Open Access

Renal proximal tubular cells constantly recycle nutrients to ensure minimal loss of vital substrates into the urine. Although most of the transport mechanisms have been discovered at the molecular level, little is known about the factors regulating these processes. Here, we show that mTORC1 and mTORC2 specifically and synergistically regulate PTC endocytosis and transport processes. Using a conditional mouse genetic approach to disable nonredundant subunits of mTORC1, mTORC2, or both, we showed that mice lacking mTORC1 or mTORC1/mTORC2 but not mTORC2 alone develop a Fanconi-like syndrome of glucosuria, phosphaturia, aminoaciduria, low molecular weight proteinuria, and albuminuria. Interestingly, proteomics and phosphoproteomics of freshly isolated kidney cortex identified either reduced expression or loss of phosphorylation at critical residues of different classes of specific transport proteins. Functionally, this resulted in reduced nutrient transport and a profound perturbation of the endocytic machinery, despite preserved absolute expression of the main scavenger receptors, MEGALIN and CUBILIN. Our findings highlight a novel mTOR–dependent regulatory network for nutrient transport in renal proximal tubular cells.

Beta-ketothiolase deficiency (mitochondrial acetoacetyl-CoA thiolase, MAT or T2 deficiency) is a rare autosomal recessive disorder of isoleucine and ketone body metabolism due to acetyl-CoA acetyltransferase-1 (ACAT1) gene mutations. The disease is characterized by recurrent episodes of ketoasidosis which starts with vomiting and followed by dehydration and tachypnea. Here, we present a patient who was admitted to the hospital with severe acidosis and dehydration because of vomiting induced by protein rich nutrient and was diagnosed with MAT deficiency. 3-hydroxy-butyric acid, acetoacetic acid and 3-hydroxy-iso-valeric acid levels were significantly increased and tiglyglycine as trace amount in the urine organic acid analysis of the patient. Genetic analysis for ACAT-1 showed compound heterozygosity for the mutations c.949G > A (p.D317N) and c.951C > T (p.D317D), which both are known to cause exon 10 skipping and to be pathogenic missense mutations.

A 9-month-old Turkish girl was admitted several times within 3 months to the hospital in reduced general condition and with extreme tachypnea. The patient had been diagnosed with phenylketonuria (PKU) in newborn screening and has been treated with a low phenylalanine diet and amino acid supplements. Each time an unexplained pronounced metabolic acidosis was noted, and the child was treated with sodium-bicarbonate and glucose-electrolyte infusions. The acidosis with only slightly abnormal glucose, normal lactate levels and pronounced ketonuria suggested a defect in ketone body utilization. Succinyl-CoA: 3-oxoacid CoA transferase (SCOT) enzyme activity was low in patient's fibroblasts. Mutation analysis of the corresponding OXCT1 gene revealed that the patient was a homozygous carrier of the mutation c.1523T>C (p.V508A). We conclude that SCOT deficiency should be considered in the differential diagnosis in patients with recurrent metabolic acidotic episodes, even if they are already known to have a metabolic disease unrelated to this.

BACKGROUND Molybdenum cofactor deficiency (resulting in combined deficiencies of the enzymes sulphite oxidase, xanthine dehydrogenase and aldehyde dehydrogenase) and isolated sulphite oxidase deficiency are inherited metabolic diseases which follow an autosomal recessive trait of inheritance. Detection of these diseases in selective screening for inborn errors of metabolism is not easy because relevant metabolites are either not routinely determined or are unstable. METHODS We have searched for additional markers for these diseases and studied plasma total homocysteine (determined by enzyme immunoassay) and S-sulphonation of transthyretin (assessed by electrospray ionization mass spectrometry). RESULTS AND CONCLUSION We found total homocysteine concentrations below the limit of quantification (<1 micromol/L) in all samples of patients with sulphite oxidase deficiency studied in this regard and that the proportion of S-sulphonated transthyretin is clearly increased in such samples. Our observations suggest additional tools for selective screening and diagnostic work-up of patients suspected of having sulphite oxidase deficiency.