Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of the large joints) caused by a recessive mutation in PLOD2
Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of the large joints) caused by a recessive mutation in PLOD2
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DOI：
10.1002/ajmg.a.30231
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发表时间：
2004-12-01
影响因子：
2
通讯作者：
Bonafé, L
中科院分区：
文献类型：
--
作者：
Ha-Vinh, R;Alanay, Y;Bonafé, L
布鲁克综合征 (BS) 是一种隐性遗传的表型疾病，其特征是类似成骨不全 (OI) 的骨骼变化与先天性大关节挛缩的不寻常组合。迄今为止报道的病例中临床异质性很明显。虽然编码胶原蛋白 1 链的基因在 BS 中不受影响，但有生化证据表明胶原蛋白 1 端肽中赖氨酸残基的羟基化存在缺陷。一个 BS 基因座已定位于 17p12，但最近在 BS 中发现了赖氨酰羟化酶 2 基因（PLOD2、3q23-q24）的两个突变，显示出遗传异质性。与 17p22（BS 1 型）相关或由 PLOD2 突变（BS 2 型）引起的 BS 病例比例仍不确定，并且缺乏表型相关性。我们报道了一名男孩，他出生时患有先天性挛缩、翼状胬肉、严重的成骨不全样骨质减少和多处骨折。他的尿液中含有大量羟脯氨酸，但胶原蛋白交联降解产物含量低；并且他被证明是纯合的，因为有一个新的突变导致 PLOD2 中的 Arg598His 被取代。该突变与之前报道的两个突变（Gly601Val 和 Thr608Ile）相邻，表明 PLOD2 中存在功能上重要的热点。正如本例所示，翼状胬肉与骨脆性的结合很难解释。这表明端肽赖氨酰羟基化必定参与产前关节形成和形态发生。尿液中的胶原蛋白降解产物和 PLOD2 突变分析可用于诊断 BS 并将其与 OI 区分开来。 (C) 2004 Wiley-Liss, Inc.
Bruck syndrome (BS) is a recessively-inherited phenotypic disorder featuring the unusual combination of skeletal changes resembling osteogenesis imperfecta (OI) with congenital contractures of the large joints. Clinical heterogeneity is apparent in cases reported thus far. While the genes coding for collagen 1 chains are unaffected in BS, there is biochemical evidence for a defect in the hydroxylation of lysine residues in collagen 1 telopeptides. One BS locus has been mapped at 17p12, but more recently, two mutations in the lysyl hydroxylase 2 gene (PLOD2, 3q23-q24) have been identified in BS, showing genetic heterogeneity. The proportion of BS cases linked to 17p22 (BS type 1) or caused by mutations in PLOD2 (BS type 2) is still uncertain, and phenotypic correlations are lacking. We report on a boy who had congenital contractures with pterygia at birth and severe OI-like osteopenia and multiple fractures. His urine contained high amounts of hydroxyproline but low amounts of collagen crosslinks degradation products; and he was shown to be homozygous for a novel mutation leading to an Arg598His substitution in PLOD2. The mutation is adjacent to the two mutations previously reported (Gly601Val and Thr608Ile), suggesting a functionally important hotspot in PLOD2. The combination of pterygia with bone fragility, as illustrated by this case, is difficult to explain; it suggests that telopeptide lysyl hydroxylation must be involved in prenatal joint formation and morphogenesis. Collagen degradation products in urine and mutation analysis of PLOD2 may be used to diagnose BS and differentiate it from OI. (C) 2004 Wiley-Liss, Inc.