The role of genes in growth and later health.

Genetic factors are of importance for the development of the metabolic syndrome and type 2 diabetes, but despite extensive research the identification of the underlying genes has not been fruitful. This report focuses on the interactions between intrauterine growth and genes in relation to adult health outcomes based upon findings from the Helsinki Birth Cohort Study. Candidate genes for type 2 diabetes and the metabolic syndrome have been focused upon and we report on interactions between polymorphisms of the peroxisome proliferator-activated receptor (PPAR)gamma-2, plasma cell glycoprotein (PC-1) and the glucocorticoid receptor (GR) genes and - prenatal growth in relation to adult health outcomes.

Cardiovascular risk: prevention and treatment of the metabolic syndrome.

The metabolic syndrome is a cluster of metabolic abnormalities, including impaired glucose metabolism, hypertension, dyslipidemia and abdominal obesity. It is a precursor to type 2 diabetes and a powerful independent risk factor for cardiovascular disease. Lifestyle changes, such as a diet high in saturated fats and a lack of physical exercise, have contributed to a worldwide increase in the prevalence of the metabolic syndrome and its associated complications.

Mice with Ppt1Deltaex4 mutation replicate the INCL phenotype and show an inflammation-associated loss of interneurons.

Infantile Neuronal Ceroid Lipofuscinosis (INCL) results from mutations in the palmitoyl protein thioesterase (PPT1, CLN1) gene and is characterized by dramatic death of cortical neurons. We generated Ppt1Deltaex4 mice by a targeted deletion of exon 4 of the mouse Ppt1 gene. Similar to the clinical phenotype, the homozygous mutants show loss of vision from the age of 8 weeks, seizures after 4 months and paralysis of hind limbs at the age of 5 months.

A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging.

Neuronal ceroid lipofuscinoses (NCL) comprise the most common group of childhood encephalopathies caused by mutations in eight genetic loci, CLN1-CLN8. Here, we have developed a novel mouse model for the human vLINCL (CLN5) by targeted deletion of exon 3 of the mouse Cln5 gene. The Cln5-/- mice showed loss of vision and accumulation of autofluorescent storage material in the central nervous system (CNS) and peripheral tissues without prominent brain atrophy.

Use of population isolates for mapping complex traits.

Geneticists have repeatedly turned to population isolates for mapping and cloning Mendelian disease genes. Population isolates possess many advantages in this regard. Foremost among these is the tendency for affected individuals to share ancestral haplotypes derived from a handful of founders.

White coat effect, blood pressure and mortality in men: prospective cohort study.

Background: Because long-term follow-up studies, which also included normotensive controls, have been lacking, the clinical significance of 'white coat' effect and of 'white coat' hypertension has remained controversial.

Methods And Results: Twenty-one-year prospective data was gathered in 536 men with cardiovascular risk factors at baseline. Blood pressure was measured both by a nurse and by a physician and 'white coat effect' was defined as the difference between the two measurements (physician minus nurse).

Cells of the neuronal lineage play a major role in the generation of amyloid precursor fragments in gelsolin-related amyloidosis.

Gelsolin-related amyloidosis or familial amyloidosis, Finnish type (FAF) (OMIM No105120) is a hereditary amyloid disease caused by a mutation in a precursor protein for amyloid (gelsolin) and characterized by corneal dystrophy and polyneuropathy. In vitro expression of the FAF-mutant (Asp187 --> Asn/Tyr) secretory gelsolin in COS cells leads to generation of an aberrant polypeptide presumably representing the precursor for tissue amyloid. Here, we provide evidence that this abnormal processing results from defective initial folding of the secreted FAF gelsolin due to the lack of the Cys188-Cys201 disulfide bond, normally formed next to the FAF mutation site.

Several cooperating binding sites mediate the interaction of a lysosomal enzyme with phosphotransferase.

Lysosomal targeting of soluble lysosomal hydrolases is mediated by mannose 6-phosphate receptors, which recognize and bind mannose 6-phosphate residues in the oligosaccharide chains of proteins destined for delivery to lysosomes. This recognition marker is generated by the sequential action of two enzymes, the first of which, UDP-N-acetylglucosamine phosphotransferase, recognizes lysosomal enzymes on the basis of a structural determinant in their polypeptide chains. This recognition event is a key step in lysosomal targeting of soluble proteins, but the exact nature of the recognition determinant is not well understood.