Gistelinck Charlotte, Weis MaryAnn, Rai Jyoti, Schwarze Ulrike, Niyazov Dmitriy, Song Kit M, Byers Peter H, Eyre David R
Department of Orthopaedics and Sports Medicine University of Washington Seattle WA.
Department of Laboratory Medicine and Pathology University of Washington Seattle WA.
JBMR Plus. 2021 Jan 3;5(3):e10454. doi: 10.1002/jbm4.10454. eCollection 2021 Mar.
Bruck syndrome (BS) is a congenital disorder characterized by joint flexion contractures, skeletal dysplasia, and increased bone fragility, which overlaps clinically with osteogenesis imperfecta (OI). On a genetic level, BS is caused by biallelic mutations in either or . encodes the lysyl hydroxylase 2 (LH2) enzyme, which is responsible for the hydroxylation of cross-linking lysine residues in fibrillar collagen telopeptide domains. This modification enables collagen to form chemically stable (permanent) intermolecular cross-links in the extracellular matrix. Normal bone collagen develops a unique mix of such stable and labile lysyl-oxidase-mediated cross-links, which contribute to bone strength, resistance to microdamage, and crack propagation, as well as the ordered deposition of mineral nanocrystals within the fibrillar collagen matrix. Bone from patients with BS caused by biallelic mutations has been shown to have abnormal collagen cross-linking; however, to date, no direct studies of human bone from BS caused by mutations have been reported. Here the results from a study of a 4-year-old boy with BS caused by compound heterozygous mutations in are discussed. Diminished hydroxylation of type I collagen telopeptide lysines but normal hydroxylation at triple-helical sites was found. Consequently, stable trivalent cross-links were essentially absent. Instead, allysine aldol dimeric cross-links dominated as in normal skin collagen. Furthermore, in contrast to the patient's bone collagen, telopeptide lysines in cartilage type II collagen cross-linked peptides from the patient's urine were normally hydroxylated. These findings shed light on the complex mechanisms that control the unique posttranslational chemistry and cross-linking of bone collagen, and how, when defective, they can cause brittle bones and related connective tissue problems. © 2020 The Authors. published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
布鲁克综合征（BS）是一种先天性疾病，其特征为关节屈曲挛缩、骨骼发育异常和骨脆性增加，在临床上与成骨不全（OI）有重叠。在基因层面，BS由 或 的双等位基因突变引起。 编码赖氨酰羟化酶2（LH2），该酶负责原纤维胶原蛋白端肽结构域中交联赖氨酸残基的羟化。这种修饰使胶原蛋白能够在细胞外基质中形成化学稳定（永久性）的分子间交联。正常骨胶原形成了这种稳定和不稳定的赖氨酰氧化酶介导的交联的独特组合，这有助于增强骨强度、抵抗微损伤和裂纹扩展，以及矿物质纳米晶体在原纤维胶原基质中的有序沉积。由双等位基因 突变引起的BS患者的骨骼已显示出胶原蛋白交联异常；然而，迄今为止，尚未有关于由 突变引起的BS患者人骨的直接研究报道。本文讨论了一名因 复合杂合突变导致BS的4岁男孩的研究结果。发现I型胶原蛋白端肽赖氨酸的羟化减少，但三螺旋位点的羟化正常。因此，基本上不存在稳定的三价交联。相反，烯赖氨酸醛醇二聚体交联如正常皮肤胶原中一样占主导。此外，与患者的骨胶原不同，患者尿液中软骨II型胶原蛋白交联肽中的端肽赖氨酸羟化正常。这些发现揭示了控制骨胶原独特的翻译后化学和交联的复杂机制，以及这些机制出现缺陷时如何导致骨骼脆弱和相关结缔组织问题。© 2020作者。由Wiley Periodicals LLC代表美国骨与矿物质研究学会出版。
