Differential Methylation Levels in CpGs of the BIN1 Gene in Individuals With Alzheimer Disease.

INTRODUCTION: Late-onset Alzheimer disease (LOAD) is the most common dementia worldwide. APOE-[Latin Small Letter Open E]4 and BIN1 (Bridging Integrator 1) have been implicated in the pathogenesis of this disease, but, although DNA methylation of dinucleotide CpGs in the BIN1 gene influences alterations, it has not been studied in Hispanics. OBJECTIVE: The objective of this study was to evaluate the BIN1 3' intergenic region DNA methylation patterns in a Colombian sample of LOAD patients. METHODS: A case-control study was conducted in 50 individuals with LOAD and 50 age-sex matched controls to determine associations of LOAD with DNA methylation. DNA was isolated from peripheral blood, and methylation levels of 8 CpGs were estimated by bisulfite conversion followed by Sanger sequencing with direct PCR analysis. Logistic regression models adjusted by age, sex, and APOE were used to calculate risk associations between methylation levels and LOAD. RESULTS: Overall, participants with LOAD had significantly lower methylation levels on CpG26 (0.86±0.11 vs. 0.95±0.05; P>0.001), CpG44 (0.84±0.09 vs. 0.94±0.06; P=0.001), and CpG87 (0.64±0.12 vs. 0.82±0.10; P>0.001). Adjusted regression models showed that decreased methylation levels of these CpGs remained as risk factors for LOAD (P<0.05). CONCLUSIONS: Hypomethylation of CpGs in BIN1 might play an important role in the expression of BIN1 and may be a biomarker for identifying individuals at high risk of developing LOAD.

Adult presentation of Bartter syndrome type IV with erythrocytosis / Apresentação tardia de síndrome de Bartter tipo IV com eritrocitose

Abstract Bartter syndrome comprises a group of rare autosomal-recessive salt-losing disorders with distinct phenotypes, but one unifying pathophysiology consisting of severe reductions of sodium reabsorption caused by mutations in five genes expressed in the thick ascending limb of Henle, coupled with increased urinary excretion of potassium and hydrogen, which leads to hypokalemic alkalosis. Bartter syndrome type IV, caused by loss-of-function mutations in barttin, a subunit of chloride channel CLC-Kb expressed in the kidney and inner ear, usually occurs in the antenatal-neonatal period. We report an unusual case of late onset presentation of Bartter syndrome IV and mild phenotype in a 20 years-old man who had hypokalemia, deafness, secondary hyperparathyroidism and erythrocytosis.

Resumo A síndrome de Bartter compreende um grupo raro de doenças autossômicas recessivas perdedoras de sal, decorrentes de mutações em genes expressos na porção ascendente espessa da alça de Henle, com fenótipos distintos, porém fisiopatogenia única, que consiste em redução severa da reabsorção de sódio, e aumento da excreção urinária de hidrogênio e potássio, levando à alcalose hipocalêmica. A síndrome de Bartter tipo IV, causada por mutações com perda de função da bartina, uma subunidade do canal de cloro CLC-Kb expressa no rim e ouvido interno, geralmente se apresenta nos períodos ante e neonatal. No presente relato, descreve-se um caso não usual de síndrome de Bartter tipo IV com apresentação tardia e fenótipo atenuado, diagnosticado por análise molecular, em um homem adulto de 20 anos que se apresentava com hipocalemia, surdez, hiperparatireoidismo secundário e eritrocitose.

Adult presentation of Bartter syndrome type IV with erythrocytosis.

Bartter syndrome comprises a group of rare autosomal-recessive salt-losing disorders with distinct phenotypes, but one unifying pathophysiology consisting of severe reductions of sodium reabsorption caused by mutations in five genes expressed in the thick ascending limb of Henle, coupled with increased urinary excretion of potassium and hydrogen, which leads to hypokalemic alkalosis. Bartter syndrome type IV, caused by loss-of-function mutations in barttin, a subunit of chloride channel CLC-Kb expressed in the kidney and inner ear, usually occurs in the antenatal-neonatal period. We report an unusual case of late onset presentation of Bartter syndrome IV and mild phenotype in a 20 years-old man who had hypokalemia, deafness, secondary hyperparathyroidism and erythrocytosis.