Dissecting the phenotypic variability of osteogenesis imperfecta.
Dissecting the phenotypic variability of osteogenesis imperfecta.
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DOI：
10.1242/dmm.049398
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发表时间：
2022-05-01
影响因子：
4.3
通讯作者：
Forlino, Antonella
中科院分区：
文献类型：
--
作者：
Garibaldi, Nadia;Besio, Roberta;Dalgleish, Raymond;Villani, Simona;Barnes, Aileen M.;Marini, Joan C.;Forlino, Antonella
成骨不全（OI）是一个异质性家族的胶原蛋白I型相关疾病的特点是骨脆性。OI最常见的原因是编码α1（I）和α2（I）胶原蛋白链的COL1A1和COL1A2基因中甘氨酸残基或外显子剪接缺陷的单核苷酸取代。突变胶原蛋白部分保留在细胞内，损害细胞内稳态。分泌后，它组装成杂乱无章的原纤维，改变矿化。OI的特征在于广泛的临床结果，即使存在相同的序列变体。鉴于I型胶原蛋白的异源三聚体性质、其氨基酸组成及其折叠的特性，几种原因可能是OI表型变异的基础。对最大的公开可用患者数据库中有关甘氨酸和剪接位点胶原替代的条目进行深入分析，发现α1（I）链变体携带者的致死表型风险高于α2（I）链。然而，剪接位点变异主要与致死表型，当它们发生在COL1A2。此外，当突变发生在细胞外基质相互作用的重要区域时，致死率增加。细胞外和细胞内的OI临床严重程度的决定因素进行了讨论，从体外和体内OI模型的研究结果。结合通过公开可用的数据库对临床病例的细致跟踪，可用的OI动物模型已被证明是一种独特的工具，可用于阐明这种罕见异质性疾病的表型确定的新调节剂。总结：这个临床难题分析了最大的公共OI数据库以及来自动物模型的数据，以解决I型胶原蛋白缺陷如何导致脆性骨病成骨细胞的表型变异。
Osteogenesis imperfecta (OI) is a heterogeneous family of collagen type I-related diseases characterized by bone fragility. OI is most commonly caused by single-nucleotide substitutions that replace glycine residues or exon splicing defects in the COL1A1 and COL1A2 genes that encode the α1(I) and α2(I) collagen chains. Mutant collagen is partially retained intracellularly, impairing cell homeostasis. Upon secretion, it assembles in disorganized fibrils, altering mineralization. OI is characterized by a wide range of clinical outcomes, even in the presence of identical sequence variants. Given the heterotrimeric nature of collagen I, its amino acid composition and the peculiarity of its folding, several causes may underlie the phenotypic variability of OI. A deep analysis of entries regarding glycine and splice site collagen substitution of the largest publicly available patient database reveals a higher risk of lethal phenotype for carriers of variants in α1(I) than in α2(I) chain. However, splice site variants are predominantly associated with lethal phenotype when they occur in COL1A2. In addition, lethality is increased when mutations occur in regions of importance for extracellular matrix interactions. Both extracellular and intracellular determinants of OI clinical severity are discussed in light of the findings from in vitro and in vivo OI models. Combined with meticulous tracking of clinical cases via a publicly available database, the available OI animal models have proven to be a unique tool to shed light on new modulators of phenotype determination for this rare heterogeneous disease. Summary: This Clinical Puzzle analyses the largest public OI database as well as data from animal models to address how type I collagen defects contribute to the phenotypic variability of the brittle bone disease osteogenesis imperfecta.
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影响因子：
6.2
作者：
Duran, Ivan;Zieba, Jennifer;Csukasi, Fabiana;Martin, Jorge H.;Wachtell, Davis;Barad, Maya;Dawson, Brian;Fafilek, Bohumil;Jacobsen, Christina M.;Ambrose, Catherine G.;Cohn, Daniel H.;Krejci, Pavel;Lee, Brendan H.;Krakow, Deborah
通讯作者：
Krakow, Deborah
影响因子：
2.9
作者：
Bart, Zachary R.;Hammond, Max A.;Wallace, Joseph M.
通讯作者：
Wallace, Joseph M.
影响因子：
14.9
作者：
Dalgleish, R
通讯作者：
Dalgleish, R
影响因子：
3.5
作者：
Bianchi, Laura;Gagliardi, Assunta;Forlino, Antonella
通讯作者：
Forlino, Antonella
影响因子：
4
作者：
Cabral, W. A.;Milgrom, S.;Marini, J. C.
通讯作者：
Marini, J. C.