The resulting Dars1 D367 Y/− offspring displayed a strong developmental delay compared to control Dars1 D367 Y/+ littermates, starting during embryogenesis. Only a small fraction of Dars1 D367 Y/− mice were born, and half of these mice died with hydrocephalus during the first 3 weeks of life. Of the few Dars1 D367 Y/− mice that were born at term, 25% displayed microphthalmia. Throughout postnatal life, Dars1 D367 Y/− mice remained smaller and lighter than their Dars1 D367 Y/+ littermates. Despite this early developmental deficit, once they made it through early adolescence Dars1 D367 Y/− mice were phenotypically inconspicuous for most of their adult life, until they developed late onset motor deficits as well as vacuolization and demyelination of the spinal cord white matter. Expression levels of the major myelin proteins were reduced in Dars1 D367 Y/− mice compared to controls. Taken together, Dars1 D367 Y/− mice model aspects of the clinical picture of the corresponding missense mutation in HBSL. This model will enable studies of late onset deficits, which is precluded in Dars1 knockout mice, and can be leveraged to test potential HBSL therapeutics including DARS1 gene replacement therapy. Leukodystrophies are inherited white matter disorders often associated with an early onset, lack of treatment options and premature death. The population incidence of all leukodystrophies taken together is relatively high with one in 7,600 live births ( Bonkowsky et al., 2010) underpinning the high unmet medical need. Hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL) belongs to this group of diseases and was first described in 2013 ( Taft et al., 2013). HBSL can be seen as a spectrum disorder with a high variance in severity (mild to severe forms) and onset of the disease (4 months to 22 years) ( Wolf et al., 2015).įollowing the initial discovery, two additional case studies, together with the original study, described a total of 16 HBSL patients ( Wolf et al., 2015 Ong et al., 2020). An early onset form of HBSL usually results in a more severe course of disease. The clinical symptoms typically include motor deficits, leg spasticity, regression, or delay of developmental milestones, hypertonia, hyperreflexia, positive Babinski sign, nystagmus, and gait abnormalities in patients who are able to mobilize ( Taft et al., 2013 Wolf et al., 2015 Ong et al., 2020). For a comprehensive clinical review of HBSL see Muthiah et al. The underlying cause of HBSL are missense mutations of the aspartyl-tRNA synthetase (AspRS) gene DARS1. AspRS belongs to a group of enzymes termed aminoacyl-tRNA synthetases (ARSs) that catalyze an aminoacylation reaction in which transfer ribonucleic acids (tRNAs) are linked to their cognate amino acids. This process is known as tRNA charging and is an essential prerequisite for successful protein biosynthesis. Each ARS is specific for the charging of one tRNA with its corresponding amino acid, e.g., AspRS specifically links tRNA Asp to aspartate, and there is no redundancy amongst these enzymes. ARSs can be subdivided into two classes depending on the cell compartment in which they catalyze the aminoacylation reaction: Cytosolic ARSs and mitochondrial ARSs (mt-ARSs).
0 Comments
Leave a Reply. |
Details
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |