Fourteen Monogenic Genes Account for 15% of Nephrolithiasis/Nephrocalcinosis

Halbritter, Jan; Baum, Michelle A.; Hynes, Ann Marie; Rice, S.J.; Thwaites, David T.; Gucev, Zoran; Fisher, Brittany; Spaneas, Leslie; Porath, Jonathan D.; Braun, Daniela A.; Wassner, Ari J.; Nelson, Caleb P.; Tasić, Velibor; Sayer, John A.; Hildebrandt, Friedhelm

doi:10.1681/asn.2014040388

Cited by 172 publications

(206 citation statements)

References 31 publications

(32 reference statements)

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“…According to the Online Mendelian Inheritance in Man (OMIM) database, mutations in at least 30 genes can cause monogenic forms of NL/NC by autosomal recessive, autosomal dominant, or X-linked transmission. Recently, we studied 166 adults and 106 children with NC or NL and detected causative mutations in 11.4% of adult and 20.8% of early-onset cases (4). This result confirmed a significant occurrence of heritable NL/NC, while also indicating that there are additional unidentified monogenic causes of NL/NC.…”

Section: Introductionsupporting

confidence: 53%

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Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis

Braun¹,

Lawson²,

Gee

et al. 2016

Clinical Journal of the American Society of Nephrology

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107

103

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Background and objectives Nephrolithiasis is a prevalent condition that affects 10%-15% of adults in their lifetime. It is associated with high morbidity due to colicky pain, the necessity for surgical intervention, and sometimes progression to CKD. In recent years, multiple monogenic causes of nephrolithiasis and nephrocalcinosis have been identified. However, the prevalence of each monogenic gene in a pediatric renal stone cohort has not yet been extensively studied.Design, setting, participants, & measurements To determine the percentage of cases that can be explained molecularly by mutations in one of 30 known nephrolithiasis/nephrocalcinosis genes, we conducted a high-throughput exon sequencing analysis in an international cohort of 143 individuals ,18 years of age, with nephrolithiasis (n=123) or isolated nephrocalcinosis (n=20). Over 7 months, all eligible individuals at three renal stone clinics in the United States and Europe were approached for study participation.Results We detected likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 16.8% (24 of 143) of affected individuals; 12 of the 27 detected mutations were not previously described as disease causing (44.4%). We observed that in our cohort all individuals with infantile manifestation of nephrolithiasis or nephrocalcinosis had causative mutations in recessive rather than dominant monogenic genes. In individuals who manifested later in life, causative mutations in dominant genes were more frequent. ConclusionsWe present the first exclusively pediatric cohort examined for monogenic causes of nephrolithiasis/ nephrocalcinosis, and suggest that important therapeutic and preventative measures may result from mutational analysis in individuals with early manifestation of nephrolithiasis or nephrocalcinosis.

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Section: Introductionsupporting

confidence: 53%

“…After obtaining informed consent, clinical data, pedigree information, and DNA samples were collected from 143 individuals. All individuals were recruited after the conclusion of the study of Halbritter et al (4), thereby excluding enrollment overlap between the two studies. The cohort consisted of 72 male and 71 female participants.…”

Section: Study Cohortmentioning

confidence: 99%

Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis

Braun¹,

Lawson²,

Gee

et al. 2016

Clinical Journal of the American Society of Nephrology

Self Cite

107

103

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“…Of note, the p.Val91_Ala97del had been identified previously by Lapointe et al [8], and suggested to be non-pathogenic whereas no information is available on the functional consequences of the p.Arg512Cys mutation [12]. lead to the observed reduced apparent affinity for P i .…”

Section: Discussionmentioning

confidence: 94%

“…al. reported that out of 272 kidney stone patients screened for mutations in 30 genes suspected to be associated with kidney stones, one patient was found with compound heterozygous mutations in slc34a1 [12]. Finally, Schlingmann et.…”

Section: Introductionmentioning

confidence: 99%

Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency

et al. 2016

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BACKGROUND Inherited metabolic disorders associated with nephrocalcinosis are rare conditions. The aim of this study was to identify the genetic cause of an Israeli-Arab boy from a consanguineous family with severe nephrocalcinosis and kidney insufficiency. METHODS Clinical and biochemical data of the proband and family members were obtained from both previous and recent medical charts. Genomic DNA was isolated from peripheral blood cells. The coding sequence and splice sites of candidate genes (CYP24A1, CYP27B1, FGF23, KLOTHO, SLC34A3 and SLC34A1) were sequenced directly. Functional studies were performed in Xenopus laevis oocytes and in transfected opossum kidney (OK) cells. RE-SULTS Our patient was identified as having nephrocalcinosis in utero, and at the age of 16.5 years, he had kidney insufficiency but no bone disease. Genetic analysis revealed a novel homozygous missense mutation, Arg215Gln, in SLC34A1, which encodes the renal sodium phosphate cotransporter NaPiIIa. Functional studies of the Arg215Gln mutant revealed reduced transport activity in Xenopus laevis oocytes and increased intracellular cytoplasmic accumulation in OK cells. CONCLUSIONS Our findings show that dysfunction of the human NaPiIIa causes severe renal calcification that may eventually lead to reduced kidney function, rather than complications of phosphate loss.

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“…A subset of USD, such as primary hyperoxaluria and cystinuria, results from monogenic conditions; $30 genes exist in which mutations result in monogenic forms of USD and/or related conditions, such as nephrocalcinosis (19,20). USD unrelated to these mutations also seems to have a marked genetic component.…”

Section: Determinants Geneticsmentioning

confidence: 99%

Urinary Stone Disease: Advancing Knowledge, Patient Care, and Population Health

Scales

Tasian

Schwaderer

et al. 2016

CJASN

119

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Expanding epidemiologic and physiologic data suggest that urinary stone disease is best conceptualized as a chronic metabolic condition punctuated by symptomatic, preventable stone events. These acute events herald substantial future chronic morbidity, including decreased bone mineral density, cardiovascular disease, and CKD. Urinary stone disease imposes a large and growing public health burden. In the United States, 1 in 11 individuals will experience a urinary stone in their lifetime. Given this high incidence and prevalence, urinary stone disease is one of the most expensive urologic conditions, with health care charges exceeding $10 billion annually. Patient care focuses on management of symptomatic stones rather than prevention; after three decades of innovation, procedural interventions are almost exclusively minimally invasive or noninvasive, and mortality is rare. Despite these advances, the prevalence of stone disease has nearly doubled over the past 15 years, likely secondary to dietary and health trends. The NIDDK recently convened a symposium to assess knowledge and treatment gaps to inform future urinary stone disease research. Reducing the public health burden of urinary stone disease will require key advances in understanding environmental, genetic, and other individual disease determinants; improving secondary prevention; and optimal population health strategies in an increasingly cost-conscious care environment.

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Fourteen Monogenic Genes Account for 15% of Nephrolithiasis/Nephrocalcinosis

Cited by 172 publications

References 31 publications

Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis

Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis

Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency

Urinary Stone Disease: Advancing Knowledge, Patient Care, and Population Health

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