Faculty of Medical and Human Sciences, Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Manchester, UK.
Faculty of Life Sciences, Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK.
Ann Rheum Dis. 2015 Jun;74(6):1249-56. doi: 10.1136/annrheumdis-2013-204309. Epub 2014 Jan 17.
Leri's pleonosteosis (LP) is an autosomal dominant rheumatic condition characterised by flexion contractures of the interphalangeal joints, limited motion of multiple joints, and short broad metacarpals, metatarsals and phalanges. Scleroderma-like skin thickening can be seen in some individuals with LP. We undertook a study to characterise the phenotype of LP and identify its genetic basis.
Whole-genome single-nucleotide polymorphism genotyping in two families with LP defined microduplications of chromosome 8q22.1 as the cause of this condition. Expression analysis of dermal fibroblasts from affected individuals showed overexpression of two genes, GDF6 and SDC2, within the duplicated region, leading to dysregulation of genes that encode proteins of the extracellular matrix and downstream players in the transforming growth factor (TGF)-β pathway. Western blot analysis revealed markedly decreased inhibitory SMAD6 levels in patients with LP. Furthermore, in a cohort of 330 systemic sclerosis cases, we show that the minor allele of a missense SDC2 variant, p.Ser71Thr, could confer protection against disease (p<1×10(-5)).
Our work identifies the genetic cause of LP in these two families, demonstrates the phenotypic range of the condition, implicates dysregulation of extracellular matrix homoeostasis genes in its pathogenesis, and highlights the link between TGF-β/SMAD signalling, growth/differentiation factor 6 and syndecan-2. We propose that LP is an additional member of the growing 'TGF-β-pathies' group of musculoskeletal disorders, which includes Myhre syndrome, acromicric dysplasia, geleophysic dysplasias, Weill-Marchesani syndromes and stiff skin syndrome. Identification of a systemic sclerosis-protective SDC2 variant lays the foundation for exploration of the role of syndecan-2 in systemic sclerosis in the future.
Leri 先天性多骨性骨肥大症（LP）是一种常染色体显性风湿性疾病，其特征为指间关节屈曲挛缩、多个关节活动受限以及掌骨、跖骨和指骨短而宽。一些 LP 患者可见硬皮病样皮肤增厚。我们进行了一项研究，以描述 LP 的表型并确定其遗传基础。
对两个 LP 家系进行全基因组单核苷酸多态性基因分型，发现 8q22.1 染色体微重复是导致这种疾病的原因。对受影响个体的真皮成纤维细胞进行表达分析显示，在重复区域内 GDF6 和 SDC2 两个基因过表达，导致编码细胞外基质蛋白和转化生长因子 (TGF)-β 通路下游因子的基因失调。Western blot 分析显示 LP 患者的抑制性 SMAD6 水平明显降低。此外，在 330 例系统性硬化症患者队列中，我们发现 SDC2 错义变体 p.Ser71Thr 的次要等位基因可能对疾病具有保护作用（p<1×10(-5)）。
我们的工作确定了这两个家系中 LP 的遗传原因，展示了该疾病的表型范围，提示细胞外基质稳态基因失调参与其发病机制，并强调了 TGF-β/SMAD 信号、生长/分化因子 6 和 syndecan-2 之间的联系。我们提出 LP 是肌肉骨骼疾病中不断增加的“TGF-β 通路”组的另一个成员，其中包括 Myhre 综合征、acrocentric dysplasia、geleophysic dysplasias、Weill-Marchesani 综合征和硬皮病综合征。鉴定出系统性硬化症保护性 SDC2 变体为未来探索 syndecan-2 在系统性硬化症中的作用奠定了基础。
