Cystinuria type I: identification of eight new mutations in SLC3A1.

BACKGROUND: Cystinuria is a heritable disorder of amino acid transport characterized by the defective transport of cystine and the dibasic amino acids through the brush border epithelial cells of the renal tubule and intestine tract. Three types of cystinuria (I, II, and III) have been described based on the urinary excretion of cystine and dibasic amino acids in obligate heterozygotes. The SLC3A1 gene coding for an amino acid transporter named rBAT is responsible for type I cystinuria, whereas the SLC7A9 gene coding for a subunit (b0,+AT) of rBAT is involved in determining non-type I (types II and III) cystinuria. METHODS: The SLC3A1 gene sequence was investigated in a sample of seven type I/type I, three type I/non-type I, six type I/untyped, and four untyped unrelated cystinuric patients by RNA single-strand conformation polymorphism (RNA-SSCP). RESULTS: Eight new point mutations (S168X, 765+1G>T, 766-2A>G, R452Q, Y461X, S547W, L564F, and C673W) and seven previously reported mutations were detected. These new mutations increase the number of mutated alleles so far characterized in SLC3A1 to 62. CONCLUSIONS: We have found SLC3A1 mutations in 0.739 of the type I chromosomes studied. The relatively high proportion of uncharacterized type I chromosomes suggests either that there may be mutations not yet found in SLC3A1 or that many of the assigned type I chromosomes in mixed type I/non-type I patients may have mutations in SLC7A9. If the hypothesis is excluded in the future, we believe that a third gene may be involved in cystinuria.

Recombinant families locate the gene for non-type I cystinuria between markers C13 and D19S587 on chromosome 19q13.1.

Cystinuria is an autosomal recessive aminoaciduria in which three urinary phenotypes have been described. The gene responsible for type I, SLC3A1, encodes the amino acid transporter rBAT. This gene is not responsible for types II or III. Recently the type III locus (CSNU3) was mapped by two groups to overlapping 6-Mb regions on chromosome 19q. In the present study, we restrict the critical region for non-type I cystinuria to 2.4 Mb by recombination analysis in Italian, German, and Spanish families. For this purpose, we have used the microsatellite markers described in the region plus new microsatellites that we have developed. Our results locate the non-type I cystinuria gene in an interval flanked by the markers C13 and D19S587, which are about 2.8 cM apart.

Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT.

Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (Refs 3,4). We have identified a new transcript, encoding a protein (bo, +AT, for bo,+ amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co-transfection of bo,+AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b o,+AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that bo,+AT is the light subunit of rBAT.

[The use of type A botulin toxin in the treatment of detrusor-sphincter dyssynergia]. / L'impiego della tossina botulinica tipo A nel trattamento della dissinergia detrusore sfintere.

The detrusor-sphincter dyssynergia (DSD) is a common and significant problem for patients with spinal cord lesions. If not treated, DSD can lead to severe and potentially lethal complications (urinary tract infections and renal damage). BTX inhibits acetylcholine release at the neuromuscular junction, producing muscle chemical denervation in the site of injection. The aim of this preliminary study was to test the safety and the effects of BTX injection in the spastic urethral rhabdosphincter in patients with DSD. Five patients (3 M, 2 F; mean age 43 years, range 22-56) with DSD entered the study. Videourodynamic parameters were controlled before BTX injection at 10 days, at 3 and 6 months after infiltration. The aim of this preliminary study was to test the safety and the effects of BTX injection in the spastic urethral rhabdosphincter in patients with DSD. The post void residual urine volume, the maximum pressure of emptying and the maximum pressure of urethral closure are reported in Tab. II-III-IV. Patients reported subjective improvement of bladder emptying and improved quality of life. No adverse effects related to pharmacological activity of BTX or to infiltration procedures were observed.

[Echographic features in the diagnosis of renal abscess]. / Aspetti ecografici nella diagnosi di ascesso renale.

The Authors emphasize sonographic aspects of Renal Abscess in early phase and in proclaimed disease. The advent of the sonography and its extensive use marked an inversion of tendency in Perinephric Abscess evolution. So it is possible to point out small Abscesses and in early phase. Leukocytes tags Scintiscan and CT can confirm the diagnostic tentative.

Molecular analysis of the cystinuria disease gene: identification of four new mutations, one large deletion, and one polymorphism.

A cystinuria disease gene (rBAT) has recently been identified, but evidence strongly suggests that only Type-I cystinuria is due to mutations in this gene. Sixteen point mutations and a large deletion causing the disease have so far been described in the rBAT gene sequence. To identify new mutated alleles, genomic DNA was analyzed, after the determination of the entire genomic structure of the rBAT gene, by RNA-single strand conformation polymorphism analysis, an accurate and sensitive method able to detect nucleotide changes. Four new point mutations, a large deletion, and a common intragenic polymorphism were detected. These new mutations increase to 22 the number of mutated alleles so far characterized in rBAT. In addition, the frequency of 21 mutations was assessed in a sample of accurately defined Type-I cystinuria chromosomes. They account for about 58% of all Type-I chromosomes, mutation M467T being the most common (0.26).

Genetic heterogeneity in cystinuria: the SLC3A1 gene is linked to type I but not to type III cystinuria.

Cystinuria is an autosomal recessive amino-aciduria where three urinary phenotypes have been described (I, II, and III). An amino acid transporter gene, SLC3A1 (formerly rBAT), was found to be responsible for this disorder. To assess whether mutations in SLC3A1 are involved in different cystinuria phenotypes, linkage with this gene and its nearest marker (D2S119) was analyzed in 22 families with type I and/or type III cystinuria. Linkage with heterogeneity was proved (alpha = 0.45; P < 0.008). Type I/I families showed homogeneous linkage to SLC3A1 (Zmax > 3.0 at theta = 0.00; alpha = 1), whereas types I/III and III/III were not linked. Our data suggest that type I cystinuria is due to mutations in the SLC3A1 gene, whereas another locus is responsible for type III. This result establishes genetic heterogeneity for cystinuria, classically considered as a multiallelic monogenic disease.

[Urethral echography: potential and limitations]. / L'ecografia uretrale: possibilità e limiti.

Since in the early years of 1980, the diagnostic for images about male's urethral injury was exclusively assigned to urethrocystography. Sially in repeated check the gonads too often are exposed to ionizing radiations. Our results show urethrocystography/ultrasonography good correlation (13/15) cases) with 86% sensibility. Even if the urethrocystography is a methodic of first instance, the urethral ultrasonography is efficacious in follow up of urethral injury, particularly in the study of anterior urethra.

[Echohysterography in the diagnosis of female sterility: preliminary results]. / L'ecoisterografia nella diagnostica della sterilità femminile: risultati preliminari.

Couple's study infertility sometimes need repeated hysterosalpingographical evaluations. In three cases the A.A. value echohysterosalpingography's utility. The echohysterosalpingography gives morphological and functional dates, is easy repeatable and the patients aren't exposed to ionizing radiations.

[Echographic characteristics of calcifying fibrous pseudotumor of the epididymis]. / Aspetti ecografici dello pseudotumore fibroso calcificante dell'epididimo.

Calcifying fibrous pseudotumor of epididymis is a rare neoplasia. The A.A. report echographical aspects about two clinical acses examined in 1993. Peculiar aspects of tumour are characterized by acoustic obstruction of the fibrous tissue and contextual iperechogenic spots, so to stimulate a calcific pseudocapsula. The A.A. revalue the echographical images after surgical exploration and discuss about differential diagnosis with TBC.

[Echography problems in acute scrotum: torsion of the hydatid of Morgagni]. / Problematiche ecografiche nello scroto acuto: torsione dell'idatide del Morgagni.

The A.A. discuss about a clinical case of acute scrotum in which the echographical aspects aren't been exhaustived for the etiology. Surgical exploration showed Morgagni's hydatid torsion while the echography doubted between acute phlogosis and neoplasia.