Genetic, pathophysiological, and clinical aspects of nephrocalcinosis

Oliveira, Ben; Kleta, Robert; Böckenhauer, Detlef; Walsh, Stephen B.

doi:10.1152/ajprenal.00211.2016

Cited by 47 publications

(52 citation statements)

References 109 publications

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“…Cortical nephrocalcinosis, the rarer type, occurs after necrosis or glomerulonephritis and is usually microscopic and therefore remains undetectable on imaging. Medullary nephrocalcinosis, the more common type, particularly in children, is usually the result of genetic conditions of the renal tubules such as hypercalciuria, renal tubular acidosis, Löwe Syndrome, Dent Disease, and so on [27]. Nephrocalcinosis requires nephrology follow-up, since renal function may deteriorate [28].…”

Section: Discussionmentioning

confidence: 99%

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Nephrocalcinosis in Amelogenesis Imperfecta Caused by the FAM20A Mutation

Koruyucu

Seymen

Gençay

et al. 2018

Nephron

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Background/Aims: Enamel-renal syndrome is characterized by nephrocalcinosis, enamel defects, gingival hyperplasia and eruption failures. It has been recently identified that recessive mutations in the FAM20A gene result in amelogenesis imperfecta (AI)-gingival fibromatosis. The aim of this research to determine whether AI patients with known FAM20A mutations also have nephrocalcinosis. Methods: Complete oral and radiological examinations were performed for all participating family members. Renal examinations were performed using ultrasound. Results: The teeth were evaluated for severe loss, and multiple eruption failures were evident from the clinical and radiological examinations. Unexpected extensive and fast crown resorption was found by radiological examination. Renal ultrasound revealed bilateral nephrocalcinosis in both affected individuals. Recessive FAM20A mutations can cause nephrocalcinosis in addition to the oral phenotype. Conclusion: AI patients with similar clinical phenotypes and FAM20A mutations should be examined for nephropathy even if they lack pertinent symptoms. Nephrology referral is warranted for patients who have clinical phenotypes related to AI-gingival fibromatosis even if they are not symptomatic.

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Section: Discussionmentioning

confidence: 99%

“…Hypercalciuria is expected to cause stone formation, but patients with enamel-renal syndrome usually have hypocalciuria rather than hypercalciuria [27]. …”

Section: Discussionmentioning

confidence: 99%

Nephrocalcinosis in Amelogenesis Imperfecta Caused by the FAM20A Mutation

Koruyucu

Seymen

Gençay

et al. 2018

Nephron

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“…Moreover, studies of families with rare monogenic disorders associated with hypercalciuric NL and NC, such as Bartter's syndrome, Dent's disease, autosomal dominant hypocalcaemia, and distal renal tubular acidosis, have identified mutations in >30 genes involved in the regulation of calcium transport (Supplemental Table S1) . Furthermore, genome‐wide association studies and targeted sequencing of genes with known roles in calcium and vitamin D metabolism have reported associations for NL and NC with common sequence variants in >10 additional genes (Supplemental Table S1) . However, these account for only ∼15% to 20% of cases, and the identification of further monogenic causes of NL and NC are limited by the availability of large families.…”

Section: Introductionmentioning

confidence: 99%

“…(3,13,14) Furthermore, genome-wide association studies and targeted sequencing of genes with known roles in calcium and vitamin D metabolism have reported associations for NL and NC with common sequence variants in >10 additional genes ( Supplemental Table S1). (2,(15)(16)(17) However, these account for only $15% to 20% of cases, (3,13) and the identification of further monogenic causes of NL and NC are limited by the availability of large families. To overcome this and to facilitate further positional cloning studies to discover other genes regulating renal calcification, we undertook an X-ray screen of first-generation (G1) offspring of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU), (18) for renal opacities, with the aim of identifying mice with renal calcium deposits, as calcium-containing stones are the most common type of kidney stones.…”

Section: Introductionmentioning

confidence: 99%

Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis

Gorvin

Loh

Stechman

et al. 2019

Journal of Bone and Mineral Research

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Nephrolithiasis (NL) and nephrocalcinosis (NC), which comprise renal calcification of the collecting system and parenchyma, respectively, have a multifactorial etiology with environmental and genetic determinants and affect ∼10% of adults by age 70 years. Studies of families with hereditary NL and NC have identified >30 causative genes that have increased our understanding of extracellular calcium homeostasis and renal tubular transport of calcium. However, these account for <20% of the likely genes that are involved, and to identify novel genes for renal calcification disorders, we investigated 1745 12‐month‐old progeny from a male mouse that had been treated with the chemical mutagen N‐ethyl‐N‐nitrosourea (ENU) for radiological renal opacities. This identified a male mouse with renal calcification that was inherited as an autosomal dominant trait with >80% penetrance in 152 progeny. The calcification consisted of calcium phosphate deposits in the renal papillae and was associated with the presence of the urinary macromolecules osteopontin and Tamm‐Horsfall protein, which are features found in Randall's plaques of patients with NC. Genome‐wide mapping located the disease locus to a ∼30 Mbp region on chromosome 17A3.3‐B3 and whole‐exome sequence analysis identified a heterozygous mutation, resulting in a missense substitution (Met149Thr, M149T), in the bromodomain‐containing protein 4 (BRD4). The mutant heterozygous (Brd4+/M149T) mice, when compared with wild‐type (Brd4+/+) mice, were normocalcemic and normophosphatemic, with normal urinary excretions of calcium and phosphate, and had normal bone turnover markers. BRD4 plays a critical role in histone modification and gene transcription, and cDNA expression profiling, using kidneys from Brd4+/M149T and Brd4+/+ mice, revealed differential expression of genes involved in vitamin D metabolism, cell differentiation, and apoptosis. Kidneys from Brd4+/M149T mice also had increased apoptosis at sites of calcification within the renal papillae. Thus, our studies have established a mouse model, due to a Brd4 Met149Thr mutation, for inherited NC. © 2019 American Society for Bone and Mineral Research.

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“…Studies of families with rare monogenic disorders associated with hypercalciuric nephrolithiasis and/or nephrocalcinosis, such as Bartter syndrome, Dent disease, autosomal dominant hypocalcaemia, and distal renal tubular acidosis have identified mutations in >30 genes involved in calcium transport regulation (Supporting Table 1) . Furthermore, genomewide association studies and targeted sequencing of genes with known roles in calcium and vitamin D metabolism have identified associations between nephrolithiasis and common sequence variants in >10 additional genes (Supporting Table 1) . However, these account for only ∼15% to 20% of cases, and the identification of further monogenic causes of nephrolithiasis are limited by the unavailability of large families.…”

Section: Introductionmentioning

confidence: 99%

An N-Ethyl-N-Nitrosourea (ENU)-Induced Tyr265Stop Mutation of the DNA Polymerase Accessory Subunit Gamma 2 (Polg2) Is Associated With Renal Calcification in Mice

Gorvin

Ahmad

Stechman

et al. 2018

Journal of Bone and Mineral Research

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Renal calcification (RCALC) resulting in nephrolithiasis and nephrocalcinosis, which affects ∼10% of adults by 70 years of age, involves environmental and genetic etiologies. Thus, nephrolithiasis and nephrocalcinosis occurs as an inherited disorder in ∼65% of patients, and may be associated with endocrine and metabolic disorders including: primary hyperparathyroidism, hypercalciuria, renal tubular acidosis, cystinuria, and hyperoxaluria. Investigations of families with nephrolithiasis and nephrocalcinosis have identified some causative genes, but further progress is limited as large families are unavailable for genetic studies. We therefore embarked on establishing mouse models for hereditary nephrolithiasis and nephrocalcinosis by performing abdominal X‐rays to identify renal opacities in N‐ethyl‐N‐nitrosourea (ENU)‐mutagenized mice. This identified a mouse with RCALC inherited as an autosomal dominant trait, designated RCALC type 2 (RCALC2). Genomewide mapping located the Rcalc2 locus to a ∼16‐Mbp region on chromosome 11D‐E2 and whole‐exome sequence analysis identified a heterozygous mutation in the DNA polymerase gamma‐2, accessory subunit ( Polg2 ) resulting in a nonsense mutation, Tyr265Stop (Y265X), which co‐segregated with RCALC2. Kidneys of mutant mice ( Polg2 + / Y265X ) had lower POLG2 mRNA and protein expression, compared to wild‐type littermates ( Polg2 +/+ ). The Polg2 +/Y265X and Polg2 + / + mice had similar plasma concentrations of sodium, potassium, calcium, phosphate, chloride, urea, creatinine, glucose, and alkaline phosphatase activity; and similar urinary fractional excretion of calcium, phosphate, oxalate, and protein. Polg2 encodes the minor subunit of the mitochondrial DNA (mtDNA) polymerase and the mtDNA content in Polg2 + / Y265X kidneys was reduced compared to Polg2 +/+ mice, and cDNA expression profiling revealed differential expression of 26 genes involved in several biological processes including mitochondrial DNA function, apoptosis, and ubiquitination, the complement pathway, and inflammatory pathways. In addition, plasma of Polg2 + / Y265X mice, compared to Polg2 + / + littermates had higher levels of reactive oxygen species. Thus, our studies have identified a mutant mouse model for inherited renal calcification associated with a Polg2 nonsense mutation. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

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Genetic, pathophysiological, and clinical aspects of nephrocalcinosis

Cited by 47 publications

References 109 publications

Nephrocalcinosis in Amelogenesis Imperfecta Caused by the <b><i>FAM20A</i></b> Mutation

Nephrocalcinosis in Amelogenesis Imperfecta Caused by the <b><i>FAM20A</i></b> Mutation

Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis

An N-Ethyl-N-Nitrosourea (ENU)-Induced Tyr265Stop Mutation of the DNA Polymerase Accessory Subunit Gamma 2 (Polg2) Is Associated With Renal Calcification in Mice

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