title: Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion.
abstract: BACKGROUND
  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 m(2)/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.
authors.affiliation: Departamento de Genética da Faculdade de Ciências Médicas, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal. jcalado.gene@fcm.unl.pt
authors.forename: Joaquim
authors.initials: J
authors.lastname: Calado
authors.forename: Yves
authors.initials: Y
authors.lastname: Sznajer
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Ana
authors.initials: A
authors.lastname: Rita
authors.forename: Marie C
authors.initials: MC
authors.lastname: Hogan
authors.forename: Antonis
authors.initials: A
authors.lastname: Kattamis
authors.forename: Mauro
authors.initials: M
authors.lastname: Scharf
authors.forename: Velibor
authors.initials: V
authors.lastname: Tasic
authors.forename: Johann
authors.initials: J
authors.lastname: Greil
authors.forename: Florian
authors.initials: F
authors.lastname: Brinkert
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Kemper
authors.forename: René
authors.initials: R
authors.lastname: Santer
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D004252:DNA Mutational Analysis; D005260:Female; D005947:Glucose; D006030:Glycosuria, Renal / Q000235:genetics* / Q000503:physiopathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D012084:Renin-Angiotensin System / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D051297:Sodium-Glucose Transporter 2 / Q000737:chemistry / Q000235:genetics*
chemical_list: D051297:Sodium-Glucose Transporter 2; D005947:Glucose