A mutation in the Z-line Cypher/ZASP protein is associated with arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of malignant arrhythmia and sudden death particularly in young people. Although it is considered a desmosomal disease, mutations in non-desmosomal genes have also been identified. We report on a family where a mutation in LDB3 is associated with this condition. The index case and first and second degree relatives underwent a complete clinical evaluation: physical examination, electrocardiography (ECG), signal-averaged ECG, 2D echocardiogram, cardiac magnetic resonance and 24-h monitoring. After ruling out mutations in the five desmosomal genes, genetic testing by means of Next Generation Sequencing was carried out on the proband. A heterozygous missense mutation in LDB3 c.1051A>G was identified. This result was confirmed by subsequent Sanger DNA sequencing. Another six carriers were identified amongst her relatives. Three subjects fulfilled the criteria for a definitive diagnosis of ARVC and one reached a borderline diagnosis. In conclusion, this is the first family with ARVC where a mutation in LDB3 is associated with ARVC. Next generation sequencing arises as a particular useful tool to point to new causative genes in ARVC.

A study of the SCN5A gene in a cohort of 76 patients with Brugada syndrome.

We aim to study the SCN5A gene in a cohort of Brugada syndrome (BS) patients and evaluate the genotype-phenotype correlation. BS is caused by mutations in up to 10 different genes, SCN5A being the most frequently involved. Large genomic rearrangements in SCN5A have been associated with conduction disease, but its prevalence in BS is unknown. Seventy-six non-related patients with BS were studied. Clinical characteristics and family risk profile were recorded. Direct sequencing and multiplex ligation-dependent probe amplification (MLPA) of the SCN5A gene for identification of mutations and larger rearrangements were performed, respectively. Eight patients (10.5%) had point mutations (R27H, E901K, G1743R (detected in three families), V728I, N1443S and E1152X). Patients with mutations had a trend toward a higher proportion of spontaneous type I Brugada electrocardiogram (ECG) (87.5% vs 52.9%, p = 0.06) and had evidence of familial disease (62.5%, vs 23.5%, p = 0.03). The symptoms and risk profile of the carriers were not different from wild-type probands. There were non-significant differences in the prevalence of type I ECG, syncope and history of arrhythmia in carriers of selected polymorphisms. None of the patients had any deletion/duplication in the SCN5A gene. In conclusion, 10.5% of our patients had mutations in the SCN5A gene. Patients with mutations seemed to have more spontaneous type I ECG, but no differences in syncope or arrhythmic events compared with patients without mutations. Larger studies are needed to evaluate the role of polymorphisms in the SCN5A in the expression of the phenotype and prognosis. Large rearrangements were not identified in the SCN5A gene using the MLPA technique.

Cholinesterases are down-expressed in human colorectal carcinoma.

The aberrations of cholinesterase (ChE) genes and the variation of ChE activity in cancerous tissues prompted us to investigate the expression of ChEs in colorectal carcinoma. The study of 55 paired specimens of healthy (HG) and cancerous gut (CG) showed that acetylcholinesterase (AChE) activity fell by 32% and butyrylcholinesterase (BuChE) activity by 58% in CG. Abundant AChE-H, fewer AChE-T, and even fewer AChE-R and BuChE mRNAs were observed in HG, and their content was greatly diminished in CG. The high level of the AChE-H mRNA explains the abundance of AChE-H subunits in HG, which as glycosylphosphatidylinositol (GPI)-anchored amphiphilic AChE dimers (G2(A)) and monomers (G1(A)) account for 69% of AChE activity. The identification of AChE-T and BuChE mRNAs justifies the occurrence in gut of A12, G4(H) and PRiMA-containing G4(A) AChE forms, besides G4(H), G4(A) and G1(H) BuChE. The down-regulation of ChEs might contribute to gut carcinogenesis by increasing acetylcholine availability and over-stimulating muscarinic receptors.

Plasmatic homocysteine concentration and its relationship with complications associated to diabetes mellitus.

BACKGROUND AND METHODS: In the search for new factors of cardiovascular risk associated to diabetes mellitus (DM), special attention has been paid in recent years to hyperhomocysteinaemia. Therefore, we have established the concentration of homocysteine (Hcy) and other biochemical parameters in the plasma of a group of 57 type 1 and 32 type 2 diabetic patients and 54 control subjects and studied whether plasmatic homocysteinaemia was related to macroangiopathy, nephropathy, retinopathy and neuropathy. Because of significant differences for plasma Hcy values between men and women in the control group, we distinguished between both groups throughout the study. RESULTS: Patients with DM had higher Hcy than control subjects (11.7+/-5.4 vs. 10.1+/-2.4 micromol/l, p<0.05). Fasting hyperhomocysteinaemia was considered as the mean of the plasma Hcy for control subjects+2 SD (14.9 micromol/l in total group, 15.6 micromol/l in males and 13.9 micromol/l in females). In the studied groups with complications, we found significant differences between normohomocysteinaemic type 1 diabetic patients and those considered hyperhomocysteinaemic by us. On the other hand, patients having type 1 DM and complications had higher plasmatic Hcy concentration than those with no complications. CONCLUSIONS: We have found a relationship between high Hcy levels and prevalence of macroangiopathy, retinopathy and nephropathy in the type 1 diabetic patients, which was not been observed in the type 2 diabetic patients of our study. As a result, we consider plasmatic Hcy a complication-risk indicator in type 1 DM, and we recommend its use together with already established biochemical parameters in the control of the evolution of the disease.