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A homozygous missense variant in NRROS gene is associated with intracranial calcifications, neurodegeneration, and severe infantile epilepsy syndrome
Journal article   Open access   Peer reviewed

A homozygous missense variant in NRROS gene is associated with intracranial calcifications, neurodegeneration, and severe infantile epilepsy syndrome

Mythily Ganapathi, Sean D. Fraser, Joseph W. Ryu, Georgette Bruenner, Daniel Page, Lisa J. Randall, Charles A. LeDuc, Shefali Karkare, Ingo Helbig, Amanda J. McPartland, …
HGG Advances, Vol.Advanced access, 100676
28-Sep-2026
DOI: https://doi.org/10.1016/j.xhgg.2026.100676
PMID: 42806633
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A homozygous missense variant in NRROS gene is associated with intracranial calcifications, neurodegeneration, and severe infantile epilepsy syndrome27.33 MBDownloadView
Accepted Version (Advanced Access) Open Access CC BY V4.0

Abstract

brain calcifications LRRC33 microgliopathy NRROS seizure SENEBAC
Biallelic loss-of-function variants in NRROS (Negative regulator of reactive oxygen species, previously LRRC33) cause a progressive neurodegenerative disorder characterized by early-onset seizures with brain calcifications. To date, 16 affected individuals from 13 unrelated families have been reported for this condition. We describe two siblings from a consanguineous family with this disorder, carrying a homozygous NRROS missense variant (c.1222A>C, p.(Asn408His), NM_198565.3). The mutational spectrum of NRROS disorder is characterized primarily by loss-of-function variants, with only four missense variants identified in affected individuals to date p.(Leu10Pro), p.(Leu62Pro), p.(Leu86Pro), and p.(Asn408His). We characterized these missense variants using silico predictions, molecular modelling and in-vitro cellular localization studies. In silico tools predict that p.(Leu10Pro) alters signal peptide cleavage, while p.(Asn408His) impedes N-linked glycosylation. Molecular modelling suggests that p.(Leu62Pro) and p.(Leu86Pro) variants may destabilize NRROS structure, while p.(Asn408His) interferes with NRROS glycosylation. In-vitro studies overexpressing HA-tagged NRROS wild type and missense variants in HEK293 cells showed altered subcellular distribution patterns for the variant proteins. In summary, we report a homozygous missense variant in NRROS associated with severe infantile epilepsy syndrome with intracranial calcifications, and neurodegeneration. Biallelic loss-of-function variants in NRROS cause SENEBAC. Here, we report two affected siblings from a consanguineous family with a homozygous missense variant in NRROS. Preliminary functional assays in HEK293 cells for all the pathogenic NRROS missense variants, including the newly identified one, showed cellular mislocalization compared to the wild-type protein.

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