Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA; Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
Am J Hum Genet. 2018 Apr 5;102(4):696-705. doi: 10.1016/j.ajhg.2018.02.018. Epub 2018 Mar 29.
AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1 mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40)] and c.1743C>A [p.Cys581]) in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs3]) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that bi-allelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.
AEBP1 编码的蛋白与细胞外基质中的胶原蛋白结合，在发育、组织修复和纤维化等方面具有多种作用。ACLP 在骨骼、血管和皮肤组织中表达，并参与成纤维细胞增殖和间充质干细胞分化为产生胶原蛋白的细胞。Aebp1 小鼠的伤口修复异常且延迟，与成纤维细胞增殖缺陷有关。在这项研究中，我们描述了来自三个无关家庭的四个人，他们表现出独特的临床特征，包括关节松弛、皮肤松弛和过度伸展、伤口愈合不良伴有异常瘢痕形成、骨质疏松症和其他类似于埃勒斯-当洛斯综合征 (EDS) 的特征。皮肤活检分析显示真皮胶原蛋白减少，胶原纤维异常，外观参差不齐。外显子组测序在第一个个体中发现 AEBP1 的复合杂合变异(c.1470delC [p.Asn490_Met495delins(40)] 和 c.1743C>A [p.Cys581])，第二个个体中发现纯合变异(c.1320_1326del [p.Arg440Serfs3])，第三个家庭的两个兄弟姐妹中发现纯合剪接位点变异(c.1630+1G>A)。我们表明，ACLP 通过其盘状结构域增强胶原蛋白聚合并与几种纤维胶原蛋白结合。这些研究支持结论，即 AEBP1 的双等位基因致病性变异是这种常染色体隐性 EDS 亚型的原因。
