A novel brachydactyly type E syndrome caused by variants in helix 8 of the PTH1R.

IF 5.9 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Gavin Monahan, Jakob Höppner, Harald Jüppner, Audrey Rick, Elyshia McNamara, William Tee, Guillermo Lay-Son, Andy Contreras, Alejandro Martínez, Cristián García, Javiera Vildoso, Thomas J Gardella, Benjamin Kamien, Gianina Ravenscroft
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引用次数: 0

Abstract

The parathyroid hormone receptor 1 (PTH1R) transmits stimuli provided by parathyroid hormone (PTH) and PTH-related protein (PTHrP) and thus plays key roles in calcium and phosphate homeostasis as well as skeletal development. Variants in PTH1R have been linked to several conditions including Jansen's metaphyseal chondrodysplasia, Blomstrand chondrodysplasia, Primary Failure of Tooth Eruption and Eiken syndrome. Here, we report a novel skeletal phenotype identified in two unrelated families associated with PTH1R variants. The clinical features include brachydactyly type E (BDE), mild short stature, and dental anomalies. A novel heterozygous PTH1R substitution (p.E469K) was identified in affected members of Family 1, while the affected individual from Family 2 had a previously described heterozygous de novo substitution (p.E465K); these two mutated sites lie within helix 8 of the PTH1R. Cell-based assays revealed reduced cell surface expression, as well as impaired basal and PTH- or PTHrP-induced cAMP signaling responses for both mutants, as compared to WT-PTH1R. Introduction of the p.E469K substitution into humanized PTH1R mice resulted in mildly increased mineralization of bones in the paws as well as shortening of long bones. Our findings demonstrate a new skeletal phenotype associated with PTH1R variants and suggest that helix 8 of the receptor contributes to PTH1R expression and/or signaling during bone development.

一种由PTH1R螺旋8变异引起的新型短指E型综合征。
甲状旁腺激素受体1 (PTH1R)传递由甲状旁腺激素(PTH)和PTH相关蛋白(PTHrP)提供的刺激,因此在钙和磷酸盐稳态以及骨骼发育中起关键作用。PTH1R的变异与多种疾病有关,包括Jansen干骺端软骨发育不良、Blomstrand软骨发育不良、原发性出牙失败和艾肯综合征。在这里,我们报告了在两个与PTH1R变异相关的不相关家族中发现的一种新的骨骼表型。临床表现为E型短指畸形,轻度身材矮小,牙齿畸形。在家族1的受影响成员中发现了一种新的杂合PTH1R替代(p.E469K),而家族2的受影响个体具有先前描述的杂合新生替代(p.E465K);这两个突变位点位于PTH1R的第8螺旋内。基于细胞的实验显示,与WT-PTH1R相比,这两种突变体的细胞表面表达降低,基础和PTH-或pthrp诱导的cAMP信号反应受损。将p.E469K代入人源化PTH1R小鼠后,爪骨矿化轻度增加,长骨缩短。我们的研究结果证明了一种与PTH1R变异相关的新的骨骼表型,并表明受体的螺旋8在骨骼发育过程中有助于PTH1R的表达和/或信号传导。
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来源期刊
Journal of Bone and Mineral Research
Journal of Bone and Mineral Research 医学-内分泌学与代谢
CiteScore
11.30
自引率
6.50%
发文量
257
审稿时长
2 months
期刊介绍: The Journal of Bone and Mineral Research (JBMR) publishes highly impactful original manuscripts, reviews, and special articles on basic, translational and clinical investigations relevant to the musculoskeletal system and mineral metabolism. Specifically, the journal is interested in original research on the biology and physiology of skeletal tissues, interdisciplinary research spanning the musculoskeletal and other systems, including but not limited to immunology, hematology, energy metabolism, cancer biology, and neurology, and systems biology topics using large scale “-omics” approaches. The journal welcomes clinical research on the pathophysiology, treatment and prevention of osteoporosis and fractures, as well as sarcopenia, disorders of bone and mineral metabolism, and rare or genetically determined bone diseases.
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