Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta

Cabral, Wayne A.; Chang, Weizhong; Barnes, Aileen M.; Weis, MaryAnn; Scott, Melissa A.; Leikin, Sergey; Makareeva, Elena; Kuznetsova, Natalia V.; Rosenbaum, Kenneth N.; Tifft, Cynthia J.; Bulas, Dorothy; Kozma, Chahira; Smith, Peter A.; Eyre, David R.; Marini, Joan C.

doi:10.1038/ng1968

Cited by 449 publications

(396 citation statements)

References 28 publications

Supporting

Mentioning

362

Contrasting

Unclassified

Order By: Relevance

“…13,14 Furthermore, complete loss-of-function mutations of CRTAP and of LEPRE1, which encode CRTAP and prolyl-1-hydroxylase (P3H1), seemed to cause autosomal recessive lethal and severe OI. 14,15,16 CRTAP, P3H1 and cyclophilin B (CyPB) encoded by PPIB form a protein complex in the rough endoplasmic reticulum (rER), which is responsible for 3-hydroxylation of proline at position 986 in the a1 chain of collagen type I. In individuals affected with lethal or severe OI due to mutations in COL1A1, COL1A2, CRTAP and LEPRE1, comparable delayed migration of collagen type I is evident, which is visible as backstreaking, increased band width or baseline shift on electrophoresis (see Figure 1).…”

Section: Introductionmentioning

confidence: 99%

CRTAP mutations in lethal and severe osteogenesis imperfecta: the importance of combining biochemical and molecular genetic analysis

et al. 2009

View full text Add to dashboard Cite

Autosomal recessive lethal and severe osteogenesis imperfecta (OI) is caused by the deficiency of cartilageassociated protein (CRTAP) and prolyl-3-hydroxylase 1 (P3H1) because of CRTAP and LEPRE1 mutations. We analyzed five families in which 10 individuals had a clinical diagnosis of lethal and severe OI with an overmodification of collagen type I on biochemical testing and without a mutation in the collagen type I genes. CRTAP mutations not described earlier were identified in the affected individuals. Although it seems that one important feature of autosomal recessive OI due to CRTAP mutations is the higher consistency of radiological features with OI type II-B/III, differentiation between autosomal dominant and autosomal recessive OI on the basis of clinical, radiological and biochemical investigations proves difficult in the affected individuals reported here. These observations confirm that once a clinical diagnosis of OI has been made in an affected individual, biochemical testing for overmodification of collagen type I should always be combined with molecular genetic analysis of the collagen type I genes. If no mutations in the collagen type I genes are found, additional molecular genetic analysis of the CRTAP and LEPRE1 genes should follow. This approach will allow proper identification of the genetic cause of lethal or severe OI, which is important in providing prenatal diagnosis, preimplantation genetic diagnosis and estimating recurrence risk.

show abstract

Section: Introductionmentioning

confidence: 99%

CRTAP mutations in lethal and severe osteogenesis imperfecta: the importance of combining biochemical and molecular genetic analysis

et al. 2009

View full text Add to dashboard Cite

show abstract

“…As such, P3H1 null muta tions give rise to a phenotype that is clin ically indis tinguish able from CRTAP deficiency. Biochemi cally, severely reduced hydroxylation of proline 986 of the α1(I) chain and type I collagen overmodification 57,60,61 , and an unantici pated 50% increase in collagen prod uction versus controls are observed in patients with P3H1 mutations 57 .…”

Section: Box 1 | Classification Of Osteogenesis Imperfectamentioning

confidence: 99%

Osteogenesis imperfecta

Marini

Forlino

Bächinger

et al. 2017

Nat Rev Dis Primers

577

582

View full text Add to dashboard Cite

| 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...

show abstract

“…The collagen prolyl hydroxylases are localised to the endoplasmic reticulum and their activity is required for proper collagen synthesis and assembly. Studies of inherited disorders of collagen biosynthesis suggest that loss of function in P3H proteins results in dysfunctional collagen; mutations in P3H1 are associated with oesteogenesis imperfecta type VIII (Cabral et al, 2007) and loss of function mutations in both P3H1-and P3H-related protein CRTAP have been described in oesteogenesis imperfecta types II and III (Baldridge et al, 2008). Evidence implicating collagen abnormalities in human tumours is afforded by studies showing methylation-dependent silencing of collagen-encoding genes in various tumour types (Sengupta et al, 2003;Ikeda et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

The prolyl 3-hydroxylases P3H2 and P3H3 are novel targets for epigenetic silencing in breast cancer

et al. 2009

View full text Add to dashboard Cite

Expression of P3H2 (Leprel1) and P3H3 (Leprel2) but not P3H1 (Leprecan) is down-regulated in breast cancer by aberrant CpG methylation in the 5 0 regulatory sequences of each gene. Methylation of P3H2 appears specific to breast cancer as no methylation was detected in a range of cell lines from other epithelial cancers or from primary brain tumours or malignant melanoma. Methylation in P3H2, but not P3H3, was strongly associated with oestrogen-receptor-positive breast cancers, whereas methylation in P3H3 was associated with higher tumour grade and Nottingham Prognostic Index. Ectopic expression of P3H2 and P3H3 in cell lines with silencing of the endogenous gene results in suppression of colony growth. This is the first demonstration of epigenetic inactivation of prolyl hydroxylases in human cancer, implying that this gene family represents a novel class of tumour suppressors. The restriction of silencing in P3H2 to breast carcinomas, and its association with oestrogen-receptor-positive cases, suggests that P3H2 may be a breast-cancer-specific tumour suppressor.

show abstract

Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta

Cited by 449 publications

References 28 publications

CRTAP mutations in lethal and severe osteogenesis imperfecta: the importance of combining biochemical and molecular genetic analysis

CRTAP mutations in lethal and severe osteogenesis imperfecta: the importance of combining biochemical and molecular genetic analysis

Osteogenesis imperfecta

The prolyl 3-hydroxylases P3H2 and P3H3 are novel targets for epigenetic silencing in breast cancer

Contact Info

Product

Resources

About