Piret Sian E, Gorvin Caroline M, Trinh Anne, Taylor John, Lise Stefano, Taylor Jenny C, Ebeling Peter R, Thakker Rajesh V
Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, United Kingdom.
Faculty of Medicine, Nursing and Health Sciences, Department of Medicine, School of Clinical Sciences, Monash Medical Centre, Monash University, Clayton, Victoria, Australia.
Am J Med Genet A. 2016 Nov;170(11):2988-2992. doi: 10.1002/ajmg.a.37755. Epub 2016 Aug 19.
The aim of this study was to identify the causative mutation in a family with an unusual presentation of autosomal dominant osteopetrosis (OPT), proximal renal tubular acidosis (RTA), renal stones, epilepsy, and blindness, a combination of features not previously reported. We undertook exome sequencing of one affected and one unaffected family member, followed by targeted analysis of known candidate genes to identify the causative mutation. This identified a missense mutation (c.643G>A; p.Gly215Arg) in the gene encoding the chloride/proton antiporter 7 (gene CLCN7, protein CLC-7), which was confirmed by amplification refractory mutation system (ARMS)-PCR, and to be present in the three available patients. CLC-7 mutations are known to cause autosomal dominant OPT type 2, also called Albers-Schonberg disease, which is characterized by osteosclerosis, predominantly of the spine, pelvis and skull base, resulting in bone fragility and fractures. Albers-Schonberg disease is not reported to be associated with RTA, but autosomal recessive OPT type 3 (OPTB3) with RTA is associated with carbonic anhydrase type 2 (CA2) mutations. No mutations were detected in CA2 or any other genes known to cause proximal RTA. Neither CLCN7 nor CA2 mutations have previously been reported to be associated with renal stones or epilepsy. Thus, we identified a CLCN7 mutation in a family with autosomal dominant osteopetrosis, RTA, renal stones, epilepsy, and blindness. © 2016 Wiley Periodicals, Inc.
本研究的目的是在一个患有常染色体显性遗传性骨硬化症（OPT）、近端肾小管酸中毒（RTA）、肾结石、癫痫和失明的家族中鉴定致病突变，这些特征的组合此前未见报道。我们对一名患病家庭成员和一名未患病家庭成员进行了外显子组测序，随后对已知的候选基因进行靶向分析以鉴定致病突变。这确定了编码氯化物/质子反向转运蛋白7（基因CLCN7，蛋白CLC-7）的基因中存在一个错义突变（c.643G>A；p.Gly215Arg），该突变通过扩增阻滞突变系统（ARMS）-PCR得到确认，并在三名现有的患者中存在。已知CLC-7突变会导致常染色体显性遗传性骨硬化症2型，也称为阿尔伯斯-尚伯格病，其特征为骨硬化，主要发生在脊柱、骨盆和颅底，导致骨质脆弱和骨折。此前未报道阿尔伯斯-尚伯格病与RTA有关，但伴有RTA的常染色体隐性遗传性骨硬化症3型（OPTB3）与碳酸酐酶2型（CA2）突变有关。在CA2或任何其他已知会导致近端RTA的基因中均未检测到突变。此前也未报道CLCN7和CA2突变与肾结石或癫痫有关。因此，我们在一个患有常染色体显性遗传性骨硬化症、RTA、肾结石、癫痫和失明的家族中鉴定出了一个CLCN7突变。© 2016威利期刊公司
