Genotypic and Phenotypic Spectrum and Pathogenesis of WNT1 Variants in a Large Cohort of Patients With OI/Osteoporosis.
Genotypic and Phenotypic Spectrum and Pathogenesis of WNT1 Variants in a Large Cohort of Patients With OI/Osteoporosis.
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大量 OI/骨质疏松症患者中 WNT1 变异的基因型和表型谱以及发病机制
DOI：
10.1210/clinem/dgac752
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发表时间：
2023-06-16
影响因子：
5.8
通讯作者：
Li, Mei
中科院分区：
文献类型：
--
作者：
Hu, Jing;Lin, Xiaoyun;Gao, Peng;Zhang, Qian;Zhou, Bingna;Wang, Ou;Jiang, Yan;Xia, Weibo;Xing, Xiaoping;Li, Mei
WNT 1突变可导致罕见的遗传性疾病，如成骨不全（OI）和早发性骨质疏松症（EOOP）。由于WNT 1基因突变的罕见性，其临床特征和致病机制尚不清楚。我们的目的是探索大量患有WNT 1相关OI/OP的患者的表型和基因型谱和治疗反应以及WNT 1变体的分子机制。评价患者的表型和基因型及其对双膦酸盐或地舒单抗的应答。使用Western印迹分析、定量聚合酶链反应和免疫荧光染色来评估1例患者胫骨或皮肤中WNT 1、总β-catenin和I型胶原的表达水平。我们纳入了16例在WNT 1中鉴定出16种突变的患者，包括一种新的突变。WNT 1基因突变类型与骨骼表型相关，双等位基因无义突变或移码突变可导致脆性骨折发生早、骨骼表型重。在该队列中发现了一些罕见的合并症，包括大脑异常、血液学疾病和垂体腺瘤。双膦酸盐和狄诺塞单抗显著增加了WNT 1突变患者的脊柱和近端髋关节BMD，并重塑了压缩的椎骨。我们首次报道了与健康对照相比，具有c.677C > T和c.502G > A的患者10的骨中β-连环蛋白水平降低，这揭示了WNT 1诱导的骨骼表型的潜在机制。WNT 1双等位基因无义突变或移码突变可导致WNT 1突变引起的OI和EOOP更早发生脆性骨折和更严重的骨骼表型。WNT通路下调导致的成骨活性降低可能是WNT 1相关的OI和EOOP的潜在致病机制。
Mutations in WNT1 can cause rare inherited disorders such as osteogenesis imperfecta (OI) and early-onset osteoporosis (EOOP). Owing to its rarity, the clinical characteristics and pathogenic mechanism of WNT1 mutations remain unclear. We aimed to explore the phenotypic and genotypic spectrum and treatment responses of a large cohort of patients with WNT1-related OI/OP and the molecular mechanisms of WNT1 variants. The phenotypes and genotypes of patients and their responses to bisphosphonates or denosumab were evaluated. Western blot analysis, quantitative polymerase chain reaction, and immunofluorescence staining were used to evaluate the expression levels of WNT1, total β-catenin, and type I collagen in the tibial bone or skin from one patient. We included 16 patients with 16 mutations identified in WNT1, including a novel mutation. The types of WNT1 mutations were related to skeletal phenotypes, and biallelic nonsense mutations or frameshift mutations could lead to an earlier occurrence of fragility fractures and more severe skeletal phenotypes. Some rare comorbidities were identified in this cohort, including cerebral abnormalities, hematologic diseases, and pituitary adenoma. Bisphosphonates and denosumab significantly increased the spine and proximal hip BMD of patients with WNT1 mutations and reshaped the compressed vertebrae. We report for the first time a decreased β-catenin level in the bone of patient 10 with c.677C > T and c.502G > A compared to the healthy control, which revealed the potential mechanisms of WNT1-induced skeletal phenotypes. Biallelic nonsense mutations or frameshift mutations of WNT1 could lead to an earlier occurrence of fragility fractures and a more severe skeletal phenotype in OI and EOOP induced by WNT1 mutations. The reduced osteogenic activity caused by WNT pathway downregulation could be a potential pathogenic mechanism of WNT1-related OI and EOOP.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
6.2
作者：
Chen, Jianquan;Long, Fanxin
通讯作者：
Long, Fanxin
影响因子：
4.8
作者：
MacDonald, Bryan T.;Hien, Annie;He, Xi
通讯作者：
He, Xi
影响因子：
3.7
作者：
Li S;Cao Y;Wang H;Li L;Ren X;Mi H;Wang Y;Guan Y;Zhao F;Mao B;Yang T;You Y;Guan X;Yang Y;Zhang X;Zhao X
通讯作者：
Zhao X
影响因子：
4.1
作者：
Palomo, Telma;Al-Jallad, Hadil;Rauch, Frank
通讯作者：
Rauch, Frank