Generation Of The Rat With ?1-antitrvpsin Deficiency By CRISPR/Cas9 And Phenotype Identification

As a serious autosomal disorder,?1-antitrypsin deficiency is associated with mutations in SERPINA1 gene locus.?1-antitrypsin produced mainly by hepatocytes and secrete into the blood and its function is to protect host tissues by inhibiting neutrophil proteases.Total absence of the gene or frame shift mutations lead to premature stop codons,as well as point mutations lead to no production or production of abnormal ?1-antitrypsin.Because ?1-antitrypsin was known to be an inhibitor of proteinase,deficiency of ?1-AT leads to excess unopposed neutrophil elastase activity,thus causing further release of neutrophil elastase and tissue damage in lung.In the commonest severe Z type point mutation,an amino acid change occur at position 342(glu-lys),although the gene is normally transcribed and translated.This change affects the mobility of the reactive center loop and produces the so called loop sheet polymerization,leading to accumulation of Z type ?1-AT in the hepatocytes and reduction in secretion of al-AT.The main presentation for individuals with AATD are lung diseases as early chronic obstructive lung disease(COPD)and liver disease.AATD associated liver disease may present clinically in a variety of ways,such as neonatal hepatitis syndrome,mild-to-moderate lobular hepatitis,steatosis,fibrosis,hepatocellular necrosis,bile duct paucity or bile duct proliferation.?1-antitrypsin deficiency is an under-recognized liver disease that has a complex pathophysiology and is highly variable in clinical course,as well as the commonest children's genetic liver disease.Further research is required to identify specific epigenetic factors that influence clinical phenotype and treatment benefit.Therefore we generate rat model of Z type ?1-antitrypsin deficiency which will contribute to monitoring and treatment.