huCFTR-G551D Mouse
Product Name
huCFTR-G551D Mouse
Product ID
C001879
Strain Name
C57BL/6NCya-Cftrem3(hCFTR*G551D)/Cya
Backgroud
C57BL/6NCya
Status
When using this mouse strain in a publication, please cite “huCFTR-G551D Mouse (Catalog C001879) were purchased from Cyagen.”
Product Type
Age
Genotype
Sex
Quantity
Gene Name
Gene Alias
CF, MRP7, ABC35, ABCC7, CFTR/MRP, TNR-CFTR, dJ760C5.1
NCBI ID
Chromosome
Chr 7
MGI ID
Datasheet
Strain Description
The cystic fibrosis transmembrane conductance regulator (CFTR) is a critical protein that maintains the salt and water balance across various human organs, including the lungs, pancreas, and sweat glands. The primary function of CFTR is to act as a chloride channel, regulating the transport of chloride and bicarbonate ions across epithelial cell membranes, thereby maintaining tissue fluid balance and pH. This process is ATP-dependent and also modulates the activity of other ion channels and transport proteins [1-2]. Mutations in the CFTR gene can lead to chloride channel dysfunction, resulting in various diseases, with cystic fibrosis (CF) being the most common. CF is the most prevalent lethal genetic disease among Caucasians, with an incidence of approximately 1/2,500 to 1/1,800, and about 90,000 cases globally [3-4]. The disease is characterized by thickened mucus in the lungs, frequent respiratory infections, pancreatic insufficiency, and male infertility, typically due to vas deferens obstruction. The G551D mutation is a clinically significant genetic defect in the CFTR gene, which is classified as a Class III mutation and is the third most common CF-associated mutation worldwide, occurring in about 3% of CF patients [5]. This missense mutation involves a single amino acid substitution where Glycine (G) is replaced by Aspartic Acid (D) at position 551 within the first Nucleotide Binding Domain (NBD1) of the CFTR protein. The defining molecular pathology is a severe gating defect; while the CFTR chloride channel is correctly processed and successfully trafficked to the apical membrane of epithelial cells, its probability of opening is drastically reduced (approximately 100-fold lower than the wild-type channel). This impairment in channel opening results in a critical reduction in chloride and bicarbonate transport, leading to the characteristic buildup of thick, dehydrated mucus in multiple organs and a severe clinical phenotype. Current treatments for CF mainly focus on CFTR modulators to restore the function of the mutated CFTR protein. CFTR modulators are classified into potentiators (which enhance CFTR function) and correctors (which assist in the proper folding and trafficking of CFTR to the cell membrane). Representative drugs include Ivacaftor, Lumacaftor, and triple-combination CFTR modulating therapy Elexacaftor-Tezacaftor-Ivacaftor [6]. The G551D mutation holds particular importance in CF research and therapy as it was the first genotype-specific mutation to be successfully targeted by a CFTR potentiator drug, Ivacaftor, which functions by increasing the opening probability of the mutant channel.
huCFTR-G551D mice were developed by introducing the G551D mutation into the CFTR-humanized mouse model (Catalog Number: C001964), creating a humanized disease model. It is suitable for research into CF mechanisms and the development of therapies targeting the CFTR G551D mutation. This strain requires feeding with intestinal cleansers to maintain survival. In addition, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen can also generate hot mutation models based on the CFTR-humanized strain and provide customized services for specific mutations to meet the experimental needs in pharmacology and other fields.
Reference
Corradi V, Vergani P, Tieleman DP. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR): CLOSED AND OPEN STATE CHANNEL MODELS. J Biol Chem. 2015 Sep 18;290(38):22891-906.
Csanády L, Vergani P, Gadsby DC. STRUCTURE, GATING, AND REGULATION OF THE CFTR ANION CHANNEL. Physiol Rev. 2019 Jan 1;99(1):707-738.
Chillón M, Casals T, Mercier B, Bassas L, Lissens W, Silber S, Romey MC, Ruiz-Romero J, Verlingue C, Claustres M, et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med. 1995 Jun 1;332(22):1475-80.
Grasemann H, Ratjen F. Cystic Fibrosis. N Engl J Med. 2023 Nov 2;389(18):1693-1707.
Bompadre SG, Sohma Y, Li M, Hwang TC. G551D and G1349D, two CF-associated mutations in the signature sequences of CFTR, exhibit distinct gating defects. J Gen Physiol. 2007 Apr;129(4):285-98. doi: 10.1085/jgp.200609667. Epub 2007 Mar 12.
Valladares KN, Jones LI, Barnes JW, Krick S. Highly Effective Modulator Therapy: Implications for the Microbial Landscape in Cystic Fibrosis. Int J Mol Sci. 2024 Nov 5;25(22):11865.
Strain Strategy
Figure 1a. Gene editing strategy of huCFTR wild-type humanized model (Catalog Number: C001964). The region from the 5'UTR to 3'UTR of the mouse Cftr gene was replaced with the 5'UTR to 3'UTR region of the human CFTR gene.
Figure 1b. Gene editing strategy of huCFTR-G551D point mutation humanized model (Catalog Number: C001879). The p.G551D (GGT to GAT) mutation was introduced into exon 12 of the human CFTR gene in huCFTR mice via gene editing technology.
Application Area
CFTR*G551D-targeted drug screening, development, and evaluation;
Research on the pathological mechanisms and therapeutic approaches of cystic fibrosis.
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