A Mild Case of Autosomal Recessive Osteopetrosis Masquerading as the Dominant Form Involving Homozygous Deep Intronic Variations in the CLCN7 Gene.
A Mild Case of Autosomal Recessive Osteopetrosis Masquerading as the Dominant Form Involving Homozygous Deep Intronic Variations in the CLCN7 Gene.
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DOI：
10.1007/s00223-022-00988-8
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发表时间：
2022-10
影响因子：
4.2
通讯作者：
Ito, Nobuaki
中科院分区：
文献类型：
--
作者：
Hofstaetter, Jochen G.;Atkins, Gerald J.;Kato, Hajime;Kogawa, Masakazu;Blouin, Stephane;Misof, Barbara M.;Roschger, Paul;Evdokiou, Andreas;Yang, Dongqing;Solomon, Lucian B.;Findlay, David M.;Ito, Nobuaki
石骨症是一组异质性的罕见遗传性疾病，其特征是骨量增加，质量差。常染色体显性骨硬化症II型（ADOII）最常由CLCN 7基因突变引起，导致骨吸收受损。常染色体隐性遗传性石骨症（ARO）是一种更严重的形式，并经常伴有其他疾病。我们报告一位成年男性，具有典型的ADOII临床及影像学特征。遗传分析表明，没有氨基酸转换突变CLCN 7，但明显的单倍不足和抑制CLCN 7 mRNA水平在外周血单核细胞。下一代测序揭示了CLCN 7的低频内含子纯合变异，表明隐性遗传。内含子重复c.595-120_595- 86 dup的计算机分析揭示了富含丝氨酸和精氨酸的剪接因子（SRSF）的额外结合位点，预计这会损害CLCN 7的表达。定量背散射电子成像和组织形态学分析显示骨组织和材料异常。除板层骨外，还存在巨大的破骨细胞，观察到大量编织骨和矿化软骨，骨水泥线的频率和厚度增加。骨矿化密度分布（BMDD）分析显示，致密骨的平均矿物质含量（CaMean T评分+10.1）和具有最高矿物质含量的骨频率（CaHigh T评分+19.6）显著增加，表明矿物质持续蓄积和缺乏骨重建。除了异常的圆形形状外，骨细胞陷窝切片（OLS）特征并不显着。总之，我们的研究结果表明，破骨细胞中CLCN 7 mRNA的表达减少，也可能是骨细胞，导致骨重塑不良，骨基质异常，矿物质含量高。这与缺乏足够的骨修复机制一起使材料变脆并易于断裂。虽然骨骼表型和病史提示ADOII，但遗传分析显示，这可能是由于深度内含子突变引起的轻度ARO病例。在线版本包含补充材料，可通过10.1007/s 00223 -022-00988-8获得。
Osteopetrosis is a heterogeneous group of rare hereditary diseases characterized by increased bone mass of poor quality. Autosomal-dominant osteopetrosis type II (ADOII) is most often caused by mutation of the CLCN7 gene leading to impaired bone resorption. Autosomal recessive osteopetrosis (ARO) is a more severe form and is frequently accompanied by additional morbidities. We report an adult male presenting with classical clinical and radiological features of ADOII. Genetic analyses showed no amino-acid-converting mutation in CLCN7 but an apparent haploinsufficiency and suppression of CLCN7 mRNA levels in peripheral blood mononuclear cells. Next generation sequencing revealed low-frequency intronic homozygous variations in CLCN7, suggesting recessive inheritance. In silico analysis of an intronic duplication c.595-120_595-86dup revealed additional binding sites for Serine- and Arginine-rich Splicing Factors (SRSF), which is predicted to impair CLCN7 expression. Quantitative backscattered electron imaging and histomorphometric analyses revealed bone tissue and material abnormalities. Giant osteoclasts were present and additionally to lamellar bone, and abundant woven bone and mineralized cartilage were observed, together with increased frequency and thickness of cement lines. Bone mineralization density distribution (BMDD) analysis 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 for an unusually circular shape. 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. While the skeletal phenotype and medical history were suggestive of ADOII, genetic analysis revealed that this is a possible mild case of ARO due to deep intronic mutation. The online version contains supplementary material available at 10.1007/s00223-022-00988-8.
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影响因子：
14.9
作者：
Cartegni, L;Wang, JH;Krainer, AR
通讯作者：
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