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<p>Early-onset hippocampal sclerosis is a major cause of focal epilepsy, yet many genetic contributors remain unknown. We investigate a 12-year-old girl with recurrent focal seizures, progressive memory impairment, and MRI evidence of left hippocampal atrophy with ipsilateral parietal gliosis. Singleton exome sequencing revealed a novel homozygous <i>NOL10</i> variant (NM_024894.4: c.682 A &gt; C; p.Asn228His), absent from population and clinical databases; both parents were heterozygous carriers. The variant alters a highly conserved residue within the WD-repeat domain. Proband fibroblasts maintained normal <i>NOL10</i> transcript levels but exhibited nucleoplasmic mislocalization and loss of interaction with AATF and NGDN, key partners in small ribosomal subunit biogenesis. Structural modeling and ΔΔG calculations predicted that N228H is strongly destabilizing. Functionally, proband cells showed specific impairment of 40S maturation with reduced 40S, 80S and polysome content, accompanied by G<sub>0</sub>/G<sub>1</sub> arrest and increased cell death. Network and expression analyses place NOL10 at the center of nucleolar rRNA processing and ribosome assembly, with substantial expression across hippocampal subfields, supporting selective vulnerability of hippocampal neurons. Collectively, our data implicate biallelic <i>NOL10:c.682 A</i> &gt; <i>C</i> as a novel, likely pathogenic cause of neurodevelopmental disorder characterized by hippocampal sclerosis and gliosis, and highlight disrupted ribosome biogenesis as a plausible disease mechanism.</p>

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NOL10 variant disrupts ribosome biogenesis and underlies hippocampal sclerosis

  • 期刊论文

  • 发表日期：

    2025年10月16日

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  • Abhishek Kumar,
  • Vishal Gaurav,
  • Yogendra Pratap Mathuria,
  • Buddhi Prakash Jain,
  • Shailesh Kumar Gupta,
  • Debasish Kumar Ghosh

摘要

Early-onset hippocampal sclerosis is a major cause of focal epilepsy, yet many genetic contributors remain unknown. We investigate a 12-year-old girl with recurrent focal seizures, progressive memory impairment, and MRI evidence of left hippocampal atrophy with ipsilateral parietal gliosis. Singleton exome sequencing revealed a novel homozygous NOL10 variant (NM_024894.4: c.682 A > C; p.Asn228His), absent from population and clinical databases; both parents were heterozygous carriers. The variant alters a highly conserved residue within the WD-repeat domain. Proband fibroblasts maintained normal NOL10 transcript levels but exhibited nucleoplasmic mislocalization and loss of interaction with AATF and NGDN, key partners in small ribosomal subunit biogenesis. Structural modeling and ΔΔG calculations predicted that N228H is strongly destabilizing. Functionally, proband cells showed specific impairment of 40S maturation with reduced 40S, 80S and polysome content, accompanied by G0/G1 arrest and increased cell death. Network and expression analyses place NOL10 at the center of nucleolar rRNA processing and ribosome assembly, with substantial expression across hippocampal subfields, supporting selective vulnerability of hippocampal neurons. Collectively, our data implicate biallelic NOL10:c.682 A > C as a novel, likely pathogenic cause of neurodevelopmental disorder characterized by hippocampal sclerosis and gliosis, and highlight disrupted ribosome biogenesis as a plausible disease mechanism.