SREBF2 – Hereditary Spastic Paraplegia

Hereditary spastic paraplegias (Hereditary spastic paraplegia) refer to a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by progressive lower limb spasticity and corticospinal tract degeneration. A substantial proportion of patients remain without a molecular diagnosis despite extensive genetic testing. Sterol regulatory element-binding factor 2 (SREBF2) is a master regulator of cholesterol biosynthesis and uptake, critically modulating membrane homeostasis and autophagy. Dysregulation of cholesterol has been implicated in neurodegeneration, but SREBF2 had not previously been linked to human hereditary spastic paraplegia.

Whole exome sequencing in a cohort of Chinese HSP patients identified three homozygous missense variants in SREBF2 in one autosomal recessive family and two sporadic probands. The variants comprised p.Leu604Trp, p.Ser517Phe, and p.Thr984Ala ([PMID:39814172]). All three changes are absent from public and in-house control databases and are predicted damaging by multiple in silico algorithms. No other known HSP-related genes were mutated in these patients, supporting SREBF2 as the primary candidate gene. This represents the first report of biallelic SREBF2 variants in human spastic paraplegia.

Segregation analysis confirmed co-segregation of each homozygous variant with disease status by Sanger sequencing of all available family members. Two additional unrelated individuals carried distinct homozygous SREBF2 variants, for a total of three unrelated probands ([PMID:39814172]). The inheritance pattern is consistent with autosomal recessive transmission, and no affected relatives were reported beyond the probands. Together, these data provide moderate genetic evidence of causality under ClinGen criteria for autosomal recessive disorders.

The identified variant spectrum comprises exclusively missense changes affecting conserved domains. One representative allele, c.2950A>G (p.Thr984Ala), disrupts a regulatory helix-loop-helix region. No loss-of-function, splice, or structural variants have been documented to date, and no recurrent or founder alleles were observed. All variants are private and absent from gnomAD and other population datasets, underscoring their rarity.

Functional validation in patient-derived fibroblasts demonstrated that SREBF2 variants lead to overactivation of SREBP2, resulting in intracellular cholesterol accumulation and consequent impairment of autophagosomal and lysosomal function. In vivo, Drosophila overexpression of mature SREBP2 recapitulated locomotor defects analogous to spastic paraplegia. These concordant cellular and animal model findings support a toxic gain-of-function mechanism mediated by hyperactive SREBP2 signaling.

Integration of genetic and experimental evidence meets ClinGen criteria for a moderate clinical validity classification: three probands with autosomal recessive biallelic variants, segregation confirmation, and robust functional concordance. While further studies in additional populations would strengthen a definitive assignment, current data justify the inclusion of SREBF2 in diagnostic gene panels for hereditary spastic paraplegia. Key Take-home: Biallelic missense variants in SREBF2 cause autosomal recessive hereditary spastic paraplegia through dysregulated cholesterol homeostasis, providing immediate clinical utility for genetic diagnosis and pathway-based therapeutic exploration.

References

• Journal of genetics and genomics = Yi chuan xue bao • 2025 • Biallelic variants in SREBF2 cause autosomal recessive spastic paraplegia PMID:39814172

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