Insertion of a Knockout-first Cassette in Ampd1 Gene Leads to Neonatal Death by Disruption of Neighboring Genes Expression

Overview

Journal Sci Rep

Specialty Science

Date 2016 Oct 25

PMID 27775065

Citations 13

Authors

Yongcheng Pan

Lusi Zhang

Qiong Liu

Ying Li

Hui Guo

Yu Peng

Hexiang Peng

Beisha Tang

Zhengmao Hu

Jingping Zhao

Kun Xia

Jia-Da Li

Affiliations

Soon will be listed here.

Abstract

AMPD1 is an adenosine monophosphate deaminase that catalyzes the deamination of AMP to IMP. To understand the physiological function of AMPD1, we obtained a strain of Ampd1 mutant mice from KOMP repository, which was generated by a knockout-first strategy. An elevated AMP level and almost complete lack of IMP was detected in the skeletal muscle of E18.5 Ampd1 mice. However, Ampd1 mice died in 2 days postnatally, which was contradicting to previous reports. After removal of the knockout-first cassette and critical exon, mice homozygous for the Ampd1 and Ampd1 alleles survived to adulthood. RNA-seq analysis indicated that the expression of two neighboring genes, Man1a2 and Nras, were disrupted in the Ampd1 mice, but normal in the Ampd1 and Ampd1 mice. The neonatal lethality phenotype in the Ampd1 mice was consistent with the Man1a2-deficient mice. Our results indicated the knockout-first cassette may cause off-target effect by influence the expression of neighboring genes. This study, together with other reports, strongly suggests that removal of targeting cassette by site-specific recombinases is very important for the accurate phenotypic interpretation on mice generated by target mutations.

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