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Autosomal recessive biallelic variants in ERLIN1 cause a rare form of hereditary spastic paraplegia, classified as SPG62. Since the initial identification of 12 individuals from five pedigrees, a recent study expanded the cohort to 13 affected individuals from six unrelated families, establishing the genetic basis of disease ([PMID:39367212]).
All affected individuals presented with childhood-onset spastic paraparesis with slow progression; six showed gait ataxia and three had superficial sensory loss, whereas intellectual disability and epilepsy were uncommon outside the index case ([PMID:39367212]). The inheritance is autosomal recessive, with pathogenic variants including splice-site and missense alleles. A representative allele is c.281T>C (p.Val94Ala), detected in homozygosity in one family and segregating with disease in others ([PMID:39367212]).
Variant spectrum comprises at least one canonical splice donor variant (c.504+1G>A) and multiple missense changes predicted to disrupt ERLIN1 structure and function. No recurrent or founder alleles have been conclusively established, and population prevalence remains undefined.
Functional studies in patient-derived RNA demonstrated aberrant splicing for intronic variants, and structural modeling using AlphaFold predicted that missense changes perturb the bell-shaped ring of the ERLIN1/ERLIN2 complex, supporting a loss-of-function mechanism ([PMID:39367212]). No in vivo or rescue assays have yet been reported.
No conflicting evidence has been published to date. Together, the genetic and experimental data support a consistent autosomal recessive loss-of-function mechanism for ERLIN1 in SPG62. Further studies including animal models and rescue experiments will solidify the pathomechanism.
Key take-home: Biallelic ERLIN1 variants underlie autosomal recessive hereditary spastic paraplegia 62, informing diagnostic genetic testing and variant interpretation.
Gene–Disease AssociationModerate13 probands from 6 families; concordant RNA-seq and structural modeling data ([PMID:39367212]) Genetic EvidenceModerate13 probands with biallelic splice and missense variants in unrelated families, consistent segregation ([PMID:39367212]) Functional EvidenceLimitedRNA-seq demonstrated abnormal splicing and modeling predicted disruption of ERLIN1/2 complex function ([PMID:39367212]) |