Laine Christine M, Wessman Maija, Toiviainen-Salo Sanna, Kaunisto Mari A, Mäyränpää Mervi K, Laine Tero, Pekkinen Minna, Kröger Heikki, Välimäki Ville-Valtteri, Välimäki Matti J, Lehesjoki Anna-Elina, Mäkitie Outi
Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Endocrinology, Institute of Medicine, Sahlgrenska University Hospital and University of Gothenburg, Gothenburg, Sweden.
J Bone Miner Res. 2015 Mar;30(3):510-8. doi: 10.1002/jbmr.2355.
Genetic factors play an important role in the development of osteoporosis. Several monogenic forms of osteoporosis have been recognized, most recently an X-chromosomal form resulting from mutations in the gene encoding plastin 3 (PLS3). PLS3 is a protein involved in actin bundle formation in the cytoskeleton. We present a large family with early onset osteoporosis and X-linked inheritance. Phenotyping was performed on 19 family members and whole-exome sequencing on 7 family members (5 with a diagnosis of early onset osteoporosis and 2 with normal bone parameters). Osteoporosis had its onset in childhood and was characterized by recurrent peripheral fractures, low bone mineral density (BMD), vertebral compression fractures, and significant height loss in adulthood. Males were in general more severely affected than females. Bone histomorphometry findings in 4 males and 1 female showed severe trabecular osteoporosis, low amount of osteoid, and decreased mineral apposition rate, indicating impaired bone formation; resorption parameters were increased in some. All affected subjects shared a single base substitution (c.73-24T > A) in intron 2 of PLS3 on Xq23. The mutation, confirmed by Sanger sequencing, segregated according to the skeletal phenotype. The mutation introduces a new acceptor splice site with a predicted splice score of 0.99 and, thereby, as confirmed by cDNA sequencing, induces the insertion of 22 bases between exons 2 and 3, causing a frameshift and premature termination of mRNA translation (p.Asp25Alafs*17). The mutation affects the first N-terminal calcium-binding EF-hand domain and abolishes all calcium- and actin-binding domains of the protein. Our results confirm the role of PLS3 mutations in early onset osteoporosis. The mechanism whereby PLS3 affects bone health is unclear, but it may be linked to osteocyte dendrite function and skeletal mechanosensing. Future studies are needed to elucidate the role of PLS3 in osteoporosis and to define optimal treatment.
遗传因素在骨质疏松症的发生发展中起着重要作用。目前已识别出几种单基因形式的骨质疏松症，最近发现一种X染色体形式的骨质疏松症是由编码丝束蛋白3（PLS3）的基因突变引起的。PLS3是一种参与细胞骨架中肌动蛋白束形成的蛋白质。我们报告了一个早发性骨质疏松症且具有X连锁遗传特征的大家族。对19名家族成员进行了表型分析，并对7名家族成员（5名诊断为早发性骨质疏松症，2名骨参数正常）进行了全外显子组测序。骨质疏松症始于儿童期，其特征为反复出现的外周骨折、低骨密度（BMD）、椎体压缩性骨折以及成年后明显的身高降低。一般来说，男性比女性受影响更严重。4名男性和1名女性的骨组织形态计量学结果显示严重的小梁骨质疏松、类骨质数量减少以及矿物质沉积率降低，表明骨形成受损；部分患者的骨吸收参数增加。所有受影响的受试者在Xq23上的PLS3基因第2内含子中均存在一个单碱基替换（c.73 - 24T＞A）。经桑格测序确认，该突变根据骨骼表型进行分离。该突变引入了一个新的剪接受体位点，预测剪接分数为0.99，因此，经cDNA测序证实，该突变导致外显子2和3之间插入22个碱基，引起移码并导致mRNA翻译提前终止（p.Asp25Alafs*17）。该突变影响第一个N端钙结合EF手结构域，并消除了该蛋白的所有钙结合和肌动蛋白结合结构域。我们的结果证实了PLS3突变在早发性骨质疏松症中的作用。PLS3影响骨骼健康的机制尚不清楚，但可能与骨细胞树突功能和骨骼机械传感有关。需要进一步的研究来阐明PLS3在骨质疏松症中的作用并确定最佳治疗方法。
