Molecular Biology Section, Institute of Biochemistry and Biotechnology, University of Veterinary and Animal Sciences, 54000, Lahore, Pakistan.
Department of Pediatrics, Boston Children's Hospital, 300 Longwood Avenue, MA, 02115, Boston, USA.
BMC Med Genomics. 2021 Nov 12;14(1):266. doi: 10.1186/s12920-021-01116-5.
Nephrolithiasis (NL) affects 1 in 11 individuals worldwide and causes significant morbidity and cost. Common variants in the calcium sensing receptor gene (CaSR) have been associated with NL. Rare inactivating CaSR variants classically cause hyperparathyroidism, hypercalcemia and hypocalciuria. However, NL and familial hypercalciuria have been paradoxically associated with select inactivating CaSR variants in three kindreds from Europe and Australia.
To discover novel NL-associated CaSR variants from a geographically distinct cohort, 57 Pakistani families presenting with pediatric onset NL were recruited. The CaSR locus was analyzed by directed or exome sequencing.
We detected a heterozygous and likely pathogenic splice variant (GRCh37 Chr3:122000958A>G; GRCh38 Chr3:12228211A>G; NM_000388:c.1609-2A>G) in CaSR in one family with recurrent calcium oxalate stones. This variant would be predicted to cause exon skipping and premature termination (p.Val537Metfs*49). Moreover, a splice variant of unknown significance in an alternative CaSR transcript (GRCh37 Chr3:122000929G>C; GRCh38 Chr3:122282082G >C NM_000388:c.1609-31G >C NM_001178065:c.1609-1G >C) was identified in two additional families.
Sequencing of the CaSR locus in Pakistani stone formers reveals a novel loss-of-function variant, expanding the connection between the CaSR locus and nephrolithiasis.
肾结石（NL）影响全球每 11 个人中的 1 人，导致显著的发病率和成本。钙敏感受体基因（CaSR）的常见变异与 NL 有关。经典的失活 CaSR 变异体通常导致甲状旁腺功能亢进、高钙血症和低钙尿症。然而，NL 和家族性高钙尿症与来自欧洲和澳大利亚的三个家族的特定失活 CaSR 变异体存在矛盾关联。
为了从地理位置不同的队列中发现新的与 NL 相关的 CaSR 变异体，招募了 57 个有小儿期 NL 起病的巴基斯坦家庭。通过定向或外显子组测序分析 CaSR 基因座。
我们在一个有复发性草酸钙结石的家庭中发现了 CaSR 的杂合且可能致病的剪接变异体（GRCh37 Chr3：122000958A>G；GRCh38 Chr3：12228211A>G；NM_000388：c.1609-2A>G）。该变异体预计会导致外显子跳跃和提前终止（p.Val537Metfs*49）。此外，在另两个家庭中还发现了一种 CaSR 转录本的未知意义剪接变异体（GRCh37 Chr3：122000929G>C；GRCh38 Chr3：122282082G>C；NM_000388：c.1609-31G>C；NM_001178065：c.1609-1G>C）。
对巴基斯坦结石形成者的 CaSR 基因座进行测序揭示了一种新的功能丧失变异体，扩大了 CaSR 基因座与肾结石之间的联系。
