<i>FAM46A</i> mutations are responsible for autosomal recessive osteogenesis imperfecta

Doyard, Mathilde; Bacrot, Séverine; Huber, Céline; Rocco, Maja Di; Goldenberg, Alice; Aglan, Mona; Brunelle, Perrine; Temtamy, Samia A.; Michot, Caroline; Otaify, Ghada A.; Haudry, Coralie; Castanet, Mireille; Leroux, J.; Jp, Bonnefont; Münnich, Arnold; Baujat, Geneviève; Lapunzina, Pablo; Monnot, Sophie; Ruiz‐Pérez, Víctor L.; Cormier‐Daire, Valérie

doi:10.1136/jmedgenet-2017-104999

Cited by 56 publications

(39 citation statements)

References 21 publications

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“…Indeed, all 19 genes known to cause osteogenesis imperfecta (OI) [58][59][60] were actively expressed 1 1 in osteocytes and 14 were present in the osteocyte transcriptome signature (Fig. 6c).…”

Section: Osteocyte Transcriptome Signature Genes Are Associated With mentioning

confidence: 99%

Osteocyte Transcriptome Mapping Identifies a Molecular Landscape Controlling Skeletal Homeostasis and Susceptibility to Skeletal Disease

Youlten

Kemp

Logan

et al. 2020

Preprint

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Osteocytes are master regulators of the skeleton. We map the transcriptome of osteocytes at different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cell-network. We define an osteocyte transcriptome signature, 1239 genes that distinguishes osteocytes from other cells. 77% have no known role in the skeleton.We show they are enriched for genes controlling neuronal network formation, suggesting this program is important in the osteocyte network. We evaluated 19 skeletal parameters in 733 mouse lines with functional-gene-deletions and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human homologues that cause monogenic skeletal dysplasias (P=6x10 -17 ), and associated with polygenic diseases, osteoporosis (P=1.8×10 -13 ), and osteoarthritis (P=2.6×10 -6 ). This reveals the molecular landscape that regulates osteocyte network formation and function, and establishes the importance of osteocytes in human skeletal disease. IntroductionThe skeleton is a highly dynamic structure that changes in shape and composition throughout life. Osteocytes are the most abundant cell type in bone and have emerged as master regulators of the skeleton. These enigmatic cells are connected via ramifying dendritic processes that form a complex multicellular network distributed throughout mineralized bone 1,2 .The scale and complexity of the osteocyte network is comparable to neurons in the brain, with 42 billion osteocytes present in the human skeleton forming 23 trillion connections 2,3 . This network enables osteocytes to detect and respond to mechanical strain, hormones and local growth factors and cytokines 1 . The network responds by regulating the formation and activity of osteoclasts and osteoblasts, instructing these cells to repair damaged bone, controlling bone mass and composition, and ensuring the optimal distribution of bone tissue in response to mechanical stress. Osteocytes also remove and replace bone surrounding the osteocyte network by the process of perilacunar remodeling, liberating calcium and phosphate in response to endocrine demands 4 . These features allow the osteocyte network to maintain both the structural integrity of the skeleton and mineral homeostasis. Osteocytes also have regulatory functions beyond the skeleton, including in skeletal muscle, adipose tissue, the central nervous system and in the control of phosphate homeostasis and energy expenditure, indicating the network acts as an important and endocrine organ 5-8 .Although osteocytes are pivotal in controlling the skeleton, the molecular programs that regulate their formation and function are poorly defined. Osteocytes are entombed in bone making them challenging to isolate and study. As a result osteocytes have been omitted from large-scale efforts to map tissue-specific transcriptomes 9-12 and studies of their transcriptome are limited [13][14][15][16] . Consequently, the influenc...

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Section: Osteocyte Transcriptome Signature Genes Are Associated With mentioning

confidence: 99%

Osteocyte Transcriptome Mapping Identifies a Molecular Landscape Controlling Skeletal Homeostasis and Susceptibility to Skeletal Disease

Youlten

Kemp

Logan

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Moreover, it has been shown that polymorphism in the second exon of TENT5A may be associated with an increased risk of large-joint osteoarthritis [ 87 ], which is consistent with severe skeletal abnormalities of TENT5A knock-out mice [ 88 ]. Finally, loss-of-function mutations in TENT5A have been reported in patients suffering from severe, autosomal recessive forms of osteogenesis imperfecta [ 89 ].…”

Section: Ncpaps and Adenylationmentioning

confidence: 99%

Terminal nucleotidyl transferases (TENTs) in mammalian RNA metabolism

Warkocki

Liudkovska

Gewartowska

et al. 2018

Phil. Trans. R. Soc. B

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In eukaryotes, almost all RNA species are processed at their 3′ ends and most mRNAs are polyadenylated in the nucleus by canonical poly(A) polymerases. In recent years, several terminal nucleotidyl transferases (TENTs) including non-canonical poly(A) polymerases (ncPAPs) and terminal uridyl transferases (TUTases) have been discovered. In contrast to canonical polymerases, TENTs' functions are more diverse; some, especially TUTases, induce RNA decay while others, such as cytoplasmic ncPAPs, activate translationally dormant deadenylated mRNAs. The mammalian genome encodes 11 different TENTs. This review summarizes the current knowledge about the functions and mechanisms of action of these enzymes.This article is part of the theme issue ‘5′ and 3′ modifications controlling RNA degradation’.

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“…Recently, mutations in the gene TENT5A (formerly known as FAM46A), encoding the terminal nucleotidyltransferase 5A were described as disease-causing in three patients. These patients are moderately to severely affected [20]. The expression of TENT5A in osteoblasts suggests a role in bone homeostasis and a previously unknown function of this enzyme in mineralized tissue was described.…”

Section: Tent5amentioning

confidence: 90%

Osteogenesis imperfecta—pathophysiology and therapeutic options

et al. 2020

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Osteogenesis imperfecta (OI) is a rare congenital disease with a wide spectrum of severity characterized by skeletal deformity and increased bone fragility as well as additional, variable extraskeletal symptoms. Here, we present an overview of the genetic heterogeneity and pathophysiological background of OI as well as OI-related bone fragility disorders and highlight current therapeutic options. The most common form of OI is caused by mutations in the two collagen type I genes. Stop mutations usually lead to reduced collagen amount resulting in a mild phenotype, while missense mutations mainly provoke structural alterations in the collagen protein and entail a more severe phenotype. Numerous other causal genes have been identified during the last decade that are involved in collagen biosynthesis, modification and secretion, the differentiation and function of osteoblasts, and the maintenance of bone homeostasis. Management of patients with OI involves medical treatment by bisphosphonates as the most promising therapy to inhibit bone resorption and thereby facilitate bone formation. Surgical treatment ensures pain reduction and healing without an increase of deformities. Timely remobilization and regular strengthening of the muscles by physiotherapy are crucial to improve mobility, prevent muscle wasting and avoid bone resorption caused by immobilization. Identification of the pathomechanism for SERPINF1 mutations led to the development of a tailored mechanism-based therapy using denosumab, and unraveling further pathomechanisms will likely open new avenues for innovative treatment approaches.

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FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta

Abstract: We conclude that mutations are responsible for a severe form of OI with congenital bowing of the lower limbs and suggest screening this gene in unexplained OI forms.

Cited by 56 publications

References 21 publications

Osteocyte Transcriptome Mapping Identifies a Molecular Landscape Controlling Skeletal Homeostasis and Susceptibility to Skeletal Disease

Osteocyte Transcriptome Mapping Identifies a Molecular Landscape Controlling Skeletal Homeostasis and Susceptibility to Skeletal Disease

Terminal nucleotidyl transferases (TENTs) in mammalian RNA metabolism

Osteogenesis imperfecta—pathophysiology and therapeutic options

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