Journal article
CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials
Human mutation, Vol.40(12), pp.2377-2392
12/2019
DOI: 10.1002/humu.23894
PMCID: PMC7493429
PMID: 31403230
Abstract
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 (KO) mouse for Capn5 and compared the retinal phenotype to both wild-type and an existing Capn5 KO mouse model. In humans, CAPN5 loss-of-function (LOF) gene variants were ascertained in large exome databases from 60,706 unrelated subjects without severe disease phenotypes. Ocular examination of the retina of Capn5 KO mice by histology and electroretinography showed no significant abnormalities. In humans, there were 22 LOF CAPN5 variants located throughout the gene and in all major protein domains. Structural modeling of coding variants showed these LOF 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 LOF 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.
Details
- Title: Subtitle
- CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials
- Creators
- Katherine J Wert - Omics Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CaliforniaSusanne F Koch - Department of Physiological Genomics, Biomedical Center, Ludwig Maximillian University, Munich, GermanyGabriel Velez - Department of Ophthalmology, Medical Scientist Training Program, University of Iowa, Iowa City, IowaChun-Wei Hsu - Departments of Ophthalmology, Pathology, and Cell Biology, 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, New YorkMaryAnn Mahajan - Omics Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CaliforniaAlexander G Bassuk - Department of Pediatrics, University of Iowa, Iowa City, IowaStephen H Tsang - Departments of Ophthalmology, Pathology, and Cell Biology, 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, New YorkVinit B Mahajan - Department of Ophthalmology, Veterans Affairs, Palo Alto Health Care System, Palo Alto, California
- Resource Type
- Journal article
- Publication Details
- Human mutation, Vol.40(12), pp.2377-2392
- Publisher
- United States
- DOI
- 10.1002/humu.23894
- PMID
- 31403230
- PMCID
- PMC7493429
- ISSN
- 1059-7794
- eISSN
- 1098-1004
- Grant note
- R01EY024698 / NEI NIH HHS T32 GM007337 / NIGMS NIH HHS R01EY026682 / NEI NIH HHS R21AG050437 / NEI NIH HHS R01EY024665 / NEI NIH HHS F30EYE027986 / NEI NIH HHS P30EY026877 / NEI NIH HHS R01EY025225 / NEI NIH HHS 5P30EY019007 / NEI NIH HHS F30 EY027986 / NEI NIH HHS
- Language
- English
- Date published
- 12/2019
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984070897102771
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