Late-onset manifestation of antenatal Bartter syndrome as a result of residual function of the mutated renal Na+-K+-2Cl- co-transporter.
Genetic defects of the Na+-K+-2Cl- (NKCC2) sodium potassium chloride co-transporter result in severe, prenatal-onset renal salt wasting accompanied by polyhydramnios, prematurity, and life-threatening hypovolemia of the neonate (antenatal Bartter syndrome or hyperprostaglandin E syndrome). Herein are described two brothers who presented with hyperuricemia, mild metabolic alkalosis, low serum potassium levels, and bilateral medullary nephrocalcinosis at the ages of 13 and 15 yr. Impaired function of sodium chloride reabsorption along the thick ascending limb of Henle's loop was deduced from a reduced increase in diuresis and urinary chloride excretion upon application of furosemide. Molecular genetic analysis revealed that the brothers were compound heterozygotes for mutations in the SLC12A1 gene coding for the NKCC2 co-transporter. Functional analysis of the mutated rat NKCC2 protein by tracer-flux assays after heterologous expression in Xenopus oocytes revealed significant residual transport activity of the NKCC2 p.F177Y mutant construct in contrast to no activity of the NKCC2-D918fs frameshift mutant construct. However, coexpression of the two mutants was not significantly different from that of NKCC2-F177Y alone or wild type. Membrane expression of NKCC2-F177Y as determined by luminometric surface quantification was not significantly different from wild-type protein, pointing to an intrinsic partial transport defect caused by the p.F177Y mutation. The partial function of NKCC2-F177Y, which is not negatively affected by NKCC2-D918fs, therefore explains a mild and late-onset phenotype and for the first time establishes a mild phenotype-associated SLC12A1 gene mutation.
Pressler
Carsten A
CA
Department of Pediatrics, Philipps University of Marburg, Marburg, Germany.
Heinzinger
Jolanta
J
Jeck
Nikola
N
Waldegger
Petra
P
Pechmann
Ulla
U
Reinalter
Stephan
S
Konrad
Martin
M
Beetz
Rolf
R
Seyberth
Hannsjörg W
HW
Waldegger
Siegfried
S
D000293:Adolescent; D017668:Age of Onset; D000818:Animals; D001477:Bartter Syndrome / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D003001:Cloning, Molecular; D004232:Diuretics / Q000494:pharmacology; D005260:Female; D005665:Furosemide / Q000494:pharmacology; D006579:Heterozygote; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008845:Microinjections; D008954:Models, Biological; D020125:Mutation, Missense; D009865:Oocytes / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D020539:Sequence Analysis, Protein; D035781:Siblings; D028021:Sodium-Potassium-Chloride Symporters / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D064466:Solute Carrier Family 12, Member 1; D013997:Time Factors; D014982:Xenopus laevis
D002712:Chlorides; D004232:Diuretics; C578714:SLC12A1 protein, human; C578716:Slc12a1 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D005665:Furosemide