Neurology. Genetics · 2026
Novel ADPRS Missense Variant (p.Leu162Pro) Causes Stress-Induced Childhood-Onset Neurodegeneration With Ataxia and Seizures.
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de Mattos Priscilla Doria, de Moura Rafael Dias, Bertolino Murilo Fígaro, Valente Penélope Ferreira, Matos Isaac Araujo, Caldas Vitor Marques, Lobao Cunha Paulo Emidio, Kok Fernando, Hoch Nicolas Carlos
Аннотация
BACKGROUND AND OBJECTIVES: ADP-ribosylation is a post-translational modification critical for DNA repair, chromatin remodeling, and cellular stress responses. The enzyme ARH3/ADPRHL2 (encoded by the ADPRS gene) is a member of the ADP-ribosyl-acceptor hydrolase family and plays a pivotal role in the removal of mono-ADP-ribosylation, particularly in response to DNA damage. Variants in the ADPRS gene cause stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS). Here, we present the case of an 11-year-old Brazilian girl with compound heterozygous variants in ADPRS, including a novel missense variant, c.485T>C; p.Leu162Pro, of unknown clinical significance. This study aimed to determine the pathogenicity of this variant and to test the molecular rationale of using minocycline as a therapeutic strategy for CONDSIAS cases.
METHODS: Clinical identification and diagnosis of the patient was based primarily on MRI and whole exome sequencing. Functional assays were performed in patient fibroblast cell lines using Western blotting and immunofluorescence-based assays and compared with an ARH3 KO cell line generated by CRISPR/Cas9 technology.
RESULTS: Our data indicate that the novel p.Leu162Pro variant, combined with a known nonsense variant, c.316C>T; p.Gln106*, causes a severe reduction of ARH3 protein levels in patient fibroblasts. This leads to defective ARH3-dependent removal of ADP-ribosylation, both under basal conditions and following oxidative stress. Our results using minocycline indicate that it is a poor PARP1 inhibitor and was ineffective in reducing basal ADP-ribosylation in ARH3-deficient cells.
DISCUSSION: This study contributes to the growing body of knowledge on ARH3 deficiency associated with CONDSIAS, by identifying a new pathogenic variant and questioning the molecular rationale underlying the therapeutic use of minocycline in patients with CONDSIAS.
METHODS: Clinical identification and diagnosis of the patient was based primarily on MRI and whole exome sequencing. Functional assays were performed in patient fibroblast cell lines using Western blotting and immunofluorescence-based assays and compared with an ARH3 KO cell line generated by CRISPR/Cas9 technology.
RESULTS: Our data indicate that the novel p.Leu162Pro variant, combined with a known nonsense variant, c.316C>T; p.Gln106*, causes a severe reduction of ARH3 protein levels in patient fibroblasts. This leads to defective ARH3-dependent removal of ADP-ribosylation, both under basal conditions and following oxidative stress. Our results using minocycline indicate that it is a poor PARP1 inhibitor and was ineffective in reducing basal ADP-ribosylation in ARH3-deficient cells.
DISCUSSION: This study contributes to the growing body of knowledge on ARH3 deficiency associated with CONDSIAS, by identifying a new pathogenic variant and questioning the molecular rationale underlying the therapeutic use of minocycline in patients with CONDSIAS.