MBTPS2 – X-linked Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a heritable skeletal dysplasia characterized by bone fragility, recurrent fractures, and deformities. Initially described as an X-linked recessive form in 2016, pathogenic variants in the membrane-bound transcription factor protease site-2 gene MBTPS2 have since been confirmed as causative for moderate to severe OI ([PMID:37305034]). Subsequent omics profiling of primary fibroblasts from three unrelated MBTPS2-OI patients revealed distinct transcriptomic and metabolic signatures compared to dermatological MBTPS2 disorders ([PMID:34093655]).

Genetic evidence for MBTPS2-OI includes a hemizygous c.516A>C (p.Glu172Asp) variant identified in a male fetus presenting with bowed long bones and short stature, confirmed by transcriptional and metabolic assays in patient-derived fibroblasts ([PMID:37305034]). In addition, three other unrelated hemizygous MBTPS2-OI patients were profiled via RNA-sequencing, establishing independent observations of MBTPS2 involvement in OI ([PMID:34093655]). No multigenerational segregation data are available, and no additional affected relatives were reported.

The MBTPS2 variant spectrum in OI consists exclusively of missense substitutions affecting intramembrane proteolysis–activation of key transcription factors. The novel c.516A>C (p.Glu172Asp) variant alters a conserved residue within the catalytic site, paralleling previously reported pathogenic missense alleles such as p.Asn455Ser modeled in mice ([PMID:37797712]).

Functional studies demonstrate that MBTPS2-OI fibroblasts exhibit stronger downregulation of fatty acid metabolism genes, reduced extracellular collagen deposition, and impaired activation of lipid and cartilage developmental transcription factors compared to controls and non-skeletal MBTPS2 disorders ([PMID:34093655]; [PMID:37305034]). These concordant results support a mechanism of haploinsufficiency and defective regulated intramembrane proteolysis.

A knock-in mouse carrying the OI-linked p.Asn455Ser variant and a knockout model show early osteoarthritis-like alterations in articular cartilage and subchondral bone, preceding classical OI bone fragility, thereby recapitulating the human phenotype and demonstrating in vivo relevance of MBTPS2 haploinsufficiency ([PMID:37797712]).

In summary, hemizygous missense variants in MBTPS2 cause X-linked recessive OI via disrupted activation of lipid and cartilage transcriptional programs, leading to defective bone development and mineralization. MBTPS2 should be included in diagnostic gene panels for male OI patients, and functional assays in fibroblasts can aid variant interpretation.

References

• Frontiers in endocrinology • 2023 • Perturbations in fatty acid metabolism and collagen production infer pathogenicity of a novel MBTPS2 variant in Osteogenesis imperfecta. PMID:37305034
• Frontiers in genetics • 2021 • Omics Profiling of S2P Mutant Fibroblasts as a Mean to Unravel the Pathomechanism and Molecular Signatures of X-Linked MBTPS2 Osteogenesis Imperfecta. PMID:34093655
• Bone • 2023 • Mice heterozygous for an osteogenesis imperfecta-linked MBTPS2 variant display a compromised subchondral osteocyte lacunocanalicular network associated with abnormal articular cartilage. PMID:37797712

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