Rational design of a genomically humanized mouse model for dominantly inherited hearing loss, DFNA9
Hear Res. 2024 Feb;442:108947. doi: 10.1016/j.heares.2023.108947. Epub 2023 Dec 31.ABSTRACTDFNA9 is a dominantly inherited form of adult-onset progressive hearing impairment caused by mutations in the COCH gene. COCH encodes cochlin, a crucial extracellular matrix protein. We established a genomically humanized mouse model for the Dutch/Belgian c.151C>T founder mutation in COCH. Considering upcoming sequence-specific genetic therapies, we exchanged the genomic murine Coch exons 3-6 for the corresponding human sequence. Introducing human-specific genetic information into mouse exons can be risky. To mitigate unforeseen consequences on cochlin function resulting from the introduction of the human COCH protein-coding sequence, we converted all human-specific amino acids to mouse equivalents. We furthermore optimized the recognition of the human COCH exons by the murine splicing machinery during pre-mRNA splicing. Subsequent observations in mouse embryonic stem cells revealed correct splicing of the hybrid Coch transcript. The inner ear of the established humanized Coch mice displays correctly-spliced wild-type and mutant humanized Coch alleles. For a comprehensive study of auditory function, mice were crossbred with C57BL/6 Cdh23753A>G mice to remove the Cdh23ahl allele from the genetic background of the mice. At 9 months, all humanized Coch genotypes showed hearing thresholds comparable to wild-type C57BL/6 Cdh23753A>G mice. This indicates that both the introduction of...
Source: Hearing Research - Category: Audiology Authors: Dorien Verdoodt Erwin van Wijk Sanne Broekman Hanka Venselaar Fien Aben Lize Sels Evi De Backer Hanne Gommeren Krystyna Szewczyk Guy Van Camp Peter Ponsaerts Vincent Van Rompaey Erik de Vrieze Source Type: research
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