Research Center for Genetic Engineering and Biotechnology Georgi
Research Center for Genetic Engineering and Biotechnology “Georgi D. Efremov”, MASA CYSTINURIA Genetic testing: Important points: Cystinuria is an autosomal recessive disorder that is characterized by an impaired transport of cystine, ornithine, lysine and arginine in the proximal renal tubule and in the epithelial cells of the gastrointestinal tract that leads in an elevated urine concentration of these amino acids. High concentration of cystine in the urinary tract leads to the formation of cystine calculi in the kidneys due to low solubility of cystine in acidic environment. Clinically, cystinuria is divided into two types: • Type I cystinuria – heterozygotes have normal excretion of cystine and dibasic amino acids, which implies that the disease is inherited autosomal-recessive, • Non-type I cystinuria - heterozygotes shows different levels of urinary hyperexcretion of cystine and dibasic amino acids, which implies that the disease is inherited autosomal-dominant with incomplete penetrance for cystine lithiasis. More than 130 and 90 mutations in SLC 3 A 1 and SLC 7 A 9 genes have been identified, respectively. There are several most common cystinuria mutations in south-eastern European countries. These are T 216 M, M 467 T, R 365 L in SLC 3 A 1 gene and G 105 R in SLC 7 A 9 gene. Cystinuria mutations are specific for certain ethnic groups. Importance of molecular testing: Determinination of the molecular defect confirms the disease. Determination of cystinuria-carrier status in individuals with a family history of cystinuria enables evaluation of the risk of having child with cystinuria. Material for testing Genetics / Inheritance pathways: Two genes responsible for cystinuria have been identified: SLC 3 A 1 gene – located on 2 p 16. 3 -21 and SLC 7 A 9 gene – located on 19 q 12 -13. 1. These genes encodes the subunits of r. BAT/b 0+AT transporter of cystine and dibasic amino acids. Based to the gene that is affected, cystinuria is divided into: • Type A cystinuria – homozygotes/compound heterozygotes for mutation in SLC 3 A 1 gene, • Type B cystinuria – homozygotes/compound heterozygotes for mutation in SLC 7 A 9 gene, • Type AB cystinuria – one mutation in SLC 3 A 1 gene and one mutation in SLC 7 A 9 gene. This cystinuria type is very rare, and probands manifest as heterozygotes for type B cystinuria. Whole blood specimens in sterile tubes with anticoagulant EDTA from the affected child and the parents. Urine samples for amino acid analysis from the affected child and the parents. Analysеs performed at RCGEB Cystinuria is characterized both on biochemical and genetic level. Amino acid analyses of cystine and dibasic amino acids (lysine, ornithine and arginine) are performed on Biochrom 30 Amino acid analyzer. Determination of the genetic defect responsible for cystinura at RCGEB is performed by sequencing analysis of the SLC 3 A 1 and SLC 7 A 9 genes. . CYSTINURIA tests performed at RCGEB Price (МКД) Determining the genetic defect in SLC 3 A 1 gene in patients with cystinuria using DNA sequencing method 25. 000 Determining the genetic defect in SLC 7 A 9 gene in patients with cystinuria using DNA sequencing method 25. 000 Carrier detection in a families with known gene defect 10. 550 Amino acid analysis 6. 100 References: 1. Online Mendelian Inheritance in Man, http: //www. ncbi. nlm. nih. gov/omim; No: # 220100 и # 104614 (Cystinuria type A) и #604144 (Cystinuria type B) 2. Segal, S. , Thier, S. O. (1989): Cystinuria, In: The metabolic bases of inherited disease. 6 th edition. Edited by Scriver, C. R. , Beaudet, A. L. , Sly, W. S. , Valle, D. New York, Mc. Graw-Hill Book Co. 2479 -2496. 3. International Cystinuria Consortium. (1999): Non-type I cystinuria caused by mutations in SLC 7 A 9, edcoding a subunit (b 0, +AT) of r. BAT. Nat. Genet. , 23, 52 -57. 4. Popovska-Jankovic et al. (2013): Molecular characterization of cystinuria in south-eastern European countires. Urolithiasis, 41(1): 21 -30. RCGEB, 2013
- Slides: 1