Journal article
A multifunction murine Col4a1 allele reveals potential gene therapy parameters for Gould syndrome
The Journal of cell biology, Vol.224(6), e202409153
06/02/2025
DOI: 10.1083/jcb.202409153
PMCID: PMC12029515
PMID: 40279671
Abstract
Basement membranes (BMs) are specialized extracellular matrix (ECM) structures essential for organ morphogenesis, architecture, and function. BM composition and properties vary between tissues, developmental stages, and disease states, and there is only a rudimentary understanding of BM dynamics. Here, we introduce a versatile mouse model carrying a multifunctional dual-color fluorescence tagged allele with knockout potential for the fundamental BM component type IV collagen alpha 1 (COL4A1). This allele enables the characterization of cell type- and time-specific contributions to BMs and the generation of a conditional Col4a1 null allele. We demonstrate the utility of this unique genetic resource in providing clinically relevant insights for individuals with Gould syndrome - a multisystem disorder caused by COL4A1 and COL4A2 mutations. We show active COL4A1 turnover in postnatal cerebrovascular BMs, identifying a potential interventional window for cerebrovascular manifestations associated with Gould syndrome. We also demonstrate that heterozygous Col4a1 deletion is significantly less pathogenic than dominant Col4a1 missense mutations, which has important implications for gene therapy.
Details
- Title: Subtitle
- A multifunction murine Col4a1 allele reveals potential gene therapy parameters for Gould syndrome
- Creators
- Mao Mao - University of California, San FranciscoYoshihiro Ishikawa - University of California, San FranciscoCassandre Labelle-Dumais - University of California, San FranciscoXiaowei Wang - University of California, San FranciscoYien-Ming Kuo - University of California, San FranciscoUma B Gaffney - University of California, San FranciscoMegan E Smith - University of California, San FranciscoCarlie N Abdala - University of California, San FranciscoMatthew D Lebedev - University of California, San FranciscoWilliam J Paradee - University of IowaDouglas B Gould - University of California, San Francisco
- Resource Type
- Journal article
- Publication Details
- The Journal of cell biology, Vol.224(6), e202409153
- DOI
- 10.1083/jcb.202409153
- PMID
- 40279671
- PMCID
- PMC12029515
- NLM abbreviation
- J Cell Biol
- ISSN
- 1540-8140
- eISSN
- 1540-8140
- Publisher
- ROCKEFELLER UNIV PRESS
- Grant note
- All May See Foundation National Institue of Neurological Disease and Stroke 1R21NS133610 / NIH HHS Research to Prevent Blindness P30 EY002162 / NEI NIH HHS
- Language
- English
- Date published
- 06/02/2025
- Academic Unit
- Medicine Administration
- Record Identifier
- 9984813156002771
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