(Taken directly from the application) The overall goal of this project is to define the molecular genetic basis of the three sub-types of cystinuria and to determine relationships between gene defects and clinical symptoms. The project will test the hypothesis that the classical sub-types of cystinuria, based on physiological and biochemical determinations, have unique genetic origins involving mutations in different genes, and that the severity of cystinuria expressed is dependent upon which gene is mutated and the specific mutation within the gene. Mutations have been found in the SLC3A1 gene in about half of the patients with Type I cystinuria examined. The molecular defect(s) in Types II an III cystinuria are unknown.
Aim 1 will test the hypothesis that Type III cystinuria is due to mutations in the low affinity cystine transporter using positional cloning of chromosomal region 19q13 to identify the gene defect and expression screening of a renal cDNA library in Xenopus oocytes in order to clone the low affinity transporter in.
Aim 2 will test the hypothesis that Type II cystinuria is caused by mutations in the 50 kDa subunit of the high affinity cystine transporter using expression cloning in COS-7 cells transfected with the SLC3A1 gene to screen a renal cDNA library for the 50 kDa subunit.
Aim 3 will test the hypothesis that Type I cystinuria is the result of at least two gene defects, one of which is in the SLC3A1 gene which codes for a 78 kDa subunit of the high affinity transporter. We will screen the SLC3A1 gene to identify mutations using RNase cleavage assays and RFLP analysis followed by sequencing to characterize mutations. Type I cystinurics with no identified SLC3A1 mutations will be subjected to linkage studies to rule out involvement of the SLC3A1 gene locus, followed by a genome wide search to identify a new chromosomal locus.
Aim 4 will test the hypothesis that the pathophysiology of cystinuria can be predicted based solely upon genomic abnormalities and that this knowledge may be used as the basis for the formulation of therapeutic treatment.
| Xu, Li Hao Richie; Maalouf, Naim M (2017) Effect of acute hyperinsulinemia on magnesium homeostasis in humans. Diabetes Metab Res Rev 33: |
| Xu, Li Hao Richie; Adams-Huet, Beverley; Poindexter, John R et al. (2017) Temporal Changes in Kidney Stone Composition and in Risk Factors Predisposing to Stone Formation. J Urol 197:1465-1471 |
| Sakhaee, Khashayar; Poindexter, John; Aguirre, Crystal (2016) The effects of bariatric surgery on bone and nephrolithiasis. Bone 84:1-8 |
| Hu, Ming Chang; Shi, Mingjun; Cho, Han Jun et al. (2015) Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol 26:1290-302 |
| Hajibeigi, Asghar; Dioum, Elhadji M; Guo, Jianfei et al. (2015) Identification of novel regulatory NFAT and TFII-I binding elements in the calbindin-D28k promoter in response to serum deprivation. Biochem Biophys Res Commun 465:414-420 |
| Yoon, Vivienne; Adams-Huet, Beverley; Sakhaee, Khashayar et al. (2013) Hyperinsulinemia and urinary calcium excretion in calcium stone formers with idiopathic hypercalciuria. J Clin Endocrinol Metab 98:2589-94 |
| Capolongo, Giovanna; Abul-Ezz, Sameh; Moe, Orson W et al. (2012) Subclinical celiac disease and crystal-induced kidney disease following kidney transplant. Am J Kidney Dis 60:662-7 |
| Cameron, MaryAnn; Maalouf, Naim M; Poindexter, John et al. (2012) The diurnal variation in urine acidification differs between normal individuals and uric acid stone formers. Kidney Int 81:1123-30 |
| Sakhaee, Khashayar; Capolongo, Giovanna; Maalouf, Naim M et al. (2012) Metabolic syndrome and the risk of calcium stones. Nephrol Dial Transplant 27:3201-9 |
| Nguyen, Trang Q; Maalouf, Naim M; Sakhaee, Khashayar et al. (2011) Comparison of insulin action on glucose versus potassium uptake in humans. Clin J Am Soc Nephrol 6:1533-9 |
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