title: Novel allelic variants and evidence for a prevalent mutation in URAT1 causing renal hypouricemia: biochemical, genetics and functional analysis.
abstract: Renal hypouricemia (RHUC) is a heterogeneous inherited disorder characterized by impaired tubular uric acid (UA) transport with severe complications, such as acute kidney injury (AKI). Type 1 is caused by a loss-of-function mutation in the SLC22A12 gene (URAT1), type 2 in the SLC2A9 gene (GLUT9). This article describes three Czech families with RHUC type 1. The serum UA in the probands was 0.9, 1.1 and 0.5 mg/dl and expressed as an increase in the fractional excretion of UA (48, 43 and 39%). The sequencing analysis of SLC22A12 revealed three novel variants: p.G366R, p.T467M and a deletion p.L415_G417del. A detailed metabolic investigation in proband C for progressive visual failure supported suspicion of neuronal ceroid lipofuscinosis type 7 conditioned by the mutation in the MFSD8 gene. Functional studies showed significantly decreased urate uptake and a mis-localized URAT1 signal in p.G366R, p.L415_G417del and p.T467M. Furthermore, colocalization studies showed accumulation of URAT1 protein in the endoplasmic reticulum. The findings suggest that loss-of-function mutations cause RHUC via loss of UA absorption partly by protein misfolding. However, they do not necessarily lead to AKI and a possible genotype-phenotype correlation was not proposed. Furthermore, results confirm an uneven geographical and ethnic distribution of SLC22A12 variants; the p.L415_G417del mutation predominates in the Roma ethnic group in the Czech Republic.
authors: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors: Blanka
authors: B
authors: Stiburkova
authors: Ivan
authors: I
authors: Sebesta
authors: Kimiyoshi
authors: K
authors: Ichida
authors: Makiko
authors: M
authors: Nakamura
authors: Helena
authors: H
authors: Hulkova
authors: Vladimir
authors: V
authors: Krylov
authors: Lenka
authors: L
authors: Kryspinova
authors: Helena
authors: H
authors: Jahnova
mesh_terms: D000042:Absorption; D058186:Acute Kidney Injury / Q000175:diagnosis / Q000209:etiology / Q000235:genetics; D000328:Adult; D000483:Alleles; D000818:Animals; D002648:Child; D018153:Czech Republic; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D006579:Heterozygote; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000175:diagnosis / Q000209:etiology / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D015499:Renal Tubular Transport, Inborn Errors / Q000150:complications / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D006178:Romani People / Q000235:genetics; D014527:Uric Acid / Q000652:urine; D014545:Urinary Calculi / Q000150:complications / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D014981:Xenopus
chemical_list: C522398:MFSD8 protein, human; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; D014527:Uric Acid
references: Am J Physiol. 1993 Oct;265(4 Pt 2):R934-42
references: 8238468
references: J Clin Endocrinol Metab. 2005 Apr;90(4):2169-74
references: 15634722
references: Hum Mol Genet. 2010 Jun 1;19(11):2321-30
references: 20197412
references: Clin Genet. 2008 Sep;74(3):243-51
references: 18492088
references: Neurol Sci. 2002 Oct;23(4):183-8
references: 12536287
references: Klin Wochenschr. 1989 Mar 1;67(5):308-12
references: 2709741
references: Ann Neurol. 2005 Nov;58(5):797-800
references: 16240356
references: Nature. 2002 May 23;417(6887):447-52
references: 12024214
references: J Am Soc Nephrol. 2010 Jan;21(1):64-72
references: 19926891
references: Mol Genet Metab. 2011 Apr;102(4):430-5
references: 21256783
references: Kidney Int. 2004 Sep;66(3):935-44
references: 15327384
references: Am J Hum Genet. 2008 Dec;83(6):744-51
references: 19026395
references: Hum Mol Genet. 2011 Oct 15;20(20):4056-68
references: 21768215
references: Nephrol Dial Transplant. 2011 Jul;26(7):2175-81
references: 21148271
references: Hypertension. 2002 Sep;40(3):355-60
references: 12215479
references: Am J Epidemiol. 1996 Sep 1;144(5):480-4
references: 8781463
references: Proc Natl Acad Sci U S A. 1981 Nov;78(11):6858-62
references: 6947260
references: Rheumatology (Oxford). 2007 Feb;46(2):215-9
references: 16837472
references: J Pharmacol Sci. 2010;114(1):115-8
references: 20736511
references: J Biol Chem. 2004 Apr 16;279(16):16229-36
references: 14739288
references: J Am Soc Nephrol. 2004 Jan;15(1):164-73
references: 14694169
references: Nephrol Ther. 2009 Nov;5(6):568-71
references: 19464979
references: Arthritis Rheum. 2006 Jan;54(1):292-300
references: 16385546
references: Curr Opin Rheumatol. 2007 Mar;19(2):151-7
references: 17278930
references: PLoS One. 2011;6(12):e28641
references: 22194875
references: Curr Pharm Des. 2005;11(32):4145-51
references: 16375736
references: Am J Nephrol. 2010;32(3):279-86
references: 20714133
references: Arthritis Rheum. 2005 Aug;52(8):2576-7
references: 16059895
references: Brain. 2009 Mar;132(Pt 3):810-9
references: 19201763
references: Cytogenet Cell Genet. 1995;70(1-2):92-4
references: 7736798
references: Pediatrics. 2011 Jun;127(6):e1621-5
references: 21536615
references: J Biol Chem. 2008 Oct 3;283(40):26834-8
references: 18701466
references: Pediatr Nephrol. 2012 Aug;27(8):1411-5
references: 22527535
references: Clin Chim Acta. 2008 Dec;398(1-2):157-8
references: 18760270
references: Clin Chim Acta. 2012 Jan 18;413(1-2):93-9
references: 21963464