on the BEST1 gene; 2. previtelliform lesions: six eyes, three affected patients; 3. vitelliform lesions: four eyes, two affected patients; 4. pseudohypopyon: three eyes, three affected patients; 5. vitelliruptive lesions (scrambled egg aspect with dispersion of the vitelliform material without sign of atrophy or fibrosis): ten eyes, six affected patients; 6. atrophic lesions (atrophy with or without residual dispersed material): seven eyes, five patients; 7. fibrotic lesions: eight eyes, five patients. Two patients presented unilateral Best VMD. Both eyes of two patients presented multifocal Best VMD features on fundus examination. Six eyes of four patients have been treated for choroidal neovascularization by thermic photocoagulation [one eye], photodynamic therapy [three eyes], and intravitreal ranibizumab injection [two eyes]. Comparison of interfamilial and intrafamilial clinical data between patients did not reveal differences in age, BCVA, and stage of the disease as evaluated by fundus autofluorescence, fluorescein angiography, and optical coherence tomography (p>0.05). Mean BCVA impairment showed a statistically significant correlation to a more advanced stage of the disease (p<0.001). CONCLUSIONS: BEST1 mutations were not correlated with the severity of the functional and clinical data in the Best VMD patients examined.

Project description:Demonstrating the utility of adaptive optics scanning light ophthalmoscopy (AOSLO) to assess outer retinal structure in Best vitelliform macular dystrophy (BVMD).To characterize outer retinal structure in BVMD using spectral-domain optical coherence tomography (SD-OCT) and AOSLO.Prospective, observational case series. Four symptomatic members of a family with BVMD with known BEST1 mutation were recruited at the Advanced Ocular Imaging Program research lab at the Medical College of Wisconsin Eye Institute, Milwaukee.Thickness of 2 outer retinal layers corresponding to photoreceptor inner and outer segments was measured using SD-OCT. Photoreceptor mosaic AOSLO images within and around visible lesions were obtained, and cone density was assessed in 2 subjects.Photoreceptor structure.Each subject was at a different stage of BVMD, with photoreceptor disruption evident by AOSLO at all stages. When comparing SD-OCT and AOSLO images from the same location, AOSLO images allowed for direct assessment of photoreceptor structure. A variable degree of retained photoreceptors was seen within all lesions. The photoreceptor mosaic immediately adjacent to visible lesions appeared contiguous and was of normal density. Fine hyperreflective structures were visualized by AOSLO, and their anatomical orientation and size were consistent with Henle fibers.AND RELEVANCE: The AOSLO findings indicate that substantial photoreceptor structure persists within active lesions, accounting for good visual acuity in these patients. Despite previous reports of diffuse photoreceptor outer segment abnormalities in BVMD, our data reveal normal photoreceptor structure in areas adjacent to clinical lesions. This study demonstrates the utility of AOSLO for understanding the spectrum of cellular changes that occur in inherited degenerations such as BVMD. Photoreceptors are often significantly affected at various stages of inherited degenerations, and these changes may not be readily apparent with current clinical imaging instrumentation.

Project description:PurposeTo analyze fixation location and stability in best vitelliform macular dystrophy (BVMD) and test their association with best-corrected visual acuity (BCVA).DesignObservational, cross-sectional study.ParticipantsThirty patients (55 eyes) affected by genetically confirmed BVMD were followed up at the Retinal Heredodystrophies Unit of IRCCS San Raffaele Scientific Institute, Milan.MethodsPatients underwent testing with macular integrity assessment (MAIA) microperimeter. Fixation location was measured as distance in degrees (°) between preferred retinal locus (PRL) and estimated fovea location (EFL); fixation was defined as eccentric when the distance between PRL and EFL exceeded 2°. Fixation stability was graded as stable, relatively unstable, or unstable and expressed as bivariate contour ellipse area (BCEA, °2).Main outcome measuresFixation location and stability.ResultsThe median distance of the PRL from the anatomic fovea was 0.7°, and fixation location was eccentric in 27% of eyes. Fixation was graded as stable in 64% of eyes, relatively unstable in 13%, and unstable in 24%, with a median 95% BCEA of 6.2°2. The atrophic/fibrotic stage was associated with worse fixation parameters (all P < 0.01). Both PRL eccentricity and fixation stability were linearly associated with BCVA: every 1° increase in PRL eccentricity was associated with a 0.07 logarithm of the minimum angle of resolution (logMAR) worse BCVA (P < 0.0001) while every 1°2 increase in 95% BCEA was associated with a 0.01 logMAR worse BCVA (P < 0.001). No significant intereye correlation was found for PRL eccentricity and fixation stability, as well as no association between the patient's age and fixation parameters.ConclusionsWe demonstrated that most eyes affected by BVMD retain a central stable fixation and provided evidence that both fixation eccentricity and stability are strongly associated with visual acuity in BVMD. These parameters may serve as secondary end points for future clinical trials.Financial disclosuresProprietary or commercial disclosure may be found after the references.

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Mutations in IMPG1 cause vitelliform macular dystrophies.

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Mutations in IMPG1 cause vitelliform macular dystrophies.

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