English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL) is a leukodystrophy caused by missense mutations of the aspartyl-tRNA synthetase-encoding gene  DARS1 . The clinical picture includes the regression of acquired motor milestones, spasticity, ataxia, seizures, nystagmus, and intellectual disabilities. Morphologically, HBSL is characterized by a distinct pattern of hypomyelination in the central nervous system including the anterior brainstem, the cerebellar peduncles and the supratentorial white matter as well as the dorsal columns and the lateral corticospinal tracts of the spinal cord. Adequate HBSL animal models are lacking.  Dars1  knockout mice are embryonic lethal precluding examination of the etiology. To address this, we introduced the HBSL-causing  Dars1   D 367 Y   point mutation into the mouse genome. Surprisingly, mice carrying this mutation homozygously were phenotypically normal. As hypomorphic mutations are more severe in trans to a deletion, we crossed  Dars1   D 367 Y / D 367 Y   mice with  Dars1-null  carriers. The resulting  Dars1   D 367 Y /−  offspring displayed a strong developmental delay compared to control  Dars1   D 367 Y /+  littermates, starting during embryogenesis. Only a small fraction of  Dars1   D 367 Y /−  mice were born, and half of these mice died with hydrocephalus during the first 3 weeks of life. Of the few  Dars1   D 367 Y /−  mice that were born at term, 25% displayed microphthalmia. Throughout postnatal life,  Dars1   D 367 Y /−  mice remained smaller and lighter than their  Dars1   D 367 Y /+  littermates. Despite this early developmental deficit, once they made it through early adolescence  Dars1   D 367 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   D 367 Y /−  mice compared to controls. Taken together,  Dars1   D 367 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.

A Hypomorphic Dars1D367Y Model Recapitulates Key Aspects of the Leukodystrophy HBSL