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Recently, researchers from the Guangzhou Institute of Biomedicine and Health of the Chinese Academy of Sciences and their collaborators used a single-base editor to perform point mutations on glucokinase and developed the first human permanent neonatal diabetic canine model
.
A related paper entitled Generation of permanent neonatal diabetes mellitus dogs with glucokinase point mutations through base editing was published online on Cell Discovery
.
Some cases of diabetic patients occur in the neonatal period and are inherited diabetes caused by genetic mutations related to the function of insulin-secreting β-cells
.
Glucokinase (GCK) is the first rate-limiting enzyme in the process of glucose metabolism and a glucose concentration sensor, which plays a key role in regulating blood glucose concentration
.
GCK gene mutations account for a large proportion of juvenile diabetes, and most of them are single nucleotide mutations.
Homozygous or compound heterozygous mutations can lead to complete inactivation of GCK protein.
Patients exhibit permanent neonatal diabetes.
Symptoms include high blood sugar on the first day of life, accompanied by slow growth, and the patient needs to inject exogenous insulin for life to survive
.
Obtaining an animal model that can accurately simulate the human disease is of great significance to the research on the mechanism of disease and the development of new treatment methods
.
Dogs are omnivorous animals, close to humans in terms of metabolism, physiology, living habits and anatomical characteristics, and are ideal animal models for studying human diabetes
.
This research is the first attempt to use a single-base editor to perform point mutations in the canine GCK gene, so that the CAG codon on the GCK gene completes the C to T transition, thereby introducing a stop codon, terminating the translation of GCK early, and completely losing the GCK protein.
Active
.
The process is to first obtain the fertilized eggs from the donor dog, and inject the in vitro transcribed base editor mRNA and sgRNA into the fertilized eggs with the help of a microscope operating system, and then transplant the injected fertilized eggs into the oviduct of the surrogate dog to make It continues to mature and give birth in the body
.
In the experiment, 56 fertilized eggs were transplanted, 17 puppies were laid, and 4 GCK gene-edited dogs were obtained, of which 3 were homozygous mutations and 1 was chimera
.
Puppies with point mutations in the GCK gene show symptoms of hyperglycemia and slow growth at birth.
If they are not injected with exogenous insulin, the newborn dog will die within two weeks.
If the insulin is injected on the first day after birth, the blood glucose concentration of the newborn dog will be It tends to a normal level, can survive for a long time, and has a greater degree of body weight recovery compared with untreated puppies
.
GO enrichment analysis of the RNA sequencing results found that the permanent neonatal diabetes model dogs injected with exogenous insulin can promote the metabolism of lipids and fatty acids, so that the dog’s physiological indicators can be maintained at a relatively normal level, thereby enabling its survival time Prolonged, the above characteristics are consistent with the symptoms of permanent neonatal diabetes in humans
.
Therefore, the single-base gene-edited dog will provide an ideal animal model for studying the mechanism of human neonatal diabetes and developing new treatment methods, such as drug therapy, stem cell therapy and gene therapy
.
The research work is supported by the national key research and development plan, the strategic pilot science and technology project of the Chinese Academy of Sciences, and the science and technology plans of Guangdong Province and Guangzhou
.
Injection of exogenous insulin for permanent neonatal diabetes model dogs, homozygous mutant on the left, chimeric mutant on the right Source: Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences
.
A related paper entitled Generation of permanent neonatal diabetes mellitus dogs with glucokinase point mutations through base editing was published online on Cell Discovery
.
Some cases of diabetic patients occur in the neonatal period and are inherited diabetes caused by genetic mutations related to the function of insulin-secreting β-cells
.
Glucokinase (GCK) is the first rate-limiting enzyme in the process of glucose metabolism and a glucose concentration sensor, which plays a key role in regulating blood glucose concentration
.
GCK gene mutations account for a large proportion of juvenile diabetes, and most of them are single nucleotide mutations.
Homozygous or compound heterozygous mutations can lead to complete inactivation of GCK protein.
Patients exhibit permanent neonatal diabetes.
Symptoms include high blood sugar on the first day of life, accompanied by slow growth, and the patient needs to inject exogenous insulin for life to survive
.
Obtaining an animal model that can accurately simulate the human disease is of great significance to the research on the mechanism of disease and the development of new treatment methods
.
Dogs are omnivorous animals, close to humans in terms of metabolism, physiology, living habits and anatomical characteristics, and are ideal animal models for studying human diabetes
.
This research is the first attempt to use a single-base editor to perform point mutations in the canine GCK gene, so that the CAG codon on the GCK gene completes the C to T transition, thereby introducing a stop codon, terminating the translation of GCK early, and completely losing the GCK protein.
Active
.
The process is to first obtain the fertilized eggs from the donor dog, and inject the in vitro transcribed base editor mRNA and sgRNA into the fertilized eggs with the help of a microscope operating system, and then transplant the injected fertilized eggs into the oviduct of the surrogate dog to make It continues to mature and give birth in the body
.
In the experiment, 56 fertilized eggs were transplanted, 17 puppies were laid, and 4 GCK gene-edited dogs were obtained, of which 3 were homozygous mutations and 1 was chimera
.
Puppies with point mutations in the GCK gene show symptoms of hyperglycemia and slow growth at birth.
If they are not injected with exogenous insulin, the newborn dog will die within two weeks.
If the insulin is injected on the first day after birth, the blood glucose concentration of the newborn dog will be It tends to a normal level, can survive for a long time, and has a greater degree of body weight recovery compared with untreated puppies
.
GO enrichment analysis of the RNA sequencing results found that the permanent neonatal diabetes model dogs injected with exogenous insulin can promote the metabolism of lipids and fatty acids, so that the dog’s physiological indicators can be maintained at a relatively normal level, thereby enabling its survival time Prolonged, the above characteristics are consistent with the symptoms of permanent neonatal diabetes in humans
.
Therefore, the single-base gene-edited dog will provide an ideal animal model for studying the mechanism of human neonatal diabetes and developing new treatment methods, such as drug therapy, stem cell therapy and gene therapy
.
The research work is supported by the national key research and development plan, the strategic pilot science and technology project of the Chinese Academy of Sciences, and the science and technology plans of Guangdong Province and Guangzhou
.
Injection of exogenous insulin for permanent neonatal diabetes model dogs, homozygous mutant on the left, chimeric mutant on the right Source: Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences
