Sequencing the CaSR locus in Pakistani stone formers reveals a novel loss-of-function variant atypically associated with nephrolithiasis
Abstract Background 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...
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oai:doaj.org-article:5e4ae64832b44762b48f994248e9fe092021-11-14T12:07:41ZSequencing the CaSR locus in Pakistani stone formers reveals a novel loss-of-function variant atypically associated with nephrolithiasis10.1186/s12920-021-01116-51755-8794https://doaj.org/article/5e4ae64832b44762b48f994248e9fe092021-11-01T00:00:00Zhttps://doi.org/10.1186/s12920-021-01116-5https://doaj.org/toc/1755-8794Abstract Background 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. Methods 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. Results 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. Conclusions 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.Ihsan UllahIsabel OttlewskiWasim ShehzadAmjad RiazSadaqat IjazAsad TufailHafiza AmmaraShrikant ManeShirlee ShrilFriedhelm HildebrandtMuhammad Yasir ZahoorAmar J. MajmundarBMCarticleCalcium sensing receptorCaSRNephrolithiasisRare diseaseInternal medicineRC31-1245GeneticsQH426-470ENBMC Medical Genomics, Vol 14, Iss 1, Pp 1-7 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Calcium sensing receptor CaSR Nephrolithiasis Rare disease Internal medicine RC31-1245 Genetics QH426-470 |
| spellingShingle |
Calcium sensing receptor CaSR Nephrolithiasis Rare disease Internal medicine RC31-1245 Genetics QH426-470 Ihsan Ullah Isabel Ottlewski Wasim Shehzad Amjad Riaz Sadaqat Ijaz Asad Tufail Hafiza Ammara Shrikant Mane Shirlee Shril Friedhelm Hildebrandt Muhammad Yasir Zahoor Amar J. Majmundar Sequencing the CaSR locus in Pakistani stone formers reveals a novel loss-of-function variant atypically associated with nephrolithiasis |
| description |
Abstract Background 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. Methods 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. Results 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. Conclusions 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. |
| format |
article |
| author |
Ihsan Ullah Isabel Ottlewski Wasim Shehzad Amjad Riaz Sadaqat Ijaz Asad Tufail Hafiza Ammara Shrikant Mane Shirlee Shril Friedhelm Hildebrandt Muhammad Yasir Zahoor Amar J. Majmundar |
| author_facet |
Ihsan Ullah Isabel Ottlewski Wasim Shehzad Amjad Riaz Sadaqat Ijaz Asad Tufail Hafiza Ammara Shrikant Mane Shirlee Shril Friedhelm Hildebrandt Muhammad Yasir Zahoor Amar J. Majmundar |
| author_sort |
Ihsan Ullah |
| title |
Sequencing the CaSR locus in Pakistani stone formers reveals a novel loss-of-function variant atypically associated with nephrolithiasis |
| title_short |
Sequencing the CaSR locus in Pakistani stone formers reveals a novel loss-of-function variant atypically associated with nephrolithiasis |
| title_full |
Sequencing the CaSR locus in Pakistani stone formers reveals a novel loss-of-function variant atypically associated with nephrolithiasis |
| title_fullStr |
Sequencing the CaSR locus in Pakistani stone formers reveals a novel loss-of-function variant atypically associated with nephrolithiasis |
| title_full_unstemmed |
Sequencing the CaSR locus in Pakistani stone formers reveals a novel loss-of-function variant atypically associated with nephrolithiasis |
| title_sort |
sequencing the casr locus in pakistani stone formers reveals a novel loss-of-function variant atypically associated with nephrolithiasis |
| publisher |
BMC |
| publishDate |
2021 |
| url |
https://doaj.org/article/5e4ae64832b44762b48f994248e9fe09 |
| work_keys_str_mv |
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