重度骨表型但CLCN7基因无氨基酸转换突变的常染色体显性II型骨硬化症1例,medRxiv - Orthopedics

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重度骨表型但CLCN7基因无氨基酸转换突变的常染色体显性II型骨硬化症1例
medRxiv - Orthopedics Pub Date : 2021-07-10 , DOI: 10.1101/2021.07.08.21257202
Jochen Hofstaetter , Gerald James Atkins , Masakazu Kogawa , Stephane Blouin , Barbara Misof , Paul Roschger , Andreas Evdokiou , Lucian Bogdan Solomon , David Malcolm Findlay , Nobuaki Ito

常染色体显性遗传性骨硬化症 II 型 (ADOII)，也称为 Albers-Schonberg 病，是由 CLCN7 氯通道基因突变引起的，其特征是骨吸收减少。在这里，我们报告了一个具有 ADOII 经典特征的个体，他从小就有骨折史，在 X 射线上显示出高骨量和特征性的夹层椎骨。我们的遗传分析显示患者 DNA 中没有氨基酸转换突变，但我们确实发现了 CLCN7 mRNA 单倍体不足的证据。基于定量背散射电子成像和组织形态测量分析，来自患者的髂嵴骨样本显示相对于正常对照的骨组织和材料异常。除了板层骨，我们还观察到大量的编织骨和矿化软骨，以及增加水泥线的频率和厚度（高达 15 微米）。存在具有大量细胞核的巨大破骨细胞。整个骨区的骨矿化密度分布（BMDD）显示致密骨的平均矿物质含量（CaMean T-score +10.1）和矿物质含量最高的骨频率（CaHigh T-score +19.6）显着增加，表明持续矿物质积累和缺乏骨重塑。除了 OLS 形状异常圆形外，骨细胞腔隙切片 (OLS) 的特征并不显着。总之，我们的研究结果表明，破骨细胞中 CLCN7 mRNA 的表达降低，可能还有骨细胞，导致骨骼重塑不良，骨基质异常，矿物质含量高。

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A case of autosomal dominant osteopetrosis type II with a severe bone phenotype but no amino acid converting mutation in the CLCN7 gene

Autosomal Dominant Osteopetrosis type II (ADOII), also known as Albers-Schonberg disease, is caused by mutation of the CLCN7 chloride channel gene and is characterized by reduced bone resorption. Here we report on an individual with the classic features of ADOII, who had a history of fractures from childhood, displayed high bone mass and characteristic sandwich vertebrae on x-ray. Our genetic analyses showed no amino acid converting mutation in the patients DNA but we did find evidence of haploinsufficiency of CLCN7 mRNA. An iliac crest bone sample from the patient revealed bone tissue and material abnormalities relative to normal controls based on quantitative backscattered electron imaging and histomorphometric analyses. Additionally to lamellar bone, we observed significant amounts of woven bone and mineralised cartilage, as well as an increased frequency and thickness (up to 15 microns) of cement lines. Giant osteoclasts with numerous nuclei were present. The bone mineralisation density distribution (BMDD) of the entire bone area revealed markedly increased average mineral content of the dense bone (CaMean T-score +10.1) and frequency of bone with highest mineral content (CaHigh T-score +19.6), suggesting continued mineral accumulation and lack of bone remodelling. Osteocyte lacunae sections (OLS) characteristics were unremarkable except the OLS shape which was unusually circular. Together, our findings suggest that the reduced expression of CLCN7 mRNA in osteoclasts, and possibly also osteocytes, causes poorly remodelled bone with abnormal bone matrix with high mineral content. This together with the lack of adequate bone repair mechanisms makes the material brittle and prone to fracture.

更新日期：2021-07-12

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