A Novel ENU-Induced Mutation Causes Motor Deficits in Mice without Causing Peripheral Neuropathy

Authors

Timothy J. Hines, The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Janice Bailey, Department of Genetics, The University of North Carolina, Chapel Hill, NC 27599, USA.
Hedi Liu, Department of Genetics, The University of North Carolina, Chapel Hill, NC 27599, USA.
Anyonya R. Guntur, Center for Molecular Medicine, Maine Health Institute for Research, Scarborough, ME 04074, USA.
Kevin L. Seburn, The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Samia L. Pratt, The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Jonathan R. Funke, The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Lisa M. Tarantino, Department of Genetics, The University of North Carolina, Chapel Hill, NC 27599, USA.
Robert W. Burgess, The Jackson Laboratory, Bar Harbor, ME 04609, USA.

Document Type

Article

Publication Date

7-3-2023

Institution/Department

Center for Molecular Medicine; MaineHealth Institute for Research

Journal Title

Biology

Abstract

Mitochondrial fission and fusion are required for maintaining functional mitochondria. The mitofusins (MFN1 and MFN2) are known for their roles in mediating mitochondrial fusion. Recently, MFN2 has been implicated in other important cellular functions, such as mitophagy, mitochondrial motility, and coordinating endoplasmic reticulum-mitochondria communication. In humans, over 100 mutations are associated with a form of inherited peripheral neuropathy, Charcot-Marie-Tooth disease type 2A (CMT2A). Here we describe an ENU-induced mutant mouse line with a recessive neuromuscular phenotype. Behavioral screening showed progressive weight loss and rapid deterioration of motor function beginning at 8 weeks. Mapping and sequencing revealed a missense mutation in exon 18 of (T1928C; Leu643Pro), within the transmembrane domain. Compared to wild-type and heterozygous littermates, mice exhibited diminished rotarod performance and decreases in activity in the open field test, muscular endurance, mean mitochondrial diameter, sensory tests, mitochondrial DNA content, and MFN2 protein levels. However, tests of peripheral nerve physiology and histology were largely normal. Mutant leg bones had reduced cortical bone thickness and bone area fraction. Together, our data indicate that causes a recessive motor phenotype with mild bone and mitochondrial defects in mice. Lack of apparent nerve pathology notwithstanding, this is the first reported mouse model with a mutation in the transmembrane domain of the protein, which may be valuable for researchers studying MFN2 biology.

ISSN

2079-7737

Recommended Citation

Hines TJ, Bailey J, Liu H, et al. A Novel ENU-Induced Mfn2 Mutation Causes Motor Deficits in Mice without Causing Peripheral Neuropathy. Biology (Basel). 2023;12(7):953. Published 2023 Jul 3. doi:10.3390/biology12070953