FK506 is an important immunosuppressive medication. However, it can provoke neurotoxicity, nephrotoxicity, and diabetes as adverse side effects. The decrease in oxygen consumption of rat cells ...treated with pharmacologically relevant concentrations of FK506, along with other evidences, has insinuated that some of the toxic effects are probably caused by drug-induced mitochondrial dysfunction at the level of gene expression. To confirm this suggestion, we have analyzed cell respiration and mitochondrial protein synthesis in human cell lines treated with FK506. This drug provokes an important decrease in oxygen consumption, accompanied by a slight reduction in the synthesis of mitochondria DNA-encoded proteins. These results are similar to those triggered by rapamycin, another macrolide with immunosuppressive properties, therefore insinuating a common toxic pathway.
Although autosomal dominant polycystic kidney disease type 2 (PKD2) is known to have a milder clinical phenotype than PKD1, neither disorder has been compared with an unaffected control population in ...terms of survival. We report the findings of a multicentre survey that aimed to define more precisely the survival and clinical expression of PKD1 and PKD2.
Clinical data from 333 people with PKD1 (31 families) were compared with data from 291 people with PKD2 (31 families) and 398 geographically matched controls. Survival analysis was used to compare age-at event data. Differences in the prevalence of complications were assessed by logistic regression.
Median age at death or onset of end-stage renal disease was 53·0 years (95% CI 51·2–54·8) in individuals with PKD1, 69·1 years (66·9–71·3) in those with PKD2, and 78·0 years (73·8–82·2) in controls. Women with PKD2 had a significantly longer median survival than men (71·0 67·4–74·8
vs 67·3 64·9–69·7 years), but no sex influence was apparent in PKD1. Age at presentation with kidney failure was later in PKD2 than in PKD1 (median age 74·0 67·2–80·8
vs 54·3 52·7–55·9 years). PKD2 patients were less likely to have hypertension (odds ration 0·25 95% CI 0·15–0·42), a history of urinary-tract infection. (0·50 0·31–0·83), or haematuria (0·59 0·35–0·98).
Although PKD2 is clinically milder than PKD1, it has a deleterious impact on overall life expectancy and cannot be regarded as a benign disorder.
An association between a common deletion comprising the late cornified envelope LCE3B and LCE3C genes (LCE3C_LCE3B-del) and Psoriasis (Ps) has been reported. The expression of these LCE genes was ...induced after skin barrier disruption and was also strong in psoriatic lesions. The damage to the skin barrier could trigger an epidermal response that includes the expression of genes involved in the formation of skin barrier.
We determined the LCE3C_LCE3B-del genotype in 405 Ps patients and 400 healthy controls from a Northern Spain region (Asturias). These patients and controls were also genotyped for the rs4112788 single nucleotide polymorphism, in strong linkage disequilibrium with the LCE3C_B cluster. The LCE3B and LCE3C gene variant was determined in the patients through SSCA, DHPLC, and direct sequencing.
Allele and genotype frequencies did not differ between patients and controls for the rs4112788 and LCE3C_LCE3B-del polymorphisms. However, del/del homozygotes were significantly higher among patients with chronic plaque type Ps who did not develop arthritis (p = 0.03; OR = 1.4; 95%CI = 1.03-1.92). The analysis of the coding sequence of LCE3B and LCE3C in the patients who had at least one copy of this showed that only one patient has a no previously reported LCE3B variant (R68C).
Our work suggested that homozygosity for a common LCE3C_LCE3B deletion contributes to the risk of developing chronic plaque type Ps without psoriatic arthritis. Our work confirmed previous reports that described an association of this marker with only skin manifestations, and supported the concept of different genetic risk factors contributing to skin and joint disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common genetic determinants of familial and sporadic Parkinson's disease (PD). Most of the mutational screenings analyzed the ...exon-coding sequence. Our aim was to determine whether LRRK2 3' untranslated region (UTR) variants were associated with the risk of developing PD in a large cohort of patients (n=743) and controls (n=523) from Spain. We identified a total of 12 3'UTR variants (two new). Single-nucleotide polymorphism (SNP) rs66737902 C allele was overrepresented in patients (P=0.005; odds ratio=1.47). This SNP was in linkage disequilibrium with the p.R1441G mutation, but the association remained significant among mutation-negative cases. We found a significant lower level of the LRRK2 transcript in the Substantia nigra (SN) of PD postmortem donors (n=9) who were rs66737902 C carriers (P=0.01). This SNP was predicted to affect a binding site for miR-138-2-3p. We showed that this microRNA was expressed in all the SN samples. In conclusion, we found a significant association between SNP rs66737902 and the risk of developing PD. This effect on PD risk could be explained by differences in LRRK2 transcript levels between the two alleles.
Long QT syndrome (LQTS) is an inheritable arrhythmogenic disorder associated with life-threatening arrhythmic events (LAEs). In general, patients with LQTS2 (
) and LQTS3 (
) are considered to be a ...greater risk of LAEs than LQTS1 (
) patients. Gender differences are also important. Series analyzing families with the same pathogenic variants may help in the progress of elaborating strong specific genotype-phenotype management strategies. In this manuscript, we describe the phenotype of seven unrelated families, carriers of the
G168R pathogenic variant.
we identified all consecutive index cases referred for genetic testing with LQTS diagnosis carriers of
G168R variant. Genetic and clinical screening for all available relatives was performed.
we evaluated seven unrelated families, with a total 34
G168R carriers (two obligated carriers died without available EKGs to evaluate the phenotype). All index cases but one were women and three of them presented with aborted sudden cardiac death (SCD) or syncope. The presence of sudden death in these families is notable, with a total of nine unexplained sudden deaths and four aborted SCD. Phenotype penetrance was 100% in women and 37.5% in men.
G168R is a pathogenic variant, with a high penetrance among women and mild penetrance among men. Risk for LAEs in this variant seems not negligible, especially among woman, and risk stratification should always be carefully evaluated.
Time-dependent variability of electrocardiogram (ECG) in patients with Brugada syndrome could affect the interpretation of provocative testing.
The aim of this study was to characterize ECG changes ...during and after flecainide infusion.
We studied 59 consecutive patients. The ECG was continuously analyzed during the first 30 minutes of provocative testing, and a single ECG was recorded 60 minutes later. We analyzed CYP2D6 and CYP3A5 variants affecting flecainide metabolism and performed blinded measurements at lead II.
At baseline, ECG patterns were classified as follows: type II in 31 patients (53%), type III in 15 (25%), and normal ECG in 13 (22%). Because of induction of type I ECG, the percentage of responders progressively increased with longer recording time periods (6.8% in 10 minutes vs 11.9% in 20-30 minutes vs 18.6% in 90 minutes; P < .01). Four patients displayed a late response, which was evidenced 90 minutes after the initiation of provocative testing. QRS width differentially increased between responders and nonresponders (P < .01), with a maximum QRS width of 110 ms during the first 30 minutes being effective for identifying possible late responders (sensitivity 100%; specificity 85.6%; positive predictive value 88%; negative predictive value 100%). The incidence of CYP2D6 variants was lower in late responders than in early or delayed responders (0% vs 75% vs 100%; P = .04), while a homogeneous distribution of CYP3A5*3/*3 was observed in our population.
Response to flecainide exhibits time-dependent variability of ECG patterns and intervals. Longer periods of ECG recording increase the recognition probability of type I ECG.
Gitelman's syndrome (GS) is an autosomal recessive disorder caused by mutations in the SLC12A3 gene. GS is characterized by hypokalaemic metabolic alkalosis, hypomagnesemia and hypocalciuria. Most of ...the reported patients of Roma ancestry are homozygous for an SLC12A3 intron 9 frameshifting mutation (c.1180+1G>T). Some forms of Bartter's syndrome result from mutations in the CLNCKB gene and clinically overlap with GS.
To characterize a second SLC12A3 mutation in Roma patients negative for the intron 9 variant.
SLC12A3 and CLNCKB genes were analyzed by next-generation sequencing in two Spanish and Greek gypsy patients who were negative for the intron 9 splicing mutation. Sanger sequencing was performed to confirm the putative mutations in patients and family members.
We identified a missense variant (p.Val647Met, c.1939G>A) in both cases, and both were homozygous for Met. This mutation was also found in three additional patients; two homozygous and one heterozygous compound with the intron 9 splicing mutation. This new SLC12A3 mutation seems to be characteristic of gipsy GS patients and was linked to the same haplotype in all cases, supporting a founder origin. All the patients showed biochemical features characteristic of GS.
We report a second founder mutation among GS patients of Roma ethnic background. The direct screening of this mutation would facilitate the characterization of patients who are negative for the more common intron 9 +1G>T mutation.
El síndrome de Gitelman (SG) es un trastorno autosómico recesivo causado por las mutaciones en el gen SLC12A3. El SG se caracteriza por una alcalosis metabólica hipopotasémica, hipomagnesemia e hipocalciuria. La mayoría de los pacientes de etnia gitana notificados son homocigotos para la mutación con desplazamiento del marco de lectura del intrón 9 de SLC12A3 (c.1180+1G>T). Algunas formas del síndrome de Bartter proceden de las mutaciones del gen CLNCKB y se solapan clínicamente con el SG.
Determinar las características de una segunda mutación en SLC12A3 en pacientes de etnia gitana con resultados negativos en la variante intrón 9.
Se analizaron los genes SLC12A3 y CLNCKB mediante secuenciación de nueva generación en 2 pacientes –uno español y otro griego– de etnia gitana con resultados negativos en la mutación de empalme del intrón 9. Se llevó a cabo una secuenciación de Sanger para confirmar las supuestas mutaciones en los pacientes y sus familiares.
Se identificó una variante con cambio de sentido (p.Val647Met, c.1939G>A) en ambos casos, y ambos eran homocigotos con respecto a Met. También se observó esta mutación en 3 pacientes adicionales, 2 homocigotos y uno heterocigoto compuesto con la mutación del intrón 9. Esta nueva mutación del SLC12A3 parece ser característica de los pacientes con SG de etnia gitana y se relacionó con el mismo haplotipo en todos los casos, lo que indica un origen fundador. Todos los pacientes presentaron rasgos bioquímicos propios del SG.
Informamos de una segunda mutación fundadora en los pacientes con SG de etnia gitana. El cribado genético directo de esta mutación facilitará la determinación de las características de los pacientes con resultados negativos en la mutación del intrón 9+1G>T, que es más frecuente.
Mutations in mitochondrial DNA (mtDNA) have been implicated in the development of Parkinson's disease (PD). Mitochondrial function is necessary to supply the energy required for cell metabolism, and ...mutations in mitochondrial genes should have a deleterious effect in neuronal function. An association between several common mtDNA-polymorphisms and the risk of PD has been described. To test this association among Spanish patients, we genotyped 271 PD-patients and 230 healthy controls for 13 single-nucleotide polymorphisms (SNPs) through polymerase chain reaction (PCR) followed by digestion with a restriction enzyme. Alleles at eight of these SNPs define nine common European haplotypes, the mitochondrial haplogroups. In our population, no haplogroup showed significantly different frequencies between patients and controls.
A significant association was found for the 4336T/C SNP (a polymorphism in the tRNA gln gene), with allele 4336C having a significantly increased frequency in PD-women compared to controls (OR
=
4.45; 95%CI
=
1.23–15.96;
p
=
0.011). We also sequenced five of the complex I genes (ND1 to ND5) in the patients who were 4336C, and no mutation in these genes was found. We also found a significantly reduced frequency of 10398G in patients (
p
=
0.009; OR
=
0.53), confirming a previously described protective effect for this allele in PD.
In conclusion, we provided further evidence of the involvement of mitochondrial DNA variation in PD. In agreement with previous reports, we described a higher risk for PD among women with the mitochondrial 4336C allele in our population, and a protective effect for 10398G.
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