P4HB recurrent missense mutation causing Cole-Carpenter syndrome
P4HB recurrent missense mutation causing Cole-Carpenter syndrome
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DOI：
10.1136/jmedgenet-2017-104899
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发表时间：
2018-03-01
影响因子：
4
通讯作者：
Stephens, David J.
中科院分区：
文献类型：
--
作者：
Balasubramanian, Meena;Padidela, Raja;Stephens, David J.
背景Cole-Carpenter综合征（CCS）是一种罕见的成骨不全（OI）疾病。这是继描述两个无关的患者非常相似的表型谁后来被证明有一个杂合错义突变P4 HB。目的在这里，我们报告一个3岁的女性患者患有严重的OI谁的外显子组测序发现携带相同的错义突变P4 HB在原来的队列报告。我们讨论了CCS的遗传异质性和P4 HB在胶原蛋白产生中的潜在机制。方法我们对本文报道的患者进行了详细的临床、放射学和分子表型分析，以及培养的成纤维细胞中的胶原蛋白分析和电子显微镜检查。结果迄今为止报道的患者的临床表型似乎一致，但有趣的是，似乎也有明确的表型线索（干骺端硬化的长管状骨的后干骺端骨折，这在OI中是不常见的）与潜在的基因型P4 HB（脯氨酰4-羟化酶，β亚基）编码PDI（蛋白质二硫化物异构酶），并且在细胞中，以其四聚体形式催化胶原蛋白中4-羟脯氨酸的形成。P4 HB的复发变异，c. 1178 A>G，p.Tyr393Cys，位于C-末端反应中心，据说干扰C-末端反应中心的二硫化物异构酶功能。P4 HB催化前胶原螺旋结构域中X-Pro-Gly重复序列内脯氨酸残基的羟基化。鉴于相互依赖的细胞外基质（ECM）组件在组装的功能性基质，我们的数据表明，它是组织和组装的功能性ECM的干扰，而不是I型胶原蛋白的分泌本身。结论我们提供了额外的证据P4 HB作为一种特殊形式的OI-CCS的原因，并扩大在这种罕见的疾病与二膦酸盐治疗的反应。
Background Cole-Carpenter syndrome (CCS) is commonly classified as a rare Osteogenesis Imperfecta (OI) disorder. This was following the description of two unrelated patients with very similar phenotypes who were subsequently shown to have a heterozygous missense mutation in P4HB.Objectives Here, we report a 3-year old female patient with severe OI who on exome sequencing was found to carry the same missense mutation in P4HB as reported in the original cohort. We discuss the genetic heterogeneity of CCS and underlying mechanism of P4HB in collagen production.Methods We undertook detailed clinical, radiological and molecular phenotyping in addition, to analysis of collagen in cultured fibroblasts and electron microscopic examination in the patient reported here.Results The clinical phenotype appears consistent in patients reported so far but interestingly, there also appears to be a definitive phenotypic clue (crumpling metadiaphyseal fractures of the long tubular bones with metaphyseal sclerosis which are findings that are uncommon in OI) to the underlying genotype (P4HB variant).Discussion P4HB (Prolyl 4-hydroxylase, betasubunit) encodes for PDI (Protein Disulfide isomerase) and in cells, in its tetrameric form, catalyses formation of 4-hydroxyproline in collagen. The recurrent variant in P4HB, c. 1178A>G, p. Tyr393Cys, sits in the C-terminal reactive centre and is said to interfere with disulphide isomerase function of the C-terminal reactive centre. P4HB catalyses the hydroxylation of proline residues within the X-Pro-Gly repeats in the procollagen helical domain. Given the inter-dependence of extracellular matrix (ECM) components in assembly of a functional matrix, our data suggest that it is the organisation and assembly of the functional ECM that is perturbed rather than the secretion of collagen type I per se.Conclusions We provide additional evidence of P4HB as a cause of a specific form of OI-CCS and expand on response to treatment with bisphosphonates in this rare disorder.