A humanized Caenorhabditis elegans model of hereditary spastic paraplegia-associated variants in KLC4.
Dis Model Mech
; 16(8)2023 08 01.
Article
em En
| MEDLINE
| ID: mdl-37565267
ABSTRACT
Hereditary spastic paraplegia (HSP) is a group of degenerative neurological disorders. We identified a variant in human kinesin light chain 4 (KLC4) that is suspected to be associated with autosomal-dominant HSP. How this and other variants relate to pathologies is unknown. We created a humanized Caenorhabditis elegans model in which klc-2 was replaced by human KLC4 (referred to as hKLC4) and assessed the extent to which hKLC4 retained function in the worm. We observed a slight decrease in motility but no nuclear migration defects in the humanized worms, suggesting that hKLC4 retains much of the function of klc-2. Five hKLC4 variants were introduced into the humanized model. The clinical variant led to early lethality, with significant defects in nuclear migration when homozygous and a weak nuclear migration defect when heterozygous, possibly correlating with the clinical finding of late-onset HSP when the proband was heterozygous. Thus, we were able to establish humanized C. elegans as an animal model for HSP and to use it to test the significance of five variants of uncertain significance in the human gene KLC4.
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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Paraplegia Espástica Hereditária
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Dis Model Mech
Assunto da revista:
MEDICINA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos