Coiled-coil helix coiled-coil helix domain containing 10 (CHCHD10) is a nuclear gene that encodes for a mitochondria-enriched protein of unknown function. This type of protein is typically imported into mitochondria via the disulfide relay system which facilitates the formation of disulfide bridges between each coiled-coil helix, resulting in maintenance of the maturely folded protein in the intermembrane space. Previous studies revealed double missense mutations in cis, CHCHD10 p.R15S + p.G58R, in members of a family displaying the features of a mitochondrial myopathy. Here, efforts to identify the genetic cause of amyotrophic lateral sclerosis (ALS) in familial cases of unknown cause are outlined. Whole exome sequence analysis, Sanger sequencing and segregation analysis indicate CHCHD10 p.R15L to be the pathogenic mutation in five unrelated families. A muscle biopsy from a CHCHD10 p.R15L-positive individual affected with ALS revealed histopathological features consistent with that diagnosis. Their brain and spinal cord pathology revealed distinguishing features including an absence of TDP-43 pathology or Bunina bodies, microvacuolation of the putamen, and large, round, Lewy body-like inclusions in surviving motor neurons of the spinal cord and hypoglossal nucleus. The incidence of different mutations in affected individuals with different diseases of the neuromuscular system highlights the pleiotropic properties of CHCHD10. A range mouse models were developed in order to better understand the pathogenic mechanism of action of mutations in CHCHD10. Transgenic mice expressing human CHCHD10 p.R15L display a severe axonal pathology in diverse neurons throughout the CNS and abundant myopathic features in skeletal muscle and heart. Despite these pathologies, the mice perform well in tests of motor behavior until soon before death, which occurs early in a transgene copy number-correlated fashion. Chchd10 p.G54R knockin mice, modeling the human CHCHD10 p.G58R mutation, are remarkably small in size, display oxygen consumption and echocardiographic deficits, and die early over a wide time frame. The small size phenotype is also apparent in homozygous CHCHD10 p.G58R transgenic mice. While further investigation is required to examine any contribution of the closely related paralog, CHCHD2, absence of these phenotypes in Chchd10-knockout mice suggest that mutant CHCHD10 exerts a toxic gain-of-function mechanism of action to cause neuromuscular disease.

Creator

• Ryan, Éanna B.

DOI

• https://doi.org/10.21985/n2-bbkh-tv26

Subject

• Neurosciences

Language

• en

Alternate Identifier

• etdadmin_upload_799720
• http://dissertations.umi.com/northwestern:15495

Date created

• 2021-01-01

Resource type

• Dissertation

Rights statement

• In Copyright