The hereditary component of nephrolithiasis is a complex polygenic trait which is a formidable challenge to unravel. The study of monogenic causes of nephrolithiasis has been most informative in uncovering genetic components of nephrolithiasis. Calcareous stones are common in patients with congenital distal renal tubular acidosis :dRTA;but sd RcoTnAs idered a very rare cause of calcium stones due to the low prevalence of the disease. Congenital dRTA is a disease of renal acidification caused by mutations in either the vacuolar :VPa;se-A T :B1 or a4 subunit;, anion exchanger-1, or carbonic anhydrase II. This proposal focuses on the B1 subunit of the V-ATPase. The heterozygous carrier state is universaly believed to be silent. The mechanisms by which a mutant B1 subunit cause pump dysfunction is not well understood. We will test 3 hypotheses in this proposal: I. Heterozygous mutations of B1 are not rare in the stone forming population. II. The burden of heterozygosity is not silent but confers propensity for or affliction by calcium phosphate or oxalate nephrolithiasis. III. Mutant B1 subunits cause pump dysfunction by multiple mechanisms such as defective pump assembly, impaired ATP binding/hydrolysis, and deranged coupling to HE translocation. We will test these hypotheses with 3 Aims: 1. Population-based studies: Define the allele frequency of all base changes in B1 in the stone forming and non-stone forming population and collect the corresponding clinical data of these individuals. 2. Inpatient human studies: Perform detailed metabolic and physicochemical studies of selected individuals heterozygous for B1 to characterize their phenotype. 3. Bench studies: Define the mechanisms of how various mutant B1 subunits cause HE pump dysfunction using cell biology and biochemistry. This is not a study of classical dRTA. Instead we may be able to prove that monogenic predisposition is actually not rare in the general stone-forming population and many stone formers may harbor B1 mutations that predispose them to calcium stones. This may set precedence, for other monogenic predispositions in the general stone forming population. These studies will also significantly advance the understanding of V-ATPase biology. These natural point mutations and their cognate mode of dysfunction will provide valuable structure-function information on the biology of the B1 protein.
Each human has a 10-20% chance of getting a kidney stone in his or her lifetime. If a person has a family member with kidney stones, that individual has a higher risk of getting kidney stones. This process can involve many genes but there are circumstances where single genes can put a person at risk for kidney stones such as in a condition is distal renal tubular acidosis (abbreviated as dRTA). Most patients with dRTA get calcium kidney stones, but most patients with calcium kidney stones do not have dRTA. This proposal examines some new ideas. Based on our work in the last year, we believe that a milder form of dRTA where one inherits one instead of two defective genes, termed """"""""heterozygous state"""""""" may be quite common in the general population of calcium kidney stones formers. The gene in question codes for a protein called """"""""B1"""""""" which in its abnormal state will change the composition in the urine resulting in kidney stone formation. We will use human population and laboratory studies to answer three questions. 1. Exactly how common are abnormal B1 in a heterozygous state in people with calcium kidney stones? 2. If one carries an abnormal copy of B1 (the heterozygous state), what exactly are the abnormalities in the urine that predispose that person to having kidney stones? 3. How does an abnormal B1 change the composition of our urine so kidney stones will form? These questions, when answered, help us understand the hereditary component of kidneys stones and how abnormalities in single proteins, such as B1, will change our urine composition in an unfavorable way allowing allow us to better predict, diagnose, and treat kidney stones.
| Benias, Petros C; Wells, Rebecca G; Sackey-Aboagye, Bridget et al. (2018) Structure and Distribution of an Unrecognized Interstitium in Human Tissues. Sci Rep 8:4947 |
| Zhang, Jianning; Fuster, Daniel G; Cameron, Mary Ann et al. (2014) Incomplete distal renal tubular acidosis from a heterozygous mutation of the V-ATPase B1 subunit. Am J Physiol Renal Physiol 307:F1063-71 |
| Di Sole, Francesca; Vadnagara, Komal; Moe, Orson W et al. (2012) Calcineurin homologous protein: a multifunctional Ca2+-binding protein family. Am J Physiol Renal Physiol 303:F165-79 |
| Sakhaee, Khashayar; Capolongo, Giovanna; Maalouf, Naim M et al. (2012) Metabolic syndrome and the risk of calcium stones. Nephrol Dial Transplant 27:3201-9 |
| Maalouf, Naim M; Moe, Orson W; Adams-Huet, Beverley et al. (2011) Hypercalciuria associated with high dietary protein intake is not due to acid load. J Clin Endocrinol Metab 96:3733-40 |
| Huang, Chou-Long; Moe, Orson W (2011) Klotho: a novel regulator of calcium and phosphorus homeostasis. Pflugers Arch 462:185-93 |
| Moe, Orson W; Pearle, Margaret S; Sakhaee, Khashayar (2011) Pharmacotherapy of urolithiasis: evidence from clinical trials. Kidney Int 79:385-92 |
| Hu, Ming-Chang; Kuro-o, Makoto; Moe, Orson W (2010) Klotho and kidney disease. J Nephrol 23 Suppl 16:S136-44 |
