Mutations in SLC26A1 Cause Nephrolithiasis

Nephrology Dialysis Transplantation, 2005

Background. Nephrolithiasis is a complex, multifactorial disease resulting from genetic and environmental interaction. The pathogenesis of nephrolithiasis is far from being understood. So far, no gene locus for autosomal dominant nephrolithiasis only has been described. We here identified a new suggestive gene locus for autosomal dominant nephrolithiasis by a genome-wide search for linkage in a Spanish kindred with nephrolithiasis. Methods. Clinical data, blood and urine samples of 18 individuals from a Spanish kindred with nephrolithiasis were collected. We performed a genome-wide search for linkage using 380 polymorphic microsatellite markers. Results. Nephrolithiasis segregated in this Spanish kindred in a pattern compatible with autosomal dominant inheritance. The total genome search yielded the highest two-point LOD score of Z max ¼ 1.99 (y ¼ 0) for marker D9S159 on chromosome 9q33.2-q34.2. Multipoint analysis of 24 polymorphic markers used for further fine mapping resulted in a LOD score of Z max ¼ 2.7 (y ¼ 0) for markers D9S1881-D9S164, thereby identifiying a new gene locus for autosomal dominant nephrolithiasis (NPL1). Two recombination events define D9S1850 as the centromeric flanking marker and D9S1818 as the telomeric flanking marker, restricting the NPL1 locus to a 14 Mb interval. Conclusion. We here identified a new suggestive gene locus (NPL1) for autosomal dominant nephrolithiasis. It is localized on chromosome 9q33.2-q34.2. The identification of the responsible gene will provide new insights into the molecular basis of nephrolithiasis.

Kidney International, 1998

Background. X-linked nephrolithiasis, or Dent's disease, encompasses several clinical syndromes of low molecular weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and renal failure, and is associated with mutations in the CLCN5 gene encoding a kidney-specific voltage-gated chloride channel. Some patients from Europe have rickets, and all symptomatic patients confirmed by mutation analysis have been male.

Journal of the American Society of Nephrology : JASN, 2017

Renal stone disease is a frequent condition, causing a huge burden on health care systems globally. Calcium-based calculi account for around 75% of renal stone disease and the incidence of these calculi is increasing, suggesting environmental and dietary factors are acting upon a preexisting genetic background. The familial nature and significant heritability of stone disease is known, and recent genetic studies have successfully identified genes that may be involved in renal stone formation. The detection of monogenic causes of renal stone disease has been made more feasible by the use of high-throughput sequencing technologies and has also facilitated the discovery of novel monogenic causes of stone disease. However, the majority of calcium stone formers remain of undetermined genotype. Genome-wide association studies and candidate gene studies implicate a series of genes involved in renal tubular handling of lithogenic substrates, such as calcium, oxalate, and phosphate, and of i...

Frontiers in Molecular Biosciences

Pediatric nephrolithiasis (NL) or Kidney stone disease (KSD) is an untethered topic in Asian population. In Western countries, the annual incidence of paediatric NL is around 6–10%. Here, we present data from West Bengal, India, on lower age (LA, 0–20 years) NL and its prevalence for the first time. To discover the mutations associated with KSD, twenty-four (18 + 6) rare LA-NL patients were selected for Whole Exome Sequencing (WES) and Sanger sequencing, respectively. It was found that GRHPR c. 494G>A mutation (MZ826703) is predominant in our study cohort. This specific homozygous mutation is functionally studied for the first time directly from human peripheral mononuclear cell (PBMC) samples. Using expression study with biochemical activity and computational analysis we assumed that the mutation is pathogenic with loss of function. Moreover, three genes, AGXT, HOGA1 and GRHPR with Novel variants known to cause hyperoxaluria were found frequently in the study cohort. Our study a...

Indian Journal of Child Health, 2021

N ephrolithiasis (NL) is a major public health issue in adults particularly in arid climates . NL has traditionally been considered a disease of adults; however, the prevalence in children is increasing worldwide . About half of children with a kidney stone have a metabolic cause . Even a single stone in children in absence of obvious risk factors should raise the suspicion of underlying metabolic cause and prompt thorough evaluation . Nephrocalcinosis (NC) in presence of NL with or without renal dysfunction is an important clue of an underlying metabolic etiology . Detail biochemical evaluation including a 24 h urine sample lead to identification of underlying etiology in most of the metabolic causes. However, majority of these diseases are inherited and have an underlying monogenic mutation which not only establishes diagnosis unequivocally but also guide in specific management . A recent study identified pathogenic disease causing mutation in a single gene in 21% of 106 children with a previously undetermined etiology, indicating its potential clinical utility in the care of these patients . To date, more than 30 genes have been implicated in NL or NC, with autosomal-dominant, recessive, and X-linked inheritance . We aimed to analyze the utility of next generation sequencing (NGS) in diagnosing suspected genetic cause of NL and/or NC in western Indian children. Children under the age of 18 years with NL with or without NC, where a next NGS was sent from September 2016 to September 2020 were included for retrospective analysis after approval of institutional ethics committee. Five milliliters of blood in ethylenediaminetetraacetic acid were sent from the patient after obtaining written informed consent to Medgenome Labs Pvt. Ltd., a private commercial laboratory at Bengaluru, India. Demographic details, history of consanguinity, similar illness in family, early onset of end stage renal disease (ESRD), involvement

Türk Üroloji Dergisi/Turkish Journal of Urology, 2021

Objective: Nephrolithiasis results from metabolic and anatomic abnormalities together with genetic factors. Claudin 14 (CLDN14) is a protein that regulates the passage of small solutes through the kidneys. Alkaline phosphatase (ALPL) hydrolyzes the pyrophosphate to free phosphate, proposing its enabling role in nephrolithiasis development. Solute carrier family 13 member 2 (SLC13A2) encodes Na+-Pi cotransporter 2a, which is responsible for the renal absorption of phosphate. We aimed to detect the association between CLDN14, ALPL, and SLC13A2 genetic variants and susceptibility to nephrolithiasis in the Egyptian pediatric population. Material and methods: We enrolled 204 consecutive pediatric patients with nephrolithiasis, and 126 normal individuals served as controls. Real-time polymerase chain reaction analysis of CLDN14 rs219780, ALPL rs1256328, and SLC34A1 rs11746443 single-nucleotide polymorphisms (SNPs) was performed. Results: We found that individuals carrying the T allele of CLDN14 rs219780 and ALPL rs1256328 SNPs had a significantly higher risk of nephrolithiasis than the controls (p= 0.001 and 0.001, respectively). Genetic association analyses identified that CLDN14 rs219780 and ALPL rs1256328SNPs were significantly associated with the nephrolithiasis status (odds ratio [OR] =4.51; 95% confidence interval [CI]=2.758-7.374; p=0.001 and OR=6.088; 95% CI=3.651-10.152; p=0.001, respectively). The sequence variant ALPL rs1256328 T allele had a significant correlation with the increased serum alkaline phosphatase levels in children with nephrolithiasis (p= 0.02). No significant association was found between SLC34A1 rs11746443 SNP and the risk of nephrolithiasis (p=0.5). Conclusion: CLDN14 rs219780 and ALPL rs1256328 SNPs might raise the risk of nephrolithiasis in Egyptian children, and might be used as genetic markers in these patients.

Nutrients, 2022

Nephrolithiasis is an increasingly prevalent condition, especially in high income countries, and is associated with high morbidity. Extraordinary progress in genetics made the identification of genetic forms of nephrolithiasis possible. These genetic diseases are usually rare and do not account for the most common forms of nephrolithiasis that are the result of several factors such as environment, dietary habits, and predisposing genes. This knowledge has shaped what we classify as nephrolithiasis, a condition that is now recognized as systemic. How and to what extent all these factors interact with one another and end in kidney stone formation, growth, and recurrence is not completely understood. Two new research fields have recently been trying to give some answers: nutrigenomics and nutrigenetics. These fields have the aim of understanding the intricate diet/genome interface that influences gene expression regulation mainly through epigenetic mechanisms and results in specific medical conditions such as cancer, metabolic syndrome, and cardiovascular diseases. Epigenetics seems to play a crucial role and could represent the link between environmental factors, that we are constantly exposed to, and risk factors for nephrolithiasis. In this systematic review, we summarize all the available evidence of proven or hypothesized epigenetic mechanisms related to nephrolithiasis.

International Journal of Anthropology, 2004

BMC Medical Genomics

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.Val...

Kidney International, 2011