Dataset Information

The Y227N mutation affects bestrophin-1 protein stability and impairs sperm function in a mouse model of Best vitelliform macular dystrophy.

ABSTRACT: Human bestrophin-1 (BEST1) is an integral membrane protein known to function as a Ca²⁺-activated and volume-regulated chloride channel. The majority of disease-associated mutations in BEST1 constitute missense mutations and were shown in vitro to lead to a reduction in mutant protein half-life causing Best disease (BD), a rare autosomal dominant macular dystrophy. To further delineate BEST1-associated pathology in vivo and to provide an animal model useful to explore experimental treatment efficacies, we have generated a knock-in mouse line (Best1^Y227N). Heterozygous and homozygous mutants revealed no significant ocular abnormalities up to 2?years of age. In contrast, knock-in animals demonstrated a severe phenotype in the male reproductive tract. In heterozygous Best1^Y227N males, Best1 protein was significantly reduced in testis and almost absent in homozygous mutant mice, although mRNA transcription of wild-type and knock-in allele is present and similar in quantity. Degradation of mutant Best1 protein in testis was associated with adverse effects on sperm motility and the capability to fertilize eggs. Based on these results, we conclude that mice carrying the Best1 Y227N mutation reveal a reproducible pathologic phenotype and thus provide a valuable in vivo tool to evaluate efficacy of drug therapies aimed at restoring Best1 protein stability and function.

SUBMITTER: Milenkovic A

PROVIDER: S-EPMC6679414 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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The Y227N mutation affects bestrophin-1 protein stability and impairs sperm function in a mouse model of Best vitelliform macular dystrophy.

Milenkovic Andrea A Schmied Denise D Tanimoto Naoyuki N Seeliger Mathias W MW Sparrow Janet R JR Weber Bernhard H F BHF

Biology open 20190702 7

Human bestrophin-1 (BEST1) is an integral membrane protein known to function as a Ca2+-activated and volume-regulated chloride channel. The majority of disease-associated mutations in BEST1 constitute missense mutations and were shown in vitro to lead to a reduction in mutant protein half-life causing Best disease (BD), a rare autosomal dominant macular dystrophy. To further delineate BEST1-associated pathology in vivo and to provide an animal model useful to expl ...[more]

PMID: 31201163

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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.

Dataset Information

The Y227N mutation affects bestrophin-1 protein stability and impairs sperm function in a mouse model of Best vitelliform macular dystrophy.

Publications

The Y227N mutation affects bestrophin-1 protein stability and impairs sperm function in a mouse model of Best vitelliform macular dystrophy.

Similar Datasets

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