Lyon, Gholson J, Longo, Joseph, Garcia, Andrew, Inusa, Fatima, Marchi, Elaine, Shi, Daniel, Dörfel, Max, Arnesen, Thomas, Aldabe, Rafael, Lyons, Scott, Nashat, Melissa, Bolton, David (April 2023) Evaluating possible maternal effect lethality of Naa10 knockout mice, and modulation of phenotypes for embryonic and neonatal lethality by genetic background and environment. (Submitted)
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Abstract
Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex, also including the accessory protein, NAA15, encoded by the autosomal gene, NAA15. Although NAA10 is an essential gene in humans, there is nonetheless extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. Likewise, the genetic spectrum for NAA15 is also extensive, where the mechanism likely involves haploinsufficiency in heterozygous individuals. The phenotypic presentation in humans with NAA10 or NAA15 variants includes variable levels of intellectual disability, delayed milestones, autism spectrum disorder, craniofacial dysmorphology, cardiac anomalies, seizures, and visual abnormalities. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we show that the mouse phenotypes are replicated with new genetic alleles, but are modulated by genetic background and environmental effects, as demonstrated by several new mouse strains and backcrossing of the original Naa10 null allele 20 generations to inbred C57BL/6J mice in a different animal facility. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/y male mice on the inbred genetic background in this different animal facility. We hypothesize that decreased NTA of many different target substrate proteins is the main explanation for the variable phenotypic outcomes, and future experiments will make use of these mice and human cell lines to address this hypothesis.
| Item Type: | Paper |
|---|---|
| Subjects: | organism description > animal organism description > animal > mammal organism description > animal > mammal > rodent > mouse organism description > animal > mammal > rodent |
| CSHL Authors: | |
| Communities: | CSHL labs > Lyons lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 27 April 2023 |
| Date Deposited: | 12 Oct 2023 19:34 |
| Last Modified: | 10 Jan 2024 20:22 |
| PMCID: | PMC10168333 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41212 |
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