Biallelic variants in ADAMTS15 cause a novel form of distal arthrogryposis.
Biallelic variants in ADAMTS15 cause a novel form of distal arthrogryposis.
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DOI：
10.1016/j.gim.2022.07.012
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发表时间：
2022-10
影响因子：
8.8
通讯作者：
Schmidt, Julia
中科院分区：
文献类型：
--
作者：
Boschann, Felix;Cogulu, Muhsin O.;Pehlivan, Davut;Balachandran, Saranya;Vallecillo-Garcia, Pedro;Grochowski, Christopher M.;Hansmeier, Nils R.;Akdemir, Zeynep H. Coban;Prada-Medina, Cesar A.;Aykut, Ayca;Fischer-Zirnsak, Bjorn;Badura, Simon;Durmaz, Burak;Ozkinay, Ferda;Haegerling, Rene;Posey, Jennifer E.;Stricker, Sigmar;Gillessen-Kaesbach, Gabriele;Spielmann, Malte;Horn, Denise;Brockmann, Knut;Lupski, James R.;Kornak, Uwe;Schmidt, Julia
我们的目标是确定一种新形式的远端关节融合的潜在遗传原因。使用基于家族的罕见变异基因组学、外显子组和疾病特异性面板测序来检测受影响个体的ADAMTS15变异。在单细胞水平上分析Adamts15在小鼠胚胎发生过程中的表达。用原位杂交和RNAScope分析其表达模式。我们在来自四个无血缘关系的家系的五个患病个体中发现了ADAMTS15的纯合子罕见变异等位基因，表现为先天性指间关节屈曲痉挛和发育不良或缺乏掌纹。放射学检查显示生理性指间关节形态。其他特征包括膝关节、跟腱和脚趾收缩、脊柱僵硬、脊柱侧弯和正畸异常。对小鼠全胚胎单细胞测序数据的分析显示，在胚胎时期E11.5和E15.0之间的肢体间充质中，Adamts15的表达受到严格调控。通过原位杂交，在发育中的小鼠肢体中有明显的肌周和腱周围表达。相应地，RNAScope分析检测到与Osr1显著共表达，但与骨骼肌或关节形成的标志物无关。综上所述，我们的发现提供了证据，证明ADAMTS15罕见的双等位隐性性状变异导致一种新的常染色体隐性遗传结缔组织疾病，从而导致远端关节融合综合征。
We aimed to identify the underlying genetic cause for a novel form of distal arthrogryposis. Rare variant family-based genomics, exome and disease-specific panel sequencing were used to detect ADAMTS15 variants in affected individuals. Adamts15 expression was analyzed at the single-cell level during murine embryogenesis. Expression patterns were characterized by in situ hybridization and RNAscope. We identified homozygous rare variant alleles of ADAMTS15 in five affected individuals from four unrelated consanguineous families, presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. Radiographic investigations showed physiological interphalangeal joint morphology. Additional features included knee, Achilles tendon, and toe contractures, spinal stiffness, scoliosis, and orthodontic abnormalities. Analysis of mouse whole-embryo single-cell sequencing data revealed a tightly regulated Adamts15 expression in the limb mesenchyme between embryonic stages E11.5 and E15.0. A perimuscular and peritendinous expression was evident by in situ hybridization in the developing mouse limb. In accordance, RNAscope analysis detected a significant co-expression with Osr1, but not with markers for skeletal muscle or joint formation. In aggregate, our findings provide evidence that rare biallelic recessive trait variants in ADAMTS15 cause a novel autosomal recessive connective tissue disorder resulting in a distal arthrogryposis syndrome.
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影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
16.6
作者：
Vallecillo-García P;Orgeur M;Vom Hofe-Schneider S;Stumm J;Kappert V;Ibrahim DM;Börno ST;Hayashi S;Relaix F;Hildebrandt K;Sengle G;Koch M;Timmermann B;Marazzi G;Sassoon DA;Duprez D;Stricker S
通讯作者：
Stricker S
影响因子：
30.8
作者：
Le Goff, Carine;Morice-Picard, Fanny;Dagoneau, Nathalie;Wang, Lauren W.;Perrot, Claire;Crow, Yanick J.;Bauer, Florence;Flori, Elisabeth;Prost-Squarcioni, Catherine;Krakow, Deborah;Ge, Gaoxiang;Greenspan, Daniel S.;Bonnet, Damien;Le Merrer, Martine;Munnich, Arnold;Apte, Suneel S.;Cormier-Daire, Valerie
通讯作者：
Cormier-Daire, Valerie
DOI：
10.1007/978-1-4939-9698-8_1
发表时间：
2020-01-01
期刊：
ADAMTS PROTEASES: METHODS AND PROTOCOLS
影响因子：
--
作者：
Apte, Suneel S.
通讯作者：
Apte, Suneel S.
影响因子：
11.8
作者：
McCulloch, Daniel R.;Nelson, Courtney M.;Dixon, Laura J.;Silver, Debra L.;Wylie, James D.;Lindner, Volkhard;Sasaki, Takako;Cooley, Marion A.;Argraves, W. Scott;Apte, Suneel S.
通讯作者：
Apte, Suneel S.