Monogenic causes account for up to 20% of nephrolithiasis instances and are crucial for developing targeted treatments. Whole-exome sequencing, genome-wide association, candidate gene, and in vitro and animal functional studies are crucial to identify these mutations. Therapies targeting monogenic variants, such as RNA-interference-based treatments, have been successfully used to treat monogenic disorders.
Nephrolithiasis is a complex disease characterized by a multifactorial aetiology encompassing genetic, biological, environmental and behavioural factors1. Monogenic causes of nephrolithiasis have been comprehensively reviewed1, but new data emerged in this field in the past few years. Monogenic causes account for up to 20% of nephrolithiasis instances. Identifying monogenic causes is crucial for accurate diagnosis, personalized treatment strategies, risk assessment and advancements in both research and clinical care.
The most recently identified gene (2022) is OXGR1 (ref. 2), encoding 2-oxoglutarate receptor 1 (OXGR1), a cysteinyl leukotriene receptor, which is involved in the adaptive regulation of bicarbonate secretion and salt reabsorption in mouse kidneys undergoing acid–base stress. Rare and putatively deleterious variants of OXGR1 were identified in a worldwide cohort of 1,108 families with oxalate nephrolithiasis and nephrocalcinosis through whole-exome sequencing2. These putatively deleterious variants of OXGR1 were functionally validated in Xenopus oocytes, where the introduction of these variants resulted in an impairment of OXGR1 function assessed through an α-ketoglutarate-dependent Ca2+ uptake assay2.
Another gene, TRPV5, which was associated with hypercalciuria in two animal models, has been associated with nephrolithiasis also in humans. In a candidate gene association study involving a small cohort of 365 patients with kidney stones, a positive correlation was observed between a non-synonymous variant of TRPV5 and an increased risk of nephrolithiasis3.
Several genes that are well known to cause other monogenic diseases have been associated with nephrolithiasis. Pathogenic variants of WDR72 are responsible for amelogenesis imperfecta type IIA3 (OMIM no. 613211), characterized by abnormal enamel formation. A meta-analysis of genome-wide association studies (GWAS) using data in the UK Biobank and Biobank Japan showed an association between nephrolithiasis and single-nucleotide polymorphisms in WDR72. Additionally, in a Thai family with hereditary distal renal tubular acidosis (dRTA) and kidney stones, two novel missense variants of WDR72 were identified through whole-exome sequencing as the potential disease cause4.
Another example is FOXI1, pathogenic variants of which are well-known monogenic causes of enlarged vestibular aqueduct (OMIM no. 600791), a condition presenting with sensorineural hearing loss, vertigo and balance problems. Foxi1 deletion in mice caused sensorineural deafness and dRTA. These results prompted a candidate approach study in which two novel FOXI1 missense variants were identified in two families with dRTA, nephrocalcinosis and sensorineural deafness. In HEK 293T cells, a reduction in FOXI1 expression and a failure to maintain normal acid–base homeostasis were shown in cells transfected with these novel variants5.
Results from GWAS with replication studies have shown associations between nephrolithiasis and two genes known as monogenic disease causing, providing insights into novel potential roles of these genes. Pathogenic variants in BCAS3 are known monogenic causes of Hengel–Maroofian–Schols syndrome (OMIM no. 619641), characterized by severe global developmental delay, whereas pathogenic variants in CLDN14 are a monogenic cause of deafness (OMIM no. 614035). Results from GWAS in two human biorepositories showed that common single-nucleotide polymorphisms in both BCAS3 and CLDN14 are associated with nephrolithiasis4.
Lastly, three genes, namely PLAU, ORAI1 and MGP, were shown to be associated with nephrolithiasis through a candidate-gene approach. PLAU, which encodes a protein involved in tissue remodelling and cell migration, is a monogenic gene causing Quebec platelet disorder (OMIM no. 601709). ORAI1 has a role in calcium influx into T cells, and pathogenic variants in the encoding gene cause monogenic myopathy (OMIM no. 615883) and immunodeficiency (OMIM no. 612782). MGP encodes a physiological inhibitor of ectopic tissue calcification, and pathogenic variants of MGP cause Keutel syndrome (OMIM no. 245150), characterized by abnormal diffuse cartilage calcification. Pathogenic variants in these genes have been identified to be associated with nephrolithiasis in humans through candidate-gene approaches6,7,8.
Identifying monogenic causes of nephrolithiasis offers valuable insights into the fundamental mechanism of this disease and also enables the development of precise interventions and therapies. Successful drug targets have been found based on the identification of monogenic causes of disease. Two examples in a monogenic kidney stone disease (primary hyperoxaluria) are the RNA-interference-based therapies lumasiran and nedosiran.
Primary hyperoxaluria type 1 (PH1) is a monogenic disorder, caused by defective AGXT and characterized by the overproduction of oxalate by the liver, leading to the formation of kidney stones, nephrocalcinosis and end-stage kidney disease1. One of the biochemical genetic pathways that leads to oxalate stone formation involves HAO1, which encodes glycolate oxidase (GO). GO catalyses the conversion of glycolate to glyoxylate in the hepatocyte peroxisomes, which is the direct precursor of oxalate.
Lumasiran is a double-stranded small interfering RNA that targets HAO1, which in turn prevents the translation of the enzyme GO, resulting in the reduction of oxalate production9. Results from clinical trials have shown that lumasiran reduces urinary oxalate excretion and plasma oxalate levels in patients with PH1, with many patients achieving normalized urinary oxalate levels10. Lumasiran was approved by the FDA in November 2020 for the treatment of PH1.
Nedosiran is also a small interfering RNA and targets the mRNA of LDHA, in turn inhibiting the production of l-lactate dehydrogenase A (LDHA), an enzyme involved in converting glyoxylate into oxalate10. Results from clinical trials have shown reduced urinary oxalate levels in patients with PH1 receiving nedosiran10, which was approved by the FDA for PH1 treatment in September 2023.
In summary, identifying monogenic causes of diseases, including kidney stone diseases, is of crucial importance. The identification of specific gene and pathogenic variants associated with nephrolithiasis offers valuable insights into the fundamental mechanisms and biochemical pathways resulting in disease onset and progression. Understanding these mechanisms enables the development of precise interventions and therapies, such as the two RNA-interference-based therapies lumasiran and nedosiran. Unravelling the genetic landscape of kidney stone diseases is an ongoing process, demanding persistent research endeavours to understand mechanisms of nephrolithiasis and further expand the individualized treatment potential for this condition.
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- Source: https://www.nature.com/articles/s41585-024-00880-0