Genetically modified mouse, methods for producing the same, and uses thereof

1 . A genetically modified mouse whose genome comprises a transgene encoding a Miltenberger blood group antigen subtype III (Mi.III antigen) comprising the amino acid sequence of SEQ ID NO: 1, wherein the transgene comprises a nucleotide sequence at least 85% identical to SEQ ID NO: 3.

2 . The genetically modified mouse of claim 1 , wherein the transgene is a complementary deoxyribonucleic acid (cDNA) of GYP.Mur gene and comprises a nucleotide sequence at least 85% identical to SEQ ID NO: 2.

3 . The genetically modified mouse of claim 2 , wherein the transgene comprises a nucleotide sequence 100% identical to SEQ ID NO: 2.

4 . The genetically modified mouse of claim 1 , wherein the transgene comprises an internal ribosome entry site (IRES), and a cDNA of GYP.Mur gene that is linked to the 3′ end of the IRES.

5 . The genetically modified mouse of claim 1 , wherein the transgene comprises a nucleotide sequence 100% identical to SEQ ID NO: 3.

6 . The genetically modified mouse of claim 1 , wherein the transgene is at the 3′ untranslated region (UTR) of an endogenous glycophorin A (GYPA) gene of the genetically modified mouse.

7 . A method of producing the genetically modified mouse of claim 1 comprising,

(a) introducing the transgene into an endogenous GYPA gene of a zygote or embryo of a mouse by

(a-1) providing a single guide ribonucleic acid (sgRNA) comprising the nucleotide sequence of SEQ ID NO: 4;

(a-2) providing a donor template comprising the transgene, a 5′ homologous arm, and a 3′ homologous arm, wherein the 5′ and 3′ homologous arms are respectively linked to the 5′ end and 3′ end of the transgene, and respectively comprise the nucleotide sequences of SEQ ID NOs: 7 and 8;

(a-3) injecting the sgRNA of (a-1), the donor template of (a-2) and a CRISPR associated protein 9 (Cas9) into the zygote or embryo; and

(b) transplanting the zygote or embryo of (a) into a recipient mouse to produce the genetically modified mouse.

8 . The method of claim 7 , wherein the transgene is a cDNA of GYP.Mur gene and comprises a nucleotide sequence at least 85% identical to SEQ ID NO: 2.

9 . The method of claim 8 , wherein the transgene comprises a nucleotide sequence 100% identical to SEQ ID NO: 2.

10 . The method of claim 7 , wherein the transgene comprises an IRES, and a cDNA of GYP.Mur gene linked to the 3′ end of the IRES.

11 . The method of claim 10 , wherein the transgene comprises a nucleotide sequence at least 85% identical to SEQ ID NO: 3.

12 . The method of claim 11 , wherein the transgene comprises a nucleotide sequence 100% identical to SEQ ID NO: 3.

13 . The method of claim 12 , wherein the donor template comprises a nucleotide sequence 100% identical to SEQ ID NO: 6.

14 . The method of claim 7 , wherein the single guide ribonucleic acid (sgRNA) comprises a nucleotide sequence 100% identical to SEQ ID NO: 5.

15 . The method of claim 7 , wherein the transgene is introduced into the 3′ UTR of the endogenous GYPA gene of the zygote or embryo.

16 . A method of identifying a drug for treating hypertension in a subject by using the genetically modified mouse of claim 1 , comprising,

(a) administering a drug candidate to the genetically modified mouse;

(b) measuring the blood pressure of the genetically modified mouse of (a); and

(c) identifying the drug candidate to be the drug when the measured blood pressure of (b) is lower than that of a control genetically modified mouse, which does not receive the administration of the drug candidate;

wherein, the drug candidate is amlodipine, hydralazine, captopril, or valsartan.

17 . The method of claim 16 , wherein the subject has the Mi.III antigen expressed on an erythrocyte membrane thereof.