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骨质石化症的遗传学、发病机制及并发症

Genetics, pathogenesis and complications of osteopetrosis.

作者信息

Del Fattore Andrea, Cappariello Alfredo, Teti Anna

机构信息

Department of Experimental Medicine, Via Vetoio - Coppito 2, 67100 L'Aquila, Italy.

出版信息

Bone. 2008 Jan;42(1):19-29. doi: 10.1016/j.bone.2007.08.029. Epub 2007 Aug 30.

Abstract

Human osteopetrosis is a rare genetic disorder caused by osteoclast failure, which ranges widely in severity. In the most severe forms, deficient bone resorption prevents enlargement of bone cavities, impairing development of bone marrow, leading to hematological failure. Closure of bone foramina causes cranial nerve compression with visual and hearing deterioration. Patients also present with osteosclerosis, short stature, malformations and brittle bones. This form is fatal in infancy, has an autosomal recessive inheritance and is cured with hematopoietic stem cell transplantation, with a rate of success <50% and unsatisfactory rescue of growth and visual deterioration. It relies on loss-of-function mutations of various genes, including the TCIRG1 gene, encoding for the a3 subunit of the H+ATPase and accounting for >50% of cases, the ClCN7 and the OSTM1 genes, which have closely related function and account for approximately 10% of cases, also presenting with neurodegeneration. Further genes are implicated in rare forms with various severities and association with other syndromes and, recently, the RANKL gene has been found to be mutated in a subset of patients lacking osteoclasts. Autosomal recessive osteopetrosis may also have intermediate severity, with a small number of cases due to loss-of-function mutations of the CAII or the PLEKHM1 genes. Dominant negative mutations of the ClCN7 gene cause the so-called Albers-Schönberg disease, which represents the most frequent and heterogeneous form of osteopetrosis, ranging from asymptomatic to intermediate/severe, thus suggesting additional genetic/environmental determinants affecting penetrance. Importantly, recent work has demonstrated that osteoblasts may also contribute to the pathogenesis of the disease, either because they are affected by intrinsic defects, or because their activity may be enhanced by deregulated osteoclasts abundantly present in most forms. Therapy is presently unsatisfactory and effort is necessary to unravel the gene defects yet unrecognized and identify new treatments to improve symptoms and save life.

摘要

人类骨质石化症是一种由破骨细胞功能障碍引起的罕见遗传性疾病,严重程度差异很大。在最严重的形式中,骨吸收不足会阻止骨腔扩大,损害骨髓发育,导致血液系统功能衰竭。骨孔闭合会导致颅神经受压,进而导致视力和听力下降。患者还会出现骨质硬化、身材矮小、畸形和骨骼脆弱等症状。这种形式在婴儿期是致命的,具有常染色体隐性遗传,可通过造血干细胞移植治愈,但成功率<50%,对生长和视力下降的挽救效果不理想。它依赖于多种基因的功能丧失突变,包括编码H+ATPase的α3亚基的TCIRG1基因,该基因占病例的>50%,ClCN7和OSTM1基因,它们具有密切相关的功能,约占病例的10%,也会出现神经退行性变。其他基因与罕见形式有关,具有不同的严重程度,并与其他综合征相关,最近发现RANKL基因在一部分缺乏破骨细胞的患者中发生突变。常染色体隐性骨质石化症也可能具有中等严重程度,少数病例是由于CAII或PLEKHM1基因的功能丧失突变引起的。ClCN7基因的显性负性突变会导致所谓的阿尔伯斯-尚伯格病,这是骨质石化症最常见和最具异质性的形式,从无症状到中度/重度不等,这表明还有其他遗传/环境决定因素影响其外显率。重要的是,最近的研究表明,成骨细胞也可能参与该疾病的发病机制,要么是因为它们受到内在缺陷的影响,要么是因为在大多数形式中大量存在的失调破骨细胞可能会增强它们的活性。目前的治疗效果不理想,需要努力揭示尚未被认识的基因缺陷,并确定新的治疗方法来改善症状和挽救生命。

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