RESUMEN
Kidney stones are a global health problem, incurring massive health costs annually. Why stones recur in many patients remains unknown but likely involves environmental, physiological, and genetic factors. The solute linked carrier (SLC) 26A1 gene has previously been linked to kidney stones in mice. SLC26A1 encodes the sulfate anion transporter 1 (SAT1) protein, and its loss in mice leads to hyperoxaluria and calcium oxalate renal stones. To investigate the possible involvement of SAT1 in human urolithiasis, we screened the SLC26A1 gene in a cohort of 13 individuals with recurrent calcium oxalate urolithiasis, which is the commonest type. DNA sequence analyses showed missense mutations in seven patients: one individual was heterozygous R372H; 4 individuals were heterozygous Q556R; one patient was homozygous Q556R; and one patient with severe nephrocalcinosis (requiring nephrectomy) was homozygous Q556R and heterozygous M132T. The M132 amino acid in human SAT1 is conserved with 15 other species and is located within the third transmembrane domain of the predicted SAT1 protein structure, suggesting that this amino acid may be important for SAT1 function. These initial findings demonstrate genetic variants in SLC26A1 of recurrent stone formers and warrant wider independent studies of SLC26A1 in humans with recurrent calcium oxalate stones.
Asunto(s)
Proteínas de Transporte de Anión/genética , Variación Genética , Cálculos Renales/genética , Adulto , Sustitución de Aminoácidos , Animales , Proteínas de Transporte de Anión/química , Proteínas de Transporte de Anión/deficiencia , Antiportadores/deficiencia , Antiportadores/genética , Secuencia de Bases , Oxalato de Calcio/química , Estudios de Cohortes , Análisis Mutacional de ADN , Frecuencia de los Genes , Heterocigoto , Homocigoto , Humanos , Cálculos Renales/química , Masculino , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Mutación Missense , Proyectos Piloto , Polimorfismo de Nucleótido Simple , Estabilidad Proteica , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Recurrencia , Homología de Secuencia de Aminoácido , Especificidad de la Especie , Transportadores de SulfatoRESUMEN
Sulfate is important for growth and development, and is supplied from mother to fetus throughout pregnancy. We used NaS1 sulfate transporter null (Nas1(-/-)) mice to investigate the role of NaS1 in maintaining sulfate homeostasis during pregnancy and to determine the physiological consequences of maternal hyposulfataemia on fetal, placental and postnatal growth. We show that maternal serum (≤0.5 mM), fetal serum (<0.1 mM) and amniotic fluid (≤0.5 mM) sulfate levels were significantly lower in pregnant Nas1(-/-) mice when compared with maternal serum (â2.0 mM), fetal serum (â1.5 mM) and amniotic fluid (â1.7 mM) sulfate levels in pregnant Nas1(+/+) mice. After 12 days of pregnancy, fetal reabsorptions led to markedly reduced (by ≥50%) fetal numbers in Nas1(-/-) mice. Placental labyrinth and spongiotrophoblast layers were increased (by â140%) in pregnant Nas1(-/-) mice when compared to pregnant Nas1(+/+) mice. Birth weights of progeny from female Nas1(-/-) mice were increased (by â7%) when compared to progeny of Nas1(+/+) mice. These findings show that NaS1 is essential to maintain high maternal and fetal sulfate levels, which is important for maintaining pregnancy, placental development and normal birth weight.
