NEDLAAD
Pavinato et al.reported patients carrying heterozygous variants in CAPRIN1, including nine nonsense mutations and two splicing mutations, along with one case involving a small deletion spanning the gene. Most of these variants were identified as de novo, except one inherited from an affected father and another from an unaffected mother. Notably, the affected father exhibited a milder phenotype than his son, with improved language abilities. These observations suggest that disorders caused by loss-of-function CAPRIN1variants may display variable expressivity and show improvement over time, in contrast to the progressive course typically seen in CONDCAC. The authors also raised the possibility of a sex bias, highlighting the presence of a healthy female carrier and the fact that 9 of the 12 affected individuals were male.
Analysis of patient-derived cells demonstrated that these variants triggered nonsense-mediated decay (NMD), resulting in a 50% reduction of CAPRIN1 mRNA and protein levels. CAPRIN1 is predicted to be haploinsufficient (GnomAD v4.0.0, pLI score = 1), suggesting that a single functional copy does not produce sufficient protein for normal cellular function. In the same study, the authors generated a human-induced pluripotent stem cell (hiPSC) line mimicking CAPRIN1 heterozygous knockout and differentiated it into cortical neurons. Compared to the wild-type control, the mutant cells displayed several abnormalities attributed to reduced CAPRIN1 dosage, including disrupted neuronal network formation, elevated reactive oxygen species levels, and impaired calcium signaling and electrical activity. Although the study did not directly assess stress granule dynamics, the results supported a loss-of-function mechanism.
In addition to these cases, three individuals with neurodevelopmental disorders associated with missense CAPRIN1 variants have been described, although detailed clinical information was not provided.
Jia et al. investigated the missense variants affecting codons 373, 446, and 484 of CAPRIN1. Notably, the variant at codon 373, located within the G3BP1-binding domain, was shown to impair interaction with G3BP1, leading to reduced stress granule formation.
CONDCAC
In 2022, Delle Vedove et al. identified three unrelated children (all under 14 years of age) carrying a de novo missense variant in the CAPRIN1 gene, NM_005898.5:c.1535C>T, resulting in the p.(Pro512Leu) substitution. These individuals presented with early-onset neurodegenerative symptoms, including gait disturbances, axonal neuropathy, and severe muscle weakness. As the disease progressed, additional features emerged, such as ataxia, progressive trunk instability, cognitive decline, and cerebral and cerebellar atrophy. Over time, the patients became dependent on wheelchairs or became bedridden. Other clinical manifestations included dysphagia, dysarthria, attention deficits, reduced social engagement, mild to borderline intellectual disability, and further cognitive deterioration. Based on these findings, CAPRIN1 was linked to a newly described autosomal dominant disorder termed "neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline" (CONDCAC, OMIM #620636). The discovery of the p.(Pro512Leu) variant associated with this early-onset neurodegenerative phenotype suggests that this condition is both extremely rare and specific to this particular mutation.
The CAPRIN1 protein contains a prion-like domain at its C-terminal region. The Pro512Leu variant, located near this domain, is thought to impair CAPRIN1’s ability to maintain proper folding and aggregation. The mutant CAPRIN1Pro512Leu protein displays decreased solubility relative to the wild-type and tends to form large intracellular inclusions. These aggregates sequester several proteins implicated in ataxia and neurodegenerative diseases, including SNCA, ATXN2, GEMIN5, and SNRNP200. Moreover, a disrupted interaction between CAPRIN1 and mRNA was observed, supporting the idea that the Pro512Leu substitution induces a toxic gain-of-function effect.
CAPRIN1