OXGR1 Is a Candidate Disease Gene for Human Calcium Oxalate Nephrolithiasis

Whole blood

Background: Genetic studies of families with IgA glomerulonephritis have implicated pathogenic variants in COL4A3-5 and SPRY2 but in few other genes.We have recently identified retinal drusen in IgA glomerulonephritis which is further evidence for complement activation.This study investigated familial IgA disease for pathogenic variants in five candidate gene lists including those reported in IgA nephropathy (102 genes), the complement system (56), drusen in macular degeneration (46), Alport syndrome (3) and FSGS (47).
Methods: Eight unrelated individuals with familial IgA nephropathy were recruited.Family members were examined for haematuria, proteinuria and eGFR.IgA nephropathy was biopsy-proven in the index case and some relatives.Whole exome sequencing of available members in each family was performed and variants curated using the GATK Best Practices pipeline.Variants were examined for a CADD score ≥10 and a minor allele frequency <0.05 in gnomAD, and pathogenic assessments made according to the ACMG criteria.Assessments included pathogenic features in in-silico prediction algorithms (≥2 of PolyPhen-2, SIFT, MutationTaster) and conservation of the affected residue in vertebrates (UCSC Genomics Institute).
Conclusions: Half the families with IgA nephropathy examined here had another explanation for their genetic kidney disease.Since IgA deposits occur in up to 20% of normal individuals, apparent familial IgA nephropathy may be secondary to another, concurrent, genetic kidney disease.

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Genetic Diseases: Diagnosis Introduction: Hypophosphatasia(HPP) is a rare inherited disorder caused by loss of function mutation of ALPL that encodes tissue nonspecific alkaline phosphate (TNSALP), characterized by impaired mineralization of bones and teeth in the presence of low activity of serum and bone alkaline phosphatase.Kidney stones and nephrocalcinosis have been reported in some cases and most of the stones are calcium containing.Late diagnosis of hypophosphatasia is not uncommon.Here we present a case of a new diagnosis of hypophosphatasia for a 61 year old man after passing pure potassium magnesium pyrophosphate pentahydrate stones, which is very rare.
Case Description: A 61-year-old with history of hypertension, diabetes, premature tooth loss, skeletal fractures and over 10 symptomatic nephrolithiasis since age 20 was sent for genetic evaluation.His most recent serum labs were relevant for creatinine 1.4 mg/dl, alkaline phosphatase (ALP) 6 U/L (40-130), bone specific ALP 1.6 µg/ml (6.5-20.1),vitamin B6 1,594.2nmol/L (20-125), PTH 39 pg/ml (15-65) and 25-vitamin D 69.6 ng/ml (31-80).Calcium and phosphate were within normal lab limits.Urines studies were unremarkable with 24-hour urine protein 480 mg, presumed to be related to diabetic nephropathy or possible tubular injury from recurrent nephrolithiasis.His most recent stone analysis showed 100% potassium magnesium pyrophosphate pentahydrate (PMPP).Family history was significant for short stature and a mechanical fall related wrist fracture in his mother, and kidney stones and color blindness in his 2 nephews.Genetic test showed two heterozygous pathogenic variants, c.1240C>A (p.Leu414Met) and c.407G>A (p.Arg136His), in the ALPL gene confirming the diagnosis of HPP.Parental testing is pending to clarify its inheritance pattern.The patient was started on recombinant human TNSALP.