NDT Advance Access published online on July 12, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn386
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Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion
1 Department of Genetics, Faculty of Medical Sciences, New University of Lisbon 2 Department of Nephrology, Hospital Curry Cabral, Lisbon, Portugal 3 Unité de Génétique Clinique Pédiatrique, Hôpital Universitaire des Enfants Reine Fabiola et Centre de Génétique Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium 4 Pediatric Endocrinology, BC Children's Hospital, Vancouver, BC, Canada 5 Division of Nephrology, Mayo Clinic, Rochester, MN, USA 6 First Department of Pediatrics, University of Athens, School of Medicine, ‘Agia Sofia’ Children's Hospital, Athens, Greece 7 Department of Pediatric Endocrinology, Diabetes Center, Curitiba, Brazil 8 Department of Pediatric Nephrology, University Children's Hospital, Skopje, Former Yugoslavian Republic of Macedonia 9 Department of Pediatrics, University of Heidelberg, Heidelberg 10 Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Correspondence and offprint requests to: Joaquim Calado, Departamento de Genética da Faculdade de Ciências Médicas, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Junqueira no. 96, 1349-008, Lisbon, Portugal. Tel: +351-2136-10297; Fax: +351-2136-22018; E-mail: jcalado.gene{at}fcm.unl.pt
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Abstract |
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Introduction. Familial renal glucosuria (FRG) is a rare renal tubular disorder caused by mutations within the SLC5A2 gene. It is characterized by persistent glucosuria in the absence of hyperglycaemia and any other signs of generalized tubular dysfunction. In small series of patients previously reported, the molecular and phenotypic findings in FRG families, including first hints of extracellular volume depletion and activation of the renin–angiotensin–aldosterone system induced by natriuresis, have been described. We have now extended this analysis to another 21 consecutive cases from 17 pedigrees, including 11 cases with severe glucose excretion.
Methods. Mutation analysis was performed by direct sequencing of the genomic coding segments of the SLC5A2 gene. In two cases with severe glucosuria, basal plasma renin activity and serum aldosterone concentrations were determined.
Results. Within the 17 pedigrees, we have identified a total of 20 different SLC5A2 mutations. Fifteen have not been previously reported. In all glucosuric individuals tested, at least one SLC5A2 mutation could be identified. Heterozygous individuals were found to have only mild glucose excretion whereas homozygous or compound heterozygous patients had severe glucosuria, ranging from 10 to 86.5 g/1.73 m2/24 h. In two patients of the latter group, basal plasma renin activity and serum aldosterone concentration were determined and found to be raised to an average of 4.6-fold and 3.1-fold of the upper limit of the normal range, respectively.
Discussion. The identification of at least one mutated allele in every affected individual in this cohort of 17 consecutively investigated families strongly suggests that genetic heterogeneity is not prevalent in FRG. Although 5 of the detected alleles have been described previously, 15 are novel, confirming that most mutations in FRG are private. Our finding of an activation of compensatory mechanisms for salt loss may warrant more detailed studies of long-term hormonal and metabolic imbalances in patients with FRG.
Keywords: glucose; renal; SGLT2; sodium
Received for publication: 15. 4.08
Accepted in revised form: 18. 6.08