Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement.
Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement.
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DOI：
10.1016/j.ajhg.2016.08.019
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发表时间：
2016-11-03
影响因子：
9.8
通讯作者：
Zschocke J
中科院分区：
文献类型：
--
作者：
Kapferer-Seebacher I;Pepin M;Werner R;Aitman TJ;Nordgren A;Stoiber H;Thielens N;Gaboriaud C;Amberger A;Schossig A;Gruber R;Giunta C;Bamshad M;Björck E;Chen C;Chitayat D;Dorschner M;Schmitt-Egenolf M;Hale CJ;Hanna D;Hennies HC;Heiss-Kisielewsky I;Lindstrand A;Lundberg P;Mitchell AL;Nickerson DA;Reinstein E;Rohrbach M;Romani N;Schmuth M;Silver R;Taylan F;Vandersteen A;Vandrovcova J;Weerakkody R;Yang M;Pope FM;Molecular Basis of Periodontal EDS Consortium;Byers PH;Zschocke J
牙周炎Ehlers-Danlos综合征（pEDS）是一种常染色体显性遗传疾病，其特征是早发性牙周炎，导致牙齿过早脱落、关节过度活动和轻度皮肤异常。一个基因座被定位到12p13.1的约5.8 Mb区域，但没有候选基因被鉴定。在一个国际联盟中，我们招募了19个独立的家庭，包括107个患有pEDS的个体，以确定基因座，描述具有明确遗传原因的患者的临床细节，并试图了解病情的生理基础。在这些家庭中的17个，我们确定了杂合错义或框内插入/缺失突变C1 R（15个家庭）或C1 S（2个家庭），连续的基因在映射的基因座编码亚基C1 r和C1 s的第一个组成部分的经典补体途径。这两种蛋白质形成异源四聚体，然后与六个C1 q亚基结合。致病性变体涉及C1 r和C1 s的亚基界面或结构域间铰链，并与细胞内滞留和轻度内质网扩大相关。这些家族中受影响个体的临床特征包括在青少年或儿童期发病的快速进展的牙周炎、先前未被认识到的附着牙龈缺乏、胫骨前色素沉着过度、皮肤和血管脆弱、容易瘀伤和可变的肌肉骨骼症状。我们的发现打开了炎症经典补体途径和结缔组织稳态之间的联系。
Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.
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影响因子：
5.4
作者：
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通讯作者：
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