MBTPS1 – S1P Deficiency in Spondyloepiphyseal Dysplasia, Kondo-Fu Type

MBTPS1 encodes Site-1 protease (S1P), a Golgi-resident serine protease that regulates sterol regulatory element-binding protein activation, endoplasmic reticulum (ER) stress response, and lysosome biogenesis. Biallelic pathogenic variants in MBTPS1 cause autosomal recessive spondyloepiphyseal dysplasia, Kondo-Fu type (MONDO:0032721), characterized by severe short stature, skeletal deformities, and elevated plasma lysosomal enzymes (PMID:30046013).

Genetically, the disorder follows autosomal recessive inheritance with four unrelated probands reported to date. The first patient carried an amorphic and hypomorphic MBTPS1 allele leading to ~1% functional transcript and presented with growth retardation and cataracts (PMID:30046013). A second individual was homozygous for a nonsense variant c.2949G>A (p.Trp983Ter) presenting with retromicrognathia and epilepsy (PMID:32420688). A Chinese boy harbored a splice-disrupting synonymous variant c.774C>T (p.Ala258=) causing exon skipping alongside a nonsense c.2656C>T (p.Tyr665Ter), manifesting short stature and severe bone mineral density reduction (PMID:36714646). A fourth case from a consanguineous Saudi family was homozygous for a missense MBTPS1 variant c.2634C>A (p.Ser878Arg) with classical spondyloepiphyseal changes (PMID:36330313).

The variant spectrum includes multiple loss-of-function alleles (nonsense, frameshift) and hypomorphic alleles (splice, missense), with no known founder variants. Segregation analysis revealed carrier parents without phenotypes, but no additional affected relatives have been documented.

Functional studies demonstrate that S1P deficiency impairs activation of the ER stress transducer BBF2H7, causing ER retention of collagen in chondrocytes and triggering chondrocyte apoptosis. Rescue of collagen trafficking defects by MBTPS1 correction or reduction of ER stress in patient-derived cells confirms a loss-of-function mechanism (PMID:30046013; PMID:36714646).

No conflicting evidence has been reported. The integration of consistent recessive inheritance, multiple probands with biallelic MBTPS1 variants, and concordant functional assays supports a strong gene–disease relationship under a loss-of-function mechanism.

Key take-home: MBTPS1 biallelic loss-of-function variants reliably diagnose autosomal recessive Spondyloepiphyseal Dysplasia, Kondo-Fu type, informing genetic counseling and potential ER-stress–targeted therapies.

References

• JCI Insight • 2018 • Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking. PMID:30046013
• American Journal of Medical Genetics Part A • 2020 • Spondyloepimetaphyseal dysplasia with elevated plasma lysosomal enzymes caused by homozygous variant in MBTPS1. PMID:32420688
• Case Reports in Pediatrics • 2022 • Identification of a New Variant of the MBTPS1 Gene of the Kondo-Fu Type of Spondyloepiphyseal Dysplasia (SEDKF) in a Saudi Patient. PMID:36330313
• Frontiers in Pediatrics • 2022 • Clinical and molecular characterization of a patient with MBTPS1 related spondyloepiphyseal dysplasia: Evidence of pathogenicity for a synonymous variant. PMID:36714646

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