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Demosthenous P, Voskarides K, Stylianou K, Hadjigavriel M, Arsali M, Patsias C, Georgaki E, Zirogiannis P, Stavrou C, Daphnis E, Pierides A, Deltas C, Hellenic Nephrogenetics Research Consortium. X-linked Alport syndrome in Hellenic families: Phenotypic heterogeneity and mutations near interruptions of the collagen domain in COL4A5. The X-linked Alport syndrome (ATS) is caused by mutations in COL4A5 and exhibits a widely variable expression. Usually ATS is heralded with continuous microhematuria which rapidly progresses to proteinuria, hypertension and chronic or end-stage renal disease (ESRD) by adolescence, frequently accompanied by sensorineural deafness and ocular complications. Milder forms of ATS also exist. We studied 42 patients (19M, 23F) of nine Hellenic families suspected clinically of X-linked ATS who presented with marked phenotypic heterogeneity. We identified mutations in COL4A5 in six families. Two males with nonsense mutation E228X reached ESRD by ages 14 and 18. Frameshift mutation 2946delT followed the same course with early onset renal involvement and deafness. However, two males with the milder missense mutation G624D, reached ESRD after 39 years and one patient showed thin basement membrane nephropathy (TBMN). Another 5/8 affected males with missense mutation P628L also developed ESRD between 30 and 57 years, while three exhibit only mild chronic renal failure (CRF). The data support previous findings that certain mutations are associated with milder phenotypes and confirm that mutation G624D may be expressed as TBMN with familial hematuria. Similar conclusions apply for missense mutation P628L. Interestingly, mutations G624D and P628L are near the 12th natural interruption of COL4A5 triple helical domain, which may explain the milder phenotype. [ABSTRACT FROM AUTHOR]

Pricing and trading practices in the Athens Derivatives Exchange, a newly established derivatives market, result in significant futures arbitrage profit opportunities for low-cost traders. We find that a large part of the mispricing is due to transaction costs, but additional factors, such as anticipated volatility and time to maturity, also contribute. Ex ante tests reveal significant arbitrage opportunities that could have been exploited up to 30 min after they had been identified. All different tests employed indicate that the derivatives market was inefficient during its early trading history because arbitrage opportunities persisted even after other market impact costs were taken into consideration. [ABSTRACT FROM AUTHOR]

Background and Aims: Cystinuria represents 3% of nephrolithiasis in humans. Two genes have been identified as the main genetic causes of cystinuria, SLC3A1 and SLC7A9, with an autosomal recessive mode of inheritance. In the present study, we studied for the first time, genetically and clinically, all the cystinuric families identified so far in the Greek-Cypriot population., Methods: Discovery of mutations was performed through polymerase chain reaction (PCR)-single analysis and DNA resequencing. New families were investigated through PCR-RFLPs. Clinical data were collected through the hospital patients' records and analytical follow-up of the families., Results and Discussion: We found a total of five mutations in 28 Greek-Cypriot cystinuric patients belonging in 12 families. The most frequent mutation among the 28 Greek-Cypriot patients is the SLC3A1-p.T216M, which is also the second most frequent mutation in Europe, representing a genetic founder effect. Sixteen of the 28 patients are homozygous for this mutation. Even though a consanguinity loop was obvious in only one family, other patients were from families in small villages where endogamy was practiced for many centuries. Timely clinical and genetic diagnosis, accompanied by early treatment, is significant for the good health of most of our patients. Only ∼14% of them developed chronic renal failure, and only one reached end-stage renal disease (ESRD)., Conclusion: Five SLC3A1 and SLC7A9 mutations appear to be responsible for the genetic basis of cystinuria in the Greek-Cypriot patients; having such a limited number of causative mutations will simplify diagnostics for this population.

The spectrum of distal renal tubular acidosis (dRTA) includes a genetically heterogeneous group of inherited conditions of both autosomal-dominant and recessive mode of inheritance. The basic defect is linked to the renal part of acid-base homeostasis, which is partly achieved by the regulated luminal secretion of H+ at the apical surface of the alpha-intercalated cells of renal collecting ducts. This is coupled to bicarbonate reabsorption with chloride counter transport across the basolateral membranes. Here, we describe the molecular findings of the first two Greek Cypriot families with recessive dRTA and the long-term clinical findings in four of five affected members. DNA linkage analysis with four polymorphic markers flanking the ATP6V1B1 gene on chromosome 2 gave evidence for positive linkage; direct DNA analysis by automated DNA sequencing revealed that patients in one family were homozygous for mutation 229+1G>T (IVS7+1G>T) and that patients in the second family were compound heterozygous for 229+1G>T and R157C. The mutations were found on four different haplotypes. Both the mutations were previously reported in patients of Turkish origin. Three known polymorphic variants were also identified. The five patients demonstrated the whole clinical spectrum of the disease including death in infancy, failure to thrive, rickets, nephrocalcinosis, nephrolithiasis, and episodes of hypokalemic paralysis. Some of the family members are now in their mid 30s and late 20s, and nephrolithiasis with recurrent renal colics is their main problem. Renal function has remained normal. In conclusion, early diagnosis in infancy and prompt treatment with alkali and potassium supplements is of great benefit to the patient with dRTA and ensures normal growth. The identification of responsible mutations facilitates antenatal or postnatal diagnosis in concerned families and improves the prognosis.

Aim: The homozygous 677TT mutation of the MTHFR gene has been linked to deep vein thrombosis and to arterial atherosclerotic events of the coronary, carotid and peripheral arteries. Its putative association with renal arteriosclerosis and chronic renal failure (CRF) in the presence of hypertensive nephrosclerosis is yet to be investigated., Methods: Two hundred and twenty-one Greek-Cypriot patients with CRF from one single renal unit in Cyprus were divided into 6 diagnostic categories: 49 due to chronic glomerulonephritis (22.2%), 43 due to diabetes mellitus (19.4%), 26 due to autosomal dominant polycystic kidney disease (11.8%), 30 due to essential hypertension leading to nephrosclerosis (13.6%), including 4 patients with primary malignant hypertension, 32 with other rarer causes of CRF (14.5%) and 41 of uncertain etiology (18.5%). These 221 CRF patients had their MTHFR C677T and A1298C genotypes analyzed by the polymerase chain reaction and agarose gel electrophoresis after restriction enzyme digestion. The frequency of the homozygous states 677TT and 1298CC and the double heterozygous 677CT/1298AC were compared to those of 210 unrelated normal local controls., Results: A statistically significant increase in the frequency of the 677TT genotype compared to controls was only found in the hypertensive nephrosclerosis CRF sub-group of patients. The prevalence rate of the 677TT genotype was 46.7% (controls 17.6%, P=0.0007). Combined together the homozygous 677TT and the double heterozygous 677CT/1298AC genotypes were found in 86.7% of the hypertensive nephrosclerotic CRF patients, compared to 46.6% in normal controls (P=0.0001)., Conclusions: The findings support the hypothesis that Caucasian patients with essential hypertension, homozygous for 677TT or doubly heterozygous for 677CT/1298AC genotypes, are predisposed to develop hypertensive nephrosclerosis and CRF.

Nitric oxide (NO) is thought to be an important factor in the deterioration of renal function. A variable-number tandem 27-bp repeat in intron 4 of the endothelial cell nitric oxide synthase (NOS3) gene has been found to be associated with the plasma levels of NO metabolites. Two alleles are of varied frequencies in different populations (a and b). The shorter allele a has been associated in Japanese populations with the progression of renal disease. Here we investigated this hypothesis by studying the putative role of this polymorphism in a Hellenic population of patients with end-stage renal disease (ESRD). We analyzed the genotypes of 361 ESRD patients and 295 healthy Hellens from Greece and Cyprus. The frequencies of NOS3-4bb, NOS3-4ab, and NOS3-4aa were 0.69, 0.27, and 0.03, respectively, in the control group and 0.71, 0.24, and 0.04 in the group of patients. The data in the two populations were analyzed by the chi-square and Fisher's exact tests. The frequencies of these three genotypes of NOS3-4 polymorphism in the Hellenic population of Greece and Cyprus are similar to those observed in other Caucasian populations. Moreover, our results from three patient groups, autosomal dominant polycystic kidney disease (ADPKD), diabetes mellitus (DM), and non-DM, showed that the frequencies of aa and ab genotypes in the patient populations were not significantly different from those observed in the control group. This work indicates that NOS3-4 polymorphism does not show any association with the development of ESRD in this studied European population. However, examination of the data regarding progression to ESRD within 5 years or after more than 5 years following clinical diagnosis of ADPKD provided evidence of statistical difference (p = 0.048, before Bonferroni correction), with faster progression in the group of ADPKD patients who carried allele a.

Familial Mediterranean Fever (FMF) is an autosomal recessive disease of high prevalence within Mediterranean countries and particularly common in four ethnic populations: Arabs, non-Ashkenazi Jews, Armenians, and Turks. The responsible gene MEFV has been assigned to chromosome 16p13.3. Our aim was to establish the frequencies of the most common mutations in Greek-Cypriots. We found that 1 in 25 is a carrier of one of three mutations. V726A, M694V, and F479L. In 68 Grek-Cypriot FMF chromosomes analyzed, we found V726A (25%), F479L (20.6%), M694V (17.6%), and others (36.8%). Mutation F479L, relatively common in this population, is very rare elsewhere. Our study indicates that FMF is not a rare condition in Cyprus and that, because of the significant morbidity associated with this disorder, which is often diagnosed only after unnecessary surgeries, a newborn screening program to detect affected in this population may be warranted.

The PKD1 gene, which is responsible for the most common form of autosomal dominant polycystic kidney disease, has recently been cloned and sequenced. Many disease-causing mutations have been characterized in this gene, most of them resulting in premature protein termination. However, mutation analysis not routinely implemented for family investigations in a clinical setting, because of the large size and complexity of the gene. Instead, genetic linkage analysis using highly polymorphic CA dinucleotide repeats that map around the gene is still the method of choice. Recently, a few intragenic polymorphisms have been described that are also useful for linkage studies. Here, a new diallelic polymorphism is described for amino acid residue 4058, Ala/Val4058, with allelic frequencies of 0.88 and 0.12, respectively, and a heterozygosity of 0.23, in the Greek and Greek-Cypriot populations. Interestingly, this polymorphism and Ala4091-A/G, which has previously been described in Caucasians, were not detected in DNA from 44 Japanese samples tested. This is particularly important when allelic frequencies in a particular population are used for linkage analysis of families of different ethnic origin. Also, observation of the two polymorphisms together as haplotypes suggests that the Ala/Val4058 polymorphism occurred more recently than the establishment of the Ala4091-A/G polymorphism, and specifically on the G allele.