MBTPS1

Inheritance Pattern: AR

Disease ID:MONDO:0032721

Submitter: Illumina

The MBTPS1 gene is located on chromosome 16 at 16q23.3-q24.1 and encodes membrane bound transcription factor peptidase, site 1. The site-1 protease, which is also referred to as S1P, is ubiquitously expressed in the Golgi and functions in cholesterol homeostasis, collagen trafficking, SREBP activation, lysosome biogenesis, and lysosomal enzyme trafficking. MBTPS1 was first reported in relation to autosomal recessive spondyloepiphyseal dysplasia, kondo-fu type in 2018 (30046013: Kondo et al. 2018). To date, two unique variants, a missense and a stop-gained, have been reported in two probands from two publications (30046013: Kondo et al. 2018; 32857899: Meyer et al. 2020). Clinical features reported in common in these individuals included poor growth, inguinal hernia, protruding ears, kyphosis, skeletal abnormalities involving the chest, and elevated plasma levels of lysosomal enzymes. Additional features observed in at least one of the cases included spondyloepiphyseal dysplasia, scoliosis, skeletal abnormalities involving the feet, motor delay, reduced bone density, failure to thrive with gastronomy tube, cataract, relative macrocephaly, triangular face, and prominent forehead and cheekbones.Evidence supporting this gene-disease relationship includes case-level data and experimental data. Loss of function (LOF) has been implicated as the mechanism of disease. This gene-disease relationship is also supported by strong expression in chondrocytes and skeletal tissue; the gene's functions in cholesterol homeostasis, collagen trafficking, SREBP activation, lysosome biogenesis, and lysosomal enzyme trafficking which are shared with other genes associated with overlapping phenotypes (e.g., MBTPS2, SREBP1, GNPTAB); a compound heterozygous zebrafish LOF mutant that shows skeletal, cartilage, collagen, and lipid abnormalities; morpholino-mediated knockdown in zebrafish that recapitulates the skeletal, chondrocyte, and cartilage abnormalities observed in the mutant; mice with chondrocyte-specific KO show skeletal abnormalities, chondrodysplasia, and signs of collagen abnormalities and ER stress; and patient fibroblasts and chondrocytes from patient iPSC-derived teratomas show defects in collagen trafficking and the unfolded protein response pathway in addition to increases in ER stress, lysosomes, and apoptosis (Schlombs et al. 2003; Patra et al. 2007; Kondo et al. 2018). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. Of note, heterozygous gain of function in this gene has also been implicated in a distinct phenotype in a single case (31070020: Schweitzer et al. 2019); this relationship will be assessed separately.

Inheritance Pattern: AR

Disease ID:MONDO:0032721

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0032721

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0032721

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0032721

Submitter: ClinGen

MBTPS1 was first reported in relation to the Autosomal Recessive Kondo-Fu type of spondyloepiphyseal dysplasia (SEDKF) in 2018 by Yuji Kondo et al. (PMID: 30046013). SEDKF is a disorder characterized by several features including short stature, chest deformity, spine abnormalities, reduced bone density, hernia, abdominal protrusion, cataracts, developmental delay, and distinctive facial features. Additional symptoms may include abnormal gait, cranial abnormalities, mild intellectual disability, and seizures. Diagnostic imaging reveals various skeletal abnormalities, and elevated levels of certain lysosomal enzymes can be detected in blood samples (Wang, Hua et al., PMID: 38048414). Biallelic variants in MBTPS1 have been reported in individuals diagnosed with SEDKF. In addition, two individuals with cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome (CAOP), and compound heterozygous a stop loss variant and another variant in MBTPS1, have been described (Chen et al. 2022, PMID: 35362222). SEDKF and CAOP present with overlapping clinical features, including bilateral cataracts and sparse hair, and may represent a clinical spectrum. Both disorders are inherited in an autosomal recessive manner. There is no clear difference in molecular mechanism, although we note that both CAOP patients have a MBTPS1 stop loss variant; stop loss variants have not been reported in SEDKF. According to criteria outlined by the ClinGen Lumping and Splitting Working Group, we have lumped CAOP and SEDKF under one disease entity: Spondyloepiphyseal dysplasia, Kondo-Fu type (OMIM: 618392). If additional cases with CAOP are reported in the future, we may re-evaluate the lumping and splitting decision. However, at the current time, there is insufficient evidence for splitting. Of note, an individual with a different phenotype than SEDKF or CAOP and a heterozygous de novo variant in MBTPS1, compatible with a gain of function mechanism, has been reported (PMID: 31070020) indicating that MBTPS1 may be associated with multiple disease entities. The disease entity resulting from de novo, gain of function variants in MBTPS1 will be curated separately in the future. Twelve variants (including missense, nonsense, and splicing variants) that have been reported in 9 probands in 8 publications (PMID: 30046013, PMID: 32857899, PMID: 32420688, PMID: 35362222, PMID: 36330313, PMID: 36714646, PMID: 38337829, PMID: 36816387) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence: Mouse lines displayed elevated plasma lysosomal enzyme activities and bone defects, similar to the patients (PMID: 30046013). An mbtps1-knockdown zebrafish model was also generated using an antisense morpholino (mbtps1-MO) and showed skeletal deformities, delayed development, and skin abnormalities (PMID: 35362222). In summary, there is definitive evidence supporting the relationship between MBTPS1 and Autosomal Recessive Kondo-Fu type of spondyloepiphyseal dysplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Lysosomal GCEP on May 7, 2024 (SOP Version 10).