Monoallelic mutations in SLCO2A1 cause autosomal dominant primary hypertrophic osteoarthropathy
Monoallelic mutations in SLCO2A1 cause autosomal dominant primary hypertrophic osteoarthropathy
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DOI：
10.1002/jbmr.4310
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发表时间：
2021-05-05
影响因子：
6.2
通讯作者：
Zhang, Zhenlin
中科院分区：
文献类型：
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作者：
Xu, Yang;Zhang, Zeng;Zhang, Zhenlin
摘要原发性肥大性骨关节病是一种罕见的隐性或不规则显性遗传疾病，其特征为指端杵状畸形、厚皮症及骨膜增生。HPGD和SLCO 2A 1的双等位基因突变扰乱前列腺素E-2（PGE（2））分解代谢并导致循环PGE（2）水平升高，分别导致PHO常染色体隐性1型（PHOAR 1）和PHO常染色体隐性2型（PHOAR 2）。然而，没有致病基因的PHO常染色体显性遗传（PHOAD）的报道。我们对7个PHOAD家系的DNA样本进行了桑格测序和全基因组测序;在排除基因组中的其他单核苷酸变异（SNV）、结构变异（SV）和拷贝数变异（CNV）后，我们报告了6个SLCO 2A 1单等位基因突变在先证者和受累家族成员中，c.1660G>A [p.G554R]、c.664G> A [p.G222R]、c.1106G>A [p.G369D]、c.1065dupA [p.Q356TfsX77]、c.1293delT [p.S432AfsX48]和c.1807C>T [p.R603X]）。然后，在另外5个先证者携带SLCO 2A 1双等位基因突变的PHO家族中，我们验证了携带SLCO 2A 1单等位基因突变的父母也显示PHO表现，这进一步证实了SLCO 2A 1单等位基因突变的致病性，并说明了PHOAD和PHOAR 2的等位基因性质。随后，通过对7例PHOAD先证者和50例PHOAR 2患者的比较，我们发现两种PHO类型的青春期发病年龄和偏侧发病率相似，但PHOAD的症状和体征较轻，包括较轻的厚皮症（p = 0.027）和骨膜病（p = 0.005），以及较少发生的回状皮肤（p = 0.011）、痤疮（p = 0.005）、关节痛（p = 0.037）和贫血（p = 0.023）。PHOAD先证者中位尿PGE（2）水平几乎是PHOAR 2患者的一半（PHOAD 277.58 ng/mmoL肌酐，PHOAR 2 473.19 ng/mmoL肌酐; p = 0.038）。此外，通过为期3个月的口服依托考昔试验，在PHOAD先证者中观察到与我们先前在PHOAR 2患者中报告的相似的有效反应。总之，我们的研究结果证实，SLCO 2A 1单等位基因突变是PHOAD的原因，扩大了PHO的表型谱。(c)2021年美国骨与矿物质研究学会（ASBMR）。
Primary hypertrophic osteoarthropathy (PHO) is a rare disease inherited as a recessive or irregular dominant trait and characterized by digital clubbing, pachydermia, and periostosis. Biallelic mutations in HPGD and SLCO2A1, disturbing prostaglandin E-2 (PGE(2)) catabolism and leading to increased circulating PGE(2) level, cause PHO autosomal recessive 1 (PHOAR1) and PHO autosomal recessive 2 (PHOAR2), respectively. However, no causative genes have been reported for PHO autosomal dominant (PHOAD). Here, we performed Sanger sequencing and whole-genome sequencing (WGS) on DNA samples from seven Chinese PHOAD families; after excluding other single-nucleotide variants (SNVs), structural variations (SVs), and copy number variations (CNVs) in the genomes, we reported six SLCO2A1 monoallelic mutations (c.1660G>A [p.G554R], c.664G>A [p.G222R], c.1106G>A [p.G369D], c.1065dupA [p.Q356TfsX77], c.1293delT [p.S432AfsX48], and c.1807C>T [p.R603X]) in the probands and affected family members. Then, in five other PHO families with probands carrying SLCO2A1 biallelic mutations, we verified that parents with SLCO2A1 monoallelic mutations also displayed PHO manifestations, which further confirmed the pathogenicity of SLCO2A1 monoallelic mutations and illustrated the allelic nature of PHOAD and PHOAR2. Subsequently, through comparison of seven PHOAD probands and 50 PHOAR2 patients, we found onset age in puberty and skewed penetrance rate were similar in both PHO types, but symptoms and signs of PHOAD were milder, including less severe pachydermia (p = .027) and periostosis (p = .005), and less frequent cutis verticis gyrata (p = .011), acne (p = .005), arthralgia (p = .037), and anemia (p = .023). The median urinary PGE(2) level in PHOAD probands was almost half that in PHOAR2 patients (PHOAD 277.58 ng/mmoL creatinine, PHOAR2 473.19 ng/mmoL creatinine; p = .038). Moreover, through the 3-month trial of oral administration of etoricoxib, an effective response similar to that we reported previously in PHOAR2 patients was observed in PHOAD probands. In conclusion, our findings confirm that SLCO2A1 monoallelic mutations are the cause of PHOAD and broaden phenotypic spectrum of PHO. (c) 2021 American Society for Bone and Mineral Research (ASBMR).