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Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking
Yuji Kondo, … , Patrick M. Gaffney, Lijun Xia
Yuji Kondo, … , Patrick M. Gaffney, Lijun Xia
Published July 26, 2018
Citation Information: JCI Insight. 2018;3(14):e121596. https://doi.org/10.1172/jci.insight.121596.
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Research Article Cell biology Genetics

Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking

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Abstract

Site-1 protease (S1P), encoded by MBTPS1, is a serine protease in the Golgi. S1P regulates lipogenesis, endoplasmic reticulum (ER) function, and lysosome biogenesis in mice and in cultured cells. However, how S1P differentially regulates these diverse functions in humans has been unclear. In addition, no human disease with S1P deficiency has been identified. Here, we report a pediatric patient with an amorphic and a severely hypomorphic mutation in MBTPS1. The unique combination of these mutations results in a frequency of functional MBTPS1 transcripts of approximately 1%, a finding that is associated with skeletal dysplasia and elevated blood lysosomal enzymes. We found that the residually expressed S1P is sufficient for lipid homeostasis but not for ER and lysosomal functions, especially in chondrocytes. The defective S1P function specifically impairs activation of the ER stress transducer BBF2H7, leading to ER retention of collagen in chondrocytes. S1P deficiency also causes abnormal secretion of lysosomal enzymes due to partial impairment of mannose-6-phosphate–dependent delivery to lysosomes. Collectively, these abnormalities lead to apoptosis of chondrocytes and lysosomal enzyme–mediated degradation of the bone matrix. Correction of an MBTPS1 variant or reduction of ER stress mitigated collagen-trafficking defects. These results define a new congenital human skeletal disorder and, more importantly, reveal that S1P is particularly required for skeletal development in humans. Our findings may also lead to new therapies for other genetic skeletal diseases, as ER dysfunction is common in these disorders.

Authors

Yuji Kondo, Jianxin Fu, Hua Wang, Christopher Hoover, J. Michael McDaniel, Richard Steet, Debabrata Patra, Jianhua Song, Laura Pollard, Sara Cathey, Tadayuki Yago, Graham Wiley, Susan Macwana, Joel Guthridge, Samuel McGee, Shibo Li, Courtney Griffin, Koichi Furukawa, Judith A. James, Changgeng Ruan, Rodger P. McEver, Klaas J. Wierenga, Patrick M. Gaffney, Lijun Xia

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Figure 1

Identification of MBTPS1 compound heterozygote variants in a patient with skeletal dysplasia and elevated circulating levels of lysosomal enzymes.

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Identification of MBTPS1 compound heterozygote variants in a patient wit...
(A) The patient exhibits skeletal dysplasia with kyphoscoliosis (I) and skeletal dysplasia with dysmorphic facial features, with large ears and pectus carinatum (II). (B) Serum lysosomal enzyme activities. (C) DNA sequences of MBTPS1 exon 3 and exon 9. Letters and numbers in red indicate mutated residues and sites in the S1P protein sequence. (D) Pedigree of the family. The black circle indicates the patient; half-black square or circles indicate heterozygotes. (E) Relative MBTPS1 expression in patient B cells by qRT-PCR normalized with control B cells. A forward primer designed in exon 19 and a reverse primer designed in exon 21 of MBTPS1 were used. Mean ± SEM; n = 3, *P < 0.01, Student’s t test. Patient cells exhibited 20% MBTPS1 expression compared with irrelevant control cells. (F) MBTPS1 cDNA sequence. The dashed box indicates an aberrant transcript. (G) Diagram showing that the maternal variant creates an alternative splice donor site, resulting in the 41-bp deletion in exon 9. The asterisk indicates the premature termination created by alternative splicing causing the 41-bp deletion in exon 9. (H) Schematic domain of S1P in the patient. Green, catalytic triad; red, mutated residues. SS, signal sequence; TM, transmembrane domain; CP, cytoplasmic domain. The three different S1P variants are expressed in the patient.
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