MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta

Lindert, Uschi; Cabral, Wayne A.; Ausavarat, Surasawadee; Tongkobpetch, Siraprapa; Ludin, Katja; Barnes, Aileen M.; Yeetong, Patra; Weis, MaryAnn; Krabichler, Birgit; Srichomthong, Chalurmpon; Makareeva, Elena; Janecke, Andreas; Leikin, Sergey; Röthlisberger, Benno; Rohrbach, Marianne; Kennerknecht, Ingo; Eyre, David R.; Suphapeetiporn, Kanya; Giunta, Cecilia; Marini, Joan C.; Shotelersuk, Vorasuk

doi:10.1038/ncomms11920

Cited by 124 publications

(97 citation statements)

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“…Upon ER stress, the proteolytic activation of BBF2H7 requires sequential actions of S1P and S2P in the Golgi membrane. Patients with deficiency of S2P have been reported (26). To differentiate our S1P-deficinet patient from the S2P-deficient patient, we identified a new S2P-deficient patient with a short stature (Supplemental Table 2) (26), suggesting that the skeletal dysplasia resembles the S1P-deficient patient.…”

Section: Resultsmentioning

confidence: 99%

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

Fu¹,

Wang²,

Hoover³

et al. 2018

JCI Insight

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Section: Resultsmentioning

confidence: 99%

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

Fu¹,

Wang²,

Hoover³

et al. 2018

JCI Insight

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“…Mutations that cause single residue substitutions in or near the ion coordination site of S2P, and impair its cleavage of substrate transcription factors, have been reported in two pedigrees with moderate to severe osteogenesis imperfecta. Hydroxylation of lysine 87 of the α1(I) chain and α2(I) chain is reduced, collagen crosslinking is altered and bone strength is impaired in bone tissues of patients with MBTPS2 mutations 108 . One of the transcription factors activated by RIP is old astro cyte specifically induced substance (OASIS; encoded by CREB3L1) (FIG.…”

Section: Box 1 | Classification Of Osteogenesis Imperfectamentioning

confidence: 99%

Osteogenesis imperfecta

Marini

Forlino

Bächinger

et al. 2017

Nat Rev Dis Primers

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| Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends on family history and clinical presentation characterized by a fracture (or fractures) during the prenatal period, at birth or in early childhood; genetic tests can confirm diagnosis. Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure. In the past decade, (mostly) recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis, processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells have been shown to cause osteogenesis imperfecta. The large number of causative genes has complicated the classic classification of the disease, and although a new genetic classification system is widely used, it is still debated. Phenotypic manifestations in many organs, in addition to bone, are reported, such as abnormalities in the cardiovascular and pulmonary systems, skin fragility, muscle weakness, hearing loss and dentinogenesis imperfecta. Management involves surgical and medical treatment of skeletal abnormalities, and treatment of other complications. More innovative approaches based on gene and cell therapy, and signalling pathway alterations, are under investigation. NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17052 | 1 PRIMER © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .In this Primer, we provide an overview of epidemio logy, genetics and pathophysiology of osteogenesis imperfecta, as well as diagnosis and management. EpidemiologyStudies from Europe and the United States have found a birth prevalence of osteogenesis imperfecta of 0.3-0.7 per 10,000 births 5,6 . These birth cohort analyses reflect more severe types of osteogenesis imperfecta and do not include more subtle types that become apparent after birth. A population based study that used the Danish National Patient Register found an annual incidence of osteogenesis imperfecta of 1.5 per 10,000 births between 1997 and 2013 (REF. 7). Population surveys in countries with comprehensive medical databases, such as Finland, estimated a prevalence of about 0.5 per 10,000 individ uals 8 , with most having phenotypically milder osteo genesis imperfecta type I and type IV (BOX 1; TABLE 1). Because these birth cohort and population surveys are based on clinical findings and tend to find mutu ally exclusive populations, a reasonable estimate of the incidence of osteogenesis imperfecta is about 1 per 10,000 individuals. Most patients are heterozygous for mutations in COL1A1 or COL1A2. No difference in the prevalence between sexes was reported.Approximately 90% of the 3,000 individuals whose mutations ha...

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“…A novel missense mutation in MPTBS2 which affected a motif that is important for protease catalytic function caused moderate/severe X-linked recessive form of OI in two independent families [7]. In the same study, OI patient osteoblasts showed reduced cleavage of Creb3l1/OASIS and decreased LH1 levels concomitant with lower levels of hydroxylation of helical lysine (K87) and higher LP/HP ratio [7]. …”

Section: Genetic Causes and Mechanisms Of Osteogenesis Imperfectamentioning

confidence: 99%

Genetic causes and mechanisms of Osteogenesis Imperfecta

Lim

Grafe

Alexander

et al. 2017

Bone

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Osteogenesis Imperfecta (OI) is a genetic disorder characterized by various clinical features including bone deformities, low bone mass, brittle bones, and connective tissue manifestations. The predominant cause of OI is due to mutations in the two genes that encode type I collagen. However, recent advances in sequencing technology has led to the discovery of novel genes that are implicated in recessive and dominant OI. These include genes that regulate the post-translational modification, secretion and processing of type I collagen as well as those required for osteoblast differentiation and bone mineralization. As such, OI has become a spectrum of genetic disorders informing about the determinants of both bone quantity and quality. Here we summarize the known genetic causes of OI, animal models that recapitulate the human disease and mechanisms that underlie disease pathogenesis. Additionally, we discuss the effects of disrupted collagen networks on extracellular matrix signaling and its impact on disease progression.

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MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta

Cited by 124 publications

References 37 publications

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

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

Osteogenesis imperfecta

Genetic causes and mechanisms of Osteogenesis Imperfecta

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