huUSH2A(E10-15)-c.2299delG/huUSH2A(E10-15) Mouse
Product Name
huUSH2A(E10-15)-c.2299delG/huUSH2A(E10-15) Mouse
Product ID
C002046
Strain Name
C57BL/6JCya-Ush2atm2(hUSH2A*c.2299delG)/Ush2atm1(hUSH2A Exon 10-15)/Cya
Backgroud
C57BL/6JCya
Status
When using this mouse strain in a publication, please cite “huUSH2A(E10-15)-c.2299delG/huUSH2A(E10-15) Mouse (Catalog C002046) were purchased from Cyagen.”
Product Type
Age
Genotype
Sex
Quantity
Gene Name
USH2A
Gene Alias
US2, RP39, USH2, dJ1111A8.1
NCBI ID
Chromosome
Chr 1 (Human)
MGI ID
Datasheet
Strain Description
The USH2A gene encodes Usherin, a basement membrane protein containing laminin EGF-like domains, pentraxin domains, and multiple fibronectin type III repeats. Usherin plays a critical role in the development of inner ear hair cells, auditory signal transduction, and the maintenance of adhesion via interactions with fibronectin in the retinal basement membrane. Mutations in the USH2A gene disrupt the normal development and function of hair cells, impair fibronectin assembly, and compromise the adhesive properties of the retinal basement membrane, leading to hearing loss and retinitis pigmentosa (RP). The USH2A gene is the primary causative gene for Usher syndrome type II (USH2), with 75%–90% of USH2 cases linked to mutations in this gene [1]. Exon 13 of the USH2A gene harbors a hotspot for pathogenic mutations associated with USH, including two common mutations, c.2299delG and c.2276G>T, which are the subject of several therapeutic investigations. The c.2299delG mutation in exon 13 causes frameshift and premature termination codons. This mutation generates a truncated Usherin protein approximately 85% of the full-length protein, resulting in loss of Usherin function [2-5]. Currently, there are no effective therapies for Usher syndrome. Ongoing research focuses on elucidating the genetic mechanisms underlying the disorder and developing gene-based therapeutic strategies.
The huUSH2A(E10-15)-c.2299delG/huUSH2A(E10-15) mouse is a humanized disease mutation model generated by crossing the huUSH2A(E10-15)-c.2299delG mouse (Catalog No.: C001850) with the huUSH2A(E10-15) mouse (Catalog No.: C001554). This model is a heterozygous humanized Ush2a mouse carrying the pathogenic c.2299delG mutation. One allele is the wild-type human USH2A (E10-15) without mutation, while the other allele is the human USH2A carrying the c.2299delG point mutation (hUSH2A*c.2299delG). It can be used for functional studies of the USH2A gene, investigation of the pathogenic mechanism of the c.2299delG mutation, as well as efficacy evaluation and mechanism-of-action studies of USH2A-targeted therapeutic strategies such as antisense oligonucleotides (ASOs) and gene editing. This model provides an important preclinical research platform for the development of innovative therapies for Usher syndrome type II (USH2) and related inherited retinal diseases
Reference
McGee TL, Seyedahmadi BJ, Sweeney MO, Dryja TP, Berson EL. Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa. J Med Genet. 2010 Jul;47(7):499-506.
Pendse ND, Lamas V, Pawlyk BS, Maeder ML, Chen ZY, Pierce EA, Liu Q. In Vivo Assessment of Potential Therapeutic Approaches for USH2A-Associated Diseases. Adv Exp Med Biol. 2019;1185:91-96. doi: 10.1007/978-3-030-27378-1_15. PMID: 31884594.
Yan D, Ouyang X, Patterson DM, Du LL, Jacobson SG, Liu XZ. Mutation analysis in the long isoform of USH2A in American patients with Usher Syndrome type II. J Hum Genet. 2009 Dec;54(12):732-8. doi: 10.1038/jhg.2009.107. Epub 2009 Oct 30. PMID: 19881469; PMCID: PMC4511341.
Dreyer B, Tranebjaerg L, Brox V, Rosenberg T, Möller C, Beneyto M, Weston MD, Kimberling WJ, Cremers CW, Liu XZ, Nilssen O. A common ancestral origin of the frequent and widespread 2299delG USH2A mutation. Am J Hum Genet. 2001 Jul;69(1):228-34. doi: 10.1086/321269. Epub 2001 Jun 8. Erratum in: Am J Hum Genet 2001 Oct;69(4):922. PMID: 11402400; PMCID: PMC1226039.
Dulla K, Slijkerman R, van Diepen HC, Albert S, Dona M, Beumer W, Turunen JJ, Chan HL, Schulkens IA, Vorthoren L, den Besten C, Buil L, Schmidt I, Miao J, Venselaar H, Zang J, Neuhauss SCF, Peters T, Broekman S, Pennings R, Kremer H, Platenburg G, Adamson P, de Vrieze E, van Wijk E. Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations. Mol Ther. 2021 Aug 4;29(8):2441-2455. doi: 10.1016/j.ymthe.2021.04.024. Epub 2021 Apr 23.
Strain Strategy
The huUSH2A(E10-15)-c.2299delG/huUSH2A(E10-15) mouse is a humanized disease mutation model generated by crossing the huUSH2A(E10-15)-c.2299delG mouse (Catalog No.: C001850) with the huUSH2A(E10-15) mouse (Catalog No.: C001554).
Figure 1. Gene editing strategy of huUSH2A(E10-15) mice. The start codon of the mouse Ush2a gene is located in exon 1, whereas the start codon of the human USH2A gene resides in exon 2. Consequently, exons 10–15 of the human USH2A gene correspond to exons 9–14 of the mouse Ush2a gene. Exons 9 to 14 of the mouse Ush2a gene and their flanking sequences were replaced by exons 10 to 15 of the human USH2A gene and their respective flanking sequences.
Figure 2. Gene editing strategy of huUSH2A(E10-15)-c.2299delG mice. The c.2299delG point mutation was introduced into exon 13 of human USH2A.
Application Area
Investigation of the pathogenic mechanisms underlying Usher syndrome (USH) and preclinical evaluation of therapeutic strategies;
Development, screening, and preclinical evaluation of USH2A-targeted therapeutics.
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