Submission Details

Autosomal recessive

09/25/2020

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.

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