Dataset Information

[Construction of a mouse model of cblC type methylmalonic acidemia with W203X mutation based on the CRISPR/Cas9 technology].

ABSTRACT: OBJECTIVE:To construct a W203X-mutant mouse model of cblC type methylmalonic acidemia based on the CRISPR/Cas9 technology. METHODS:At first, BLAST was used to compare the conservative nature of the cblC gene and protein sequences in humans and mice, and then, the CRISPR/Cas9 technology was used for microinjection of mouse fertilized eggs to obtain heterozygous F1 mice. Hybridization was performed for these mice to obtain homozygous W203X-mutant mice. The blood level of the metabolite propionyl carnitine (C3) was measured for homozygous mutant mice, heterozygous littermates, and wild-type mice. RESULTS:The gene and protein sequences of MMACHC, the pathogenic gene for cblC type methylmalonic acidemia, were highly conserved in humans and mice. The homozygous W203X-mutant mice were successfully obtained by the CRISPR/Cas9 technology, and there was a significant increase in C3 in these mice at 24 hours after birth (P<0.001). CONCLUSIONS:A W203X-mutant mouse model of cblC type methylmalonic acidemia is successfully constructed by the CRISPR/Cas9 technology.

SUBMITTER: Ma F

PROVIDER: S-EPMC7389904 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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[Construction of a mouse model of cblC type methylmalonic acidemia with W203X mutation based on the CRISPR/Cas9 technology].

Ma Fei F Shi Cong-Cong CC Liang Pu-Ping PP Li Si-Tao ST Gu Xia X Xiao Xin X Hao Hu H

Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 20190801 8

<h4>Objective</h4>To construct a W203X-mutant mouse model of cblC type methylmalonic acidemia based on the CRISPR/Cas9 technology.<h4>Methods</h4>At first, BLAST was used to compare the conservative nature of the cblC gene and protein sequences in humans and mice, and then, the CRISPR/Cas9 technology was used for microinjection of mouse fertilized eggs to obtain heterozygous F1 mice. Hybridization was performed for these mice to obtain homozygous W203X-mutant mice. The blood level of the metabol ...[more]

PMID: 31416510

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Project description:Background: Methylmalonic acidemia (MMA) can display many clinical manifestations, among which acute lymphoblastic leukemia (ALL) has not been reported, and congenital heart disease (CHD) is also rare. Case presentation: We report an MMA case with ALL and CHD in a 5.5-year-old girl. With developmental delay and local brain atrophy in MRI, she was diagnosed with cerebral palsy at 9 months old. Rehabilitation was performed since then. This time she was admitted to hospital because of weakness and widespread bleeding spots. ALL-L2 (pre-B-cell) was confirmed by bone marrow morphology and immunophenotyping. Echocardiography showed patent foramen ovale. The girl was treated with VDLD and CAML chemotherapy, during which she developed seizures, edema and renal insufficiency. Decrease of muscle strength was also found in physical examination. Screening for inherited metabolic disorders showed significantly elevated levels of methylmalonate-2, acetylcarnitine (C2), propionylcarnitine (C3), C3/C2 and homocysteine. Gene analysis revealed a compound heterozygous mutaion in MMACHC (NM_015,560): c.80A > G (p.Gln27Arg) and c.609G > A (p.Trp203*). CblC type MMA was diagnosed. Intramuscular injection of cyanocobalamin and intravenous L-carnitine treatment were applied. The edema vanished gradually, and chemotherapy of small dosage of vindesine was given intermittently when condition permitted. 2 months later, muscle strength of both lower limbs were significantly improved to nearly grade 5. The levels of methylmalonic acid and homocysteine were improved. Conclusion: Metabolic disease screening and gene analysis are very necessary for diseases with complex clinical symptoms. ALL can be a rare manifestation for MMA. Synopsis: We report a case of methylmalonic acidemia with acute lymphoblastic leukemia and congenital heart disease, which uncovered the importance of genetic testing and metabolic diseases screening in patients with multiple systemic organ involvement.

Dataset Information

[Construction of a mouse model of cblC type methylmalonic acidemia with W203X mutation based on the CRISPR/Cas9 technology].

Publications

[Construction of a mouse model of cblC type methylmalonic acidemia with W203X mutation based on the CRISPR/Cas9 technology].

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