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Hum Mutat. 2019 Aug 12. doi: 10.1002/humu.23894. [Epub ahead of print]

CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials.

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Omics Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA, 94304, U.S.A.
Physiological Genomics, Biomedical Center, Ludwig Maximillians University, Munich, 82152, Germany.
Medical Scientist Training Program, University of Iowa, Iowa City, IA, 52242, U.S.A.
Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, 10032, U.S.A.
Jonas Children's Vision Care and Bernard and Shirlee Brown Glaucoma Laboratory, Institute of Human Nutrition, College of Physicians and Surgeons, Columbia Stem Cell Initiative (CSCI), Columbia University, New York, NY, 10032, U.S.A.
Department of Pediatrics, University of Iowa, Iowa City, IA, 52242, U.S.A.
Departments of Ophthalmology, Pathology & Cell Biology, and Institute of Human Nutrition, Columbia University, New York, NY, 10032, U.S.A.
Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, 94304, U.S.A.


Small molecule pharmacological inhibition of dominant human genetic disease is a feasible treatment that does not rely on the development of individual, patient-specific gene therapy vectors. However, the consequences of protein inhibition as a clinical therapeutic are not well-studied. In advance of human therapeutic trials for CAPN5 vitreoretinopathy, genetic inactivation can be used to infer the effect of protein inhibition in vivo. We created a photoreceptor-specific knockout mouse for Capn5 and compared the retinal phenotype to both wild-type and an existing Capn5 knockout mouse model. In humans, CAPN5 loss-of-function gene variants were ascertained in large exome databases from 60,706 unrelated subjects without severe disease phenotypes. Ocular examination of the retina of Capn5 knockout mice by histology and electroretinography showed no significant abnormalities. In humans, there were 22 loss-of-function CAPN5 variants located throughout the gene and in all major protein domains. Structural modeling of coding variants showed these loss-of-function variants were nearby known disease-causing variants within the proteolytic core and in regions of high homology between human CAPN5 and 150 homologs, yet the loss-of-function of CAPN5 was tolerated as opposed to gain-of-function disease-causing variants. These results indicate that localized inhibition of CAPN5 is a viable strategy for hyperactivating disease alleles. This article is protected by copyright. All rights reserved.


ADNIV; calpain-5; gene therapy; human gene variants; loss of function; retina


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