Isolated polycystic liver disease genes define effectors of polycystin-1 function.

Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B.

Isolated polycystic liver disease genes define effectors of polycystin-1 function.

Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B.

Relationship between ubiquilin-1 and BACE1 in human Alzheimer's disease and APdE9 transgenic mouse brain and cell-based models.

Accumulation of β-amyloid (Aβ) and phosphorylated tau in the brain are central events underlying Alzheimer's disease (AD) pathogenesis. Aβ is generated from amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase-mediated cleavages. Ubiquilin-1, a ubiquitin-like protein, genetically associates with AD and affects APP trafficking, processing and degradation.

Quantitation of serum angiopoietin-like proteins 3 and 4 in a Finnish population sample.

We have developed and validated quantitative ELISAs for human angiopoietin-like (ANGPTL)3 and 4 and correlated their serum levels with parameters of lipid and carbohydrate metabolism. For this study, we used a random subsample of the Health 2000 Health Examination Survey consisting of 125 men and 125 women, aged 30-94 years. The anthropometric and biochemical parameters of subjects were characterized in detail.

Polycystic liver and kidney diseases.

There have been remarkable advances in research on polycystic liver and kidney diseases recently, covering cloning of new genes, refining disease classifications, and advances in understanding more about the molecular pathology of these diseases. Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary disease affecting kidneys. It affects 1/400 to 1/1000 live births and accounts for 5% of the end stage renal disease in the United States and Europe, and is caused by gene defects in the PKD1 or PKD2 genes.

Interrelationships between low density lipoprotein receptor defect, serum fatty acid composition, and serum cholesterol concentration.

It is known that, in the general human population, serum fatty acid composition is correlated with serum triacylglycerol and cholesterol concentrations. The goal of the present study was to analyze whether the same is true of individuals who have a low density lipoprotein receptor (LDL-R) defect. Concentrations of 16 different fatty acids, cholesterol, triacylglycerol, and major lipoproteins in serum were determined in eight individuals who had (FH-North Karelia), the most common LDL-R defect in Finland, which causes familial hypercholesterolemia, and in their 30 relatives belonging to a single large pedigree as controls.

Active and low-active forms of serum phospholipid transfer protein in a normal Finnish population sample.

Human serum phospholipid transfer protein (PLTP) exists as a catalytically active (HA-PLTP) and a low-active (LA-PLTP) form. In this study, the association of PLTP activity and the concentrations of both forms with lipid and carbohydrate parameters were investigated. In a random Finnish population sample, serum PLTP concentration (n=250) was 6.

Mutations in SEC63 cause autosomal dominant polycystic liver disease.

Mutations in PRKCSH, encoding the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum (ER), cause autosomal dominant polycystic liver disease. We found that mutations in SEC63, encoding a component of the protein translocation machinery in the ER, also cause this disease. These findings are suggestive of a role for cotranslational protein-processing pathways in maintaining epithelial luminal structure and implicate noncilial ER proteins in human polycystic disease.

Abnormal hepatocystin caused by truncating PRKCSH mutations leads to autosomal dominant polycystic liver disease.

Mutations in protein kinase C substrate 80K-H (PRKCSH), encoding for the protein hepatocystin, cause autosomal dominant polycystic liver disease (PCLD), which is clinically characterized by the presence of multiple liver cysts. PCLD has been documented in families from Europe (Netherlands, Belgium, Finland) as well as from the United States. In this article, we report results from extensive mutational analysis of the PRKCSH gene in a group of 14 PCLD families and 65 singleton cases of Dutch and Finnish descent with multiple simple liver cysts.

Quantitation of the active and low-active forms of human plasma phospholipid transfer protein by ELISA.

Human plasma contains two forms of phospholipid transfer protein (PLTP), one catalytically active [high-activity PLTP (HA-PLTP)] and the other a low-activity (LA-PLTP) form. We present here a PLTP ELISA that allows not only for accurate measurement of PLTP concentration in plasma but also of the distribution of both LA- and HA-PLTP. To achieve similar immunoreactivity of the two PLTP forms, a denaturing sample pretreatment with 0.

Polycystic liver disease is genetically heterogeneous: clinical and linkage studies in eight Finnish families.

Background/aims: Polycystic liver disease (PCLD), a dominantly inherited condition separate from polycystic kidney disease (PKD), has recently been found to be linked to a locus on chromosome 19p13.2-13.1 in two North American families.

Intestinal fatty acid binding protein polymorphism at codon 54 is not associated with postprandial responses to fat and glucose tolerance tests in healthy young Europeans. Results from EARS II participants.

Unlabelled: Polymorphism Ala54Thr of the intestinal fatty acid-binding protein 2 (FABP2) has been reported to have an effect on the protein's affinity for long chain fatty acids and to be associated with serum lipid and insulin levels in fasting and especially postprandial states. We wanted to test whether this genetic variation is associated with fasting and postprandial glucose, insulin or lipid levels in 666 male university students participating in the second European Atherosclerosis Study (EARS II). We also studied whether the subgroup of 330 students with paternal history of myocardial infarction (MI) before the age of 55 have different genotype distribution than 336 matched controls.

Quantification of human plasma phospholipid transfer protein (PLTP): relationship between PLTP mass and phospholipid transfer activity.

A sensitive sandwich-type enzyme-linked immunosorbent assay (ELISA) for human plasma phospholipid transfer protein (PLTP) has been developed using a monoclonal capture antibody and a polyclonal detection antibody. The ELISA allows for the accurate quantification of PLTP in the range of 25-250 ng PLTP/assay. Using the ELISA, the mean plasma PLTP concentration in a Finnish population sample (n = 159) was determined to be 15.

Development of molecular genetics.

Human genetics has rapidly evolved from vague impression that descendants resemble their parents, to science which is now of utmost importance to the development of new principles and practice in medicine. It was only in the beginning of this century when it was suggested that chromosomes might carry genetic information. During the two last decades researchers have developed amazing methods to study and manipulate genes.

Serum phospholipid transfer protein activity and genetic variation of the PLTP gene.

The inverse relationship between serum levels of high density lipoproteins (HDL) and risk of coronary heart disease is well established. The phospholipid transfer protein (PLTP) promotes the transfer of phospholipids between lipoproteins and modulates HDL size and composition. It thus plays a central role in HDL metabolism.

Cholesteryl ester transfer protein gene effect on CETP activity and plasma high-density lipoprotein in European populations. The EARS Group.

Background: Variation at the cholesteryl ester transfer protein (CETP) gene locus has been implicated in determining the levels and activity of CETP, apoAI and high-density lipoprotein (HDL) plasma concentration and the risk of developing coronary artery disease.

Study Design: The effects of two common polymorphisms of CETP, TaqIB in intron 1 and isoleucine 405 to valine (I405-->V) in exon 14, were examined in a sample of 822 men age 18-28 years from 11 countries in Europe who had participated in a study (the European Atherosclerosis Research Study II) of the offspring of myocardial infarction sufferers before the age of 55 years and age-matched control subjects.

Results: The frequency of the rare TaqIB allele (B2) and the rare V405 allele was 0.

Haplotypes of the ApoA-I/C-III/A-IV gene cluster and familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is the most frequent familial lipoprotein disorder associated with premature coronary heart disease. However, no genetic defect(s) underlying FCHL has been identified. A linkage between FCHL and the apoA-I/C-III/A-IV gene cluster has been reported but not verified in other populations.

Autosomal recessive cornea plana. A clinical and genetic study of 78 cases in Finland.

Purpose: To review the literature of autosomal recessive cornea plana (RCP) and to perform a clinical and genetic study on this disorder in Finland. The 78 Finnish RCP patients represent the majority of RCP cases worldwide; outside Finland only 35 cases have been reported.

Methods: Families with RCP, particularly in northern Finland, have been followed up by the senior author since the 1950s and extensive genealogical studies have been made.

Association of variation in hepatic lipase activity with promoter variation in the hepatic lipase gene. The LOCAT Study Invsestigators.

The associations between six genetic polymorphisms in the hepatic lipase (HL) gene (LIPC) and variation in postheparin HL activity and fasting serum lipoproteins were evaluated in 395 male Finnish coronary heart disease patients with HDL cholesterol concentrations View Article and Find Full Text PDF

Hepatic lipase gene polymorphisms influence plasma HDL levels. Results from Finnish EARS participants. European Atherosclerosis Research Study.

Hepatic lipase (HL), a triglyceride lipase found in liver, adrenals, testes, and ovaries, takes part in the uptake, remodeling, and function of lipoproteins including HDL, as well as VLDL and chylomicrons. In the present study, the genotype distribution of five HL polymorphisms (-C480T, V133V, T202T, L334F, T457T) and their association to plasma lipid values were investigated. The study participants included 92 students with paternal history of myocardial infarction before the age of 55 and 194 matched control subjects, ie, the Finnish participants of the European Atherosclerosis Research Study (EARS).

Refined mapping of the Cohen syndrome gene by linkage disequilibrium.

The Cohen syndrome is a rare autosomal recessively inherited disorder. Contrary to many case reports published elsewhere, the phenotype is uniform in Finland including nonprogressive mental and motor retardation, typical dysmorphic features, granulocytopenia and marked ophthalmological changes. By linkage analysis in five Finnish multiplex nuclear families, the COH1 locus for the Cohen syndrome was recently assigned to a 10-cM region between loci D8S270 and D8S521 on the long arm of chromosome 8.

Autosomal dominant cornea plana: clinical findings in a Cuban family and a review of the literature.

Cornea plana may occur in connection with malformations of the eye or of other parts of the body. As an isolated ocular anomaly, it may be inherited in an autosomal recessive or in an autosomal dominant fashion. We have previously mapped genes for both forms of the disease to 12q21.

Linkage disequilibrium and physical mapping of X-linked juvenile retinoschisis.

X-linked juvenile retinoschisis (RS) is a recessively inherited disorder resulting in poor visual acuity. Affected males typically show retinal degeneration and intraretinal splitting. The prevalence of RS is 1:15,000-1:30,000.