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Loss of function mutation of Eftud2, the gene responsible for mandibulofacial dysostosis with microcephaly (MFDM), leads to pre-implantation arrest in mouse.
PLoS One. 2019; 14(7):e0219280.Plos

Abstract

Mutations in EFTUD2 are responsible for the autosomal dominant syndrome named MFDM (mandibulofacial dysostosis with microcephaly). However, it is not clear how reduced levels of EFTUD2 cause abnormalities associated with this syndrome. To determine if the mouse can serve as a model for uncovering the etiology of abnormalities found in MFDM patients, we used in situ hybridization to characterize expression of Eftud2 during mouse development, and used CRISPR/Cas9 to generate a mutant mouse line with deletion of exon 2 of the mouse gene. We found that Eftud2 was expressed throughout embryonic development, though its expression was enriched in the developing head and craniofacial regions. Additionally, Eftud2 heterozygous mutant embryos had reduced EFTUD2 mRNA and protein levels. Moreover, Eftud2 heterozygous embryos were born at the expected Mendelian frequency, and were viable and fertile despite being developmentally delayed. In contrast, Eftud2 homozygous mutant embryos were not found post-implantation but were present at the expected Mendelian frequency at embryonic day (E) 3.5. Furthermore, only wild-type and heterozygous E3.5 embryos survived ex vivo culture. Our data indicate that Eftud2 expression is enriched in the precusor of structures affected in MFDM patients and show that heterozygous mice carrying deletion of exon 2 do not model MFDM. In addition, we uncovered a requirement for normal levels of Eftud2 for survival of pre-implantation zygotes.

Authors+Show Affiliations

Department of Pediatrics, McGill University, Montreal, QC, Canada. McGill University Health Centre at Glen Site, Montreal, QC, Canada.Department of Human Genetics, McGill University, Montreal, QC, Canada.Department of Pediatrics, McGill University, Montreal, QC, Canada.Department of Pediatrics, McGill University, Montreal, QC, Canada.McGill University Health Centre at Glen Site, Montreal, QC, Canada. Department of Human Genetics, McGill University, Montreal, QC, Canada.McGill University Health Centre at Glen Site, Montreal, QC, Canada. Department of Human Genetics, McGill University, Montreal, QC, Canada.Department of Pediatrics, McGill University, Montreal, QC, Canada. McGill University Health Centre at Glen Site, Montreal, QC, Canada. Department of Human Genetics, McGill University, Montreal, QC, Canada. Department of Anatomy and Cell Biology, McGill University, Strathcona Anatomy and Dentistry Building, Montreal, Quebec.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31276534

Citation

Beauchamp, Marie-Claude, et al. "Loss of Function Mutation of Eftud2, the Gene Responsible for Mandibulofacial Dysostosis With Microcephaly (MFDM), Leads to Pre-implantation Arrest in Mouse." PloS One, vol. 14, no. 7, 2019, pp. e0219280.
Beauchamp MC, Djedid A, Daupin K, et al. Loss of function mutation of Eftud2, the gene responsible for mandibulofacial dysostosis with microcephaly (MFDM), leads to pre-implantation arrest in mouse. PLoS One. 2019;14(7):e0219280.
Beauchamp, M. C., Djedid, A., Daupin, K., Clokie, K., Kumar, S., Majewski, J., & Jerome-Majewska, L. A. (2019). Loss of function mutation of Eftud2, the gene responsible for mandibulofacial dysostosis with microcephaly (MFDM), leads to pre-implantation arrest in mouse. PloS One, 14(7), e0219280. https://doi.org/10.1371/journal.pone.0219280
Beauchamp MC, et al. Loss of Function Mutation of Eftud2, the Gene Responsible for Mandibulofacial Dysostosis With Microcephaly (MFDM), Leads to Pre-implantation Arrest in Mouse. PLoS One. 2019;14(7):e0219280. PubMed PMID: 31276534.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Loss of function mutation of Eftud2, the gene responsible for mandibulofacial dysostosis with microcephaly (MFDM), leads to pre-implantation arrest in mouse. AU - Beauchamp,Marie-Claude, AU - Djedid,Anissa, AU - Daupin,Kevin, AU - Clokie,Kayla, AU - Kumar,Shruti, AU - Majewski,Jacek, AU - Jerome-Majewska,Loydie Anne, Y1 - 2019/07/05/ PY - 2018/06/19/received PY - 2019/05/23/accepted PY - 2019/7/6/entrez PY - 2019/7/6/pubmed PY - 2020/2/23/medline SP - e0219280 EP - e0219280 JF - PloS one JO - PLoS One VL - 14 IS - 7 N2 - Mutations in EFTUD2 are responsible for the autosomal dominant syndrome named MFDM (mandibulofacial dysostosis with microcephaly). However, it is not clear how reduced levels of EFTUD2 cause abnormalities associated with this syndrome. To determine if the mouse can serve as a model for uncovering the etiology of abnormalities found in MFDM patients, we used in situ hybridization to characterize expression of Eftud2 during mouse development, and used CRISPR/Cas9 to generate a mutant mouse line with deletion of exon 2 of the mouse gene. We found that Eftud2 was expressed throughout embryonic development, though its expression was enriched in the developing head and craniofacial regions. Additionally, Eftud2 heterozygous mutant embryos had reduced EFTUD2 mRNA and protein levels. Moreover, Eftud2 heterozygous embryos were born at the expected Mendelian frequency, and were viable and fertile despite being developmentally delayed. In contrast, Eftud2 homozygous mutant embryos were not found post-implantation but were present at the expected Mendelian frequency at embryonic day (E) 3.5. Furthermore, only wild-type and heterozygous E3.5 embryos survived ex vivo culture. Our data indicate that Eftud2 expression is enriched in the precusor of structures affected in MFDM patients and show that heterozygous mice carrying deletion of exon 2 do not model MFDM. In addition, we uncovered a requirement for normal levels of Eftud2 for survival of pre-implantation zygotes. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/31276534/Loss_of_function_mutation_of_Eftud2_the_gene_responsible_for_mandibulofacial_dysostosis_with_microcephaly__MFDM__leads_to_pre_implantation_arrest_in_mouse_ DB - PRIME DP - Unbound Medicine ER -