The enzyme 3-deoxy-D-arabinoheptulosonate-7-phosphate (DAHP) synthase catalyses the first step in aromatic amino acid biosynthesis in prokaryotes, plants and fungi. Cells of Saccharomyces cerevisiae contain two catalytically redundant DAHP synthases, encoded by the genes ARO3 and ARO4, whose activities are feedback-inhibited by phenylalanine and tyrosine, respectively. ARO3/4 gene transcription is controlled by GCN4. The authors previously cloned an ARO3 gene orthologue from Candida albicans and found that : (1) it can complement an aro3 aro4 double mutation in S. cerevisiae, an effect inhibited by excess phenylalanine, and (2) a homozygous aro3-deletion mutant of C. albicans is phenotypically Aro M , suggesting the existence of another isozyme(s). They now report the identification and functional characterization of the C. albicans orthologue of S. cerevisiae Aro4p. The two Aro4p enzymes share 68 % amino acid identity. Phylogenetic analysis places the fungal DAHP synthases in a cluster separate from prokaryotic orthologues and suggests that ARO3 and ARO4 arose from a single gene via a gene duplication event early in fungal evolution. C. albicans ARO4 mRNA is elevated upon amino acid starvation, consistent with the presence of three putative Gcn4p-responsive elements (GCREs) in the gene promoter sequence. C. albicans ARO4 complements an aro3 aro4 double mutation in S. cerevisiae, an effect inhibited by excess tyrosine. The authors engineered ∆aro3/∆aro3 ∆aro4/MET3p ::ARO4 cells of C. albicans (with one wild-type copy of ARO4 placed under control of the repressible MET3 promoter) and found that they fail to grow in the absence of aromatic amino acids when ARO4 expression is repressed, and that this growth defect can be partially rescued by aromatic amino acids and certain aromatic amino acid pathway intermediates. It is concluded that, like S. cerevisiae, C. albicans contains two DAHP synthases required for the first step in the aromatic amino acid biosynthetic pathway.
Background and aim Familial Neurohypophyseal Diabetes Insipidus (FNDI) is a rare autossomal dominant disorder caused by mutations in the vasopressin (AVP) gene and is characterised by childhood onset of polyuria and polydipsia. The authors present a case of FNDI caused by a new mutation in AVP gene in a Portuguese family. Case Report Twelve year-old boy with unremarkable past medical history admitted at our outpatient clinic with complaints of polydipsia (20 Litres/day) and polyuria since early childhood. Polyphagia, weight loss, enuresis and urinary incontinence were denied. His mother, grandmother, great grandfather and second/third degree uncles/aunts presented the same symptoms. Basal laboratorial tests revealed: plasma osmolality 292 mOsm/KgH2O, plasma Na + 137 mEq/L and a normal renal function. 24-hour urinalysis (volume 7450 mL) showed a low urine osmolality (150 mOsm/KgH2O) and normal Na+ and creatinine concentrations. Water deprivation test was positive for Diabetes Insipidus. The positive response after 20 mcg of intranasal desmopressin confirmed the diagnosis of neurohypophyseal Diabetes Insipidus. The MRI showed a hyper-intense signal corresponding to an ectopic neurohypophysis in the supra-celar cistern. The genetic test confirmed the diagnosis of FNDI: mutation c.293G > C (p. Cys98Ser) in the AVP gene (heterozygous) in the proband, mother and grandmother. The patient started daily oral desmopressin with relieve of complaints. Genetic counselling was given to the family. Conclusion The presented case revealed an AVP gene mutation not described in the literature. The diagnosis, not recognised until the fourth generation, allowed a prompt treatment and genetic counselling of the family and an improvement in quality of life of affected members.
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