UFSP2, encoding UFM1-specific peptidase 2, is a gene that codes for a highly conserved cysteine protease. It is involved in the UFMylation pathway, cleaving two C-terminal residues from ubiquitin-fold modifier 1, an ubiquitin-like post-translational modifier protein. This pathway is crucial for various cellular activities and protein modification processes [1,3].

Mutations in UFSP2 have been linked to multiple diseases. A novel heterozygous variant in UFSP2 (exon 11: c.1277A > C) was first reported to cause spondyloepimetaphyseal dysplasia (SEMD), characterized by short stature, anterior vertebral dysplasia, hip dysplasia, etc. Another study described a boy with SEMD due to a novel mutation (exon 11: c.1283A > G, leading to p. H428R) of UFSP2 [1]. A homozygous variant (c.344T > A; p.V115E) in UFSP2 was identified in children from South Asian families with neurodevelopmental delay and epilepsy, where it impaired de-UFMylation [3]. In silica-induced pulmonary injury mouse models, UFSP2 expression was upregulated in 7-day models, indicating its involvement in this process [2].

In summary, UFSP2 plays an essential role in the UFMylation pathway. Studies on UFSP2-related mutations in humans and its expression changes in mouse models have revealed its significance in skeletal development, neurodevelopment, and pulmonary injury. These findings contribute to understanding the molecular mechanisms underlying these disease conditions and may offer potential directions for therapeutic interventions.