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Ectopic expression of BBS1 rescues male infertility, but not retinal degeneration, in a BBS1 mouse model

Gene Therapy volume 29, pages 227–235 (2022)Cite this article

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Abstract

Bardet–Biedl syndrome (BBS) is a rare ciliopathy for which there are no current effective treatments. BBS is a genetically heterogeneous disease, though the M390R mutation in BBS1 is involved in ~25% of all genetic diagnoses of BBS. The principle features of BBS include retinal degeneration, obesity, male infertility, polydactyly, intellectual disability, and renal abnormalities. Patients with mutations in BBS genes often present with night blindness within the first decade of life, which progresses to complete blindness. This is due to progressive loss of photoreceptor cells. Male infertility is caused by a lack of spermatozoa flagella, rendering them immobile. In this study, we have crossed the wild-type human BBS1 gene, driven by the CAG promoter, onto the Bbs1M390R/M390R mouse model to determine if ectopic expression of BBS1 rescues male infertility and retinal degeneration. qRT-PCR indicates that the BBS1 transgene is expressed in multiple tissues throughout the mouse, with the highest expression seen in the testes, and much lower expression in the eye and hypothalamus. Immunohistochemistry of the transgene in the eye showed little if any expression in the photoreceptor outer nuclear layer. When male Bbs1M30R/M390R;BBS1TG+ mice are housed with WT females, they are able to sire offspring, indicating that the male infertility phenotype of BBS is rescued by the transgene. Using electroretinography (ERGs) to measure retinal function and optical coherence tomography to measure retinal thickness, we show that the transgene does not confer protection against retinal degeneration in Bbs1M300R/M390R;BBS1TG+ mice. The results of this study indicate that the male infertility aspect of BBS is an attractive target for gene therapy.

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Fig. 1: Evaluation of expression of the BBS1 transgene.
Fig. 2: Transgene rescue of spermatozoa flagella formation.
Fig. 3: Functional evaluation of mouse retinas using electroretinography.
Fig. 4: Evaluation of outer nuclear layer thickness using optical coherence tomography.

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Funding

This work was funded by the National Institutes of Health, Grant numbers R01 EY011298 (VCS) and R01 EY017168 (VCS), as well as the Roy J. Carver Charitable Trust (VCS). This work also benefitted from the University of Iowa Visual Science Core Facilities funded by NIH P30EY025580 (VCS).

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Authors and Affiliations

  1. Division of Medical Genetics and Genomics, Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA

    Matthew R. Cring, Charles C. Searby, Michael Cave & Val C. Sheffield

  2. Interdisciplinary Genetics Ph.D. Program, University of Iowa, Iowa City, IA, USA

    Matthew R. Cring, Michael G. Anderson & Val C. Sheffield

  3. Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA

    Matthew R. Cring, Charles C. Searby, Michael G. Anderson & Val C. Sheffield

  4. Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA

    Kacie J. Meyer, Adam Hedberg-Buenz & Michael G. Anderson

  5. Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, USA

    Kai Wang

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  1. Matthew R. Cring
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Correspondence to Val C. Sheffield.

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Cring, M.R., Meyer, K.J., Searby, C.C. et al. Ectopic expression of BBS1 rescues male infertility, but not retinal degeneration, in a BBS1 mouse model. Gene Ther 29, 227–235 (2022). https://doi.org/10.1038/s41434-021-00241-1

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