An integrated map of chromosome 18 CAG trinucleotide repeat loci.

Expansions of trinucleotide CAG repeats have been demonstrated in at least eight neurodegenerative disorders, and suggested to occur in several others, including bipolar disorder and schizophrenia. Chromosome 18 loci have been implicated in bipolar disorder pedigrees by linkage analysis. To address this putative link between chromosome 18 CAG trinucleotide repeats and neuropsychiatric illness, we have screened a chromosome 18 cosmid library (LL18NCO2" AD") and identified 14 novel candidate loci.

The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice.

Neuropeptide Y (NPY) and the endogenous melanocortin receptor antagonist, agouti gene-related protein (AGRP), coexist in the arcuate nucleus, and both exert orexigenic effects. The present study aimed primarily at determining the brain distribution of AGRP. AGRP mRNA-expressing cells were limited to the arcuate nucleus, representing a major subpopulation (95%) of the NPY neurons, which also was confirmed with immunohistochemistry.

Multivariate analysis of factors influencing repeat expansion detection.

Repeat expansion detection (RED) is a powerful tool for detection of expanded repeat sequences in the genome. In RED, DNA serves as a template for a repeat-specific oligonucleotide. A thermostable ligase is used to ligate oligonucleotides that have annealed at adjacent positions, creating multimers in a thermal cycling procedure.

Two commonly expanded CAG/CTG repeat loci: involvement in affective disorders?

An association between bipolar affective disorder and CAG/CTG trinucleotide repeat expansions (TRE) has previously been detected using the repeat expansion detection (RED) method. Here we report that 89% of RED products (CAG/CTG repeats) > 120 nt (n = 202) detected in affective disorder patients as well as unaffected family members and controls correlate with expansions at two repeat loci, ERDA1 on chromosome 17q21.3 and CTG18.

Low leptin gene expression and hyperleptinemia in chronic renal failure.

Background: The ob gene product leptin is thought to be a key regulator of food intake and body weight. Patients having advanced chronic renal failure (CRF) have markedly higher serum leptin levels. It is not known whether the increase in leptin levels in CRF is caused by a decreased plasma clearance and/or increased production.

Reduced gene expression of UCP2 but not UCP3 in skeletal muscle of human obese subjects.

Massive overweight is an increasing health problem and underlies several complications which in turn result in premature death. The mechanisms underlying the imbalance between energy intake and energy expenditure, that lead to obesity in humans, are still only partly understood. In rodents, heat generation and the burning of calories by the mitochondrial uncoupling protein 1 (UCP1) are important for metabolic control.

Large CAG/CTG repeats are associated with childhood-onset schizophrenia.

Recent studies have shown an association between trinucleotide repeat expansions (TREs) and adult-onset schizophrenia (AOS). Childhood-onset schizophrenia (COS) is a severe variant of schizophrenia with onset of symptoms before age 12 years. We have used the repeat expansion detection (RED) method to investigate the occurrence of repeat expansions in a group of well-characterized COS patients as well as a set of clinically related childhood-onset psychosis cases labeled 'multidimensionally impaired' (MDI).

Differential expression of IGF-I and IGF-binding protein-1 and -2 in periportal and perivenous zones of rat liver.

IGF-I has important roles in regulating growth and metabolism. Circulating IGF-I is bound to specific binding proteins (IGFBP-1 to -6), with hepatocytes containing IGF-I, IGFBP-1 and -2 mRNA. Although many hepatic proteins are regionally expressed in the liver acinus, no studies have reported zonation of IGF protein expression.

Neuropeptide Y: some viewpoints on a multifaceted peptide in the normal and diseased nervous system.

Using immunohistochemical and in situ hybridization methodologies the localization of neuropeptide tyrosine (NPY) and two of its receptors, the Y1- and the Y2-receptor (R), has been analysed in various tissues in normal animals and animals subjected to different experimental procedures as well as animals with a genetic and an acquired disease. (1) Dorsal root ganglion (DRG) neurons are discussed with special focus on the effect of peripheral nerve injury. In normal DRG neurons NPY cannot be detected, whereas Y1-R mRNA and Y1-R-like immunoreactivity (LI) are strongly expressed.

Linkage analysis of candidate loci in families with recurrent major depression.

Recurrent major depression, RMD, is characterized by the occurrence of depressive episodes in the absence of mania and/or hypomania. In linkage studies, RMD (or, in general, unipolar depression) are frequently grouped together with bipolar illnesses into a broad definition of affective disorders. However, twin studies suggest that RMD and bipolar disorders might have different genetic determinants.

Expanded trinucleotide CAG repeats in families with bipolar affective disorder.

Clinical anticipation has been reported in bipolar affective disorder (BPAD). The hypothesis that expanded trinucleotide repeats are related to anticipation and transmission pattern in families with bipolar affective disorder is tested in this study. Eighty-seven two-generation pairs of patients recruited from 29 bipolar families were analyzed.

Increased leptin messenger RNA and serum leptin levels in children with Prader-Willi syndrome and nonsyndromal obesity.

To study the potential role of the ob gene pathway in childhood obesity, we have investigated leptin mRNA levels in s.c. adipose tissue obtained from nonobese prepubertal children (n = 20), obese nonsyndromal children (n = 6), and children with Prader-Willi syndrome (n = 6) by in situ hybridization histochemistry.

Polymorphic expression of multidrug resistance mRNA in lung parenchyma of nonpregnant and pregnant rats: a comparison to cystic fibrosis mRNA expression.

Multidrug resistance (MDR1b) and cystic fibrosis transmembrane conductance regulator (CFTR) proteins are members of the "ATP-binding cassette" superfamily of transporters. They are associated with chloride channel activities and ATP secretion and have complementary patterns of expression in several organs. In the rat uterus, CFTR expression is replaced by MDR1b expression during pregnancy.

Tumor-specific decreased expression of calcium sensing receptor messenger ribonucleic acid in sporadic primary hyperparathyroidism.

Secretion of PTH is regulated by extracellular calcium via calcium receptors (CaR) on the parathyroid cell surface. Recent studies have shown a decreased expression of CaR messenger RNA (mRNA) and CaR protein in pathological parathyroids. We studied the expression of CaR mRNA in pairs of adenoma and adenoma-associated normal gland from the same patients (n = 17) and in biopsies of normal parathyroid glands of normocalcemic subjects (n = 4) using in situ hybridization with oligonucleotide probes on frozen sections.

Protein kinase C in the developing kidney: isoform expression and effects of ceramide and PKC inhibitors.

Protein kinase C (PKC) is a serine/threonine kinase recognized as a key enzyme in signal transduction mechanisms in various biological processes. During development, PKC is involved in the regulation of growth and differentiation. In mature tissue PKC is important for homeostatic functions.

Hypothalamic neurohistochemistry of the murine anorexia (anx/anx) mutation: altered processing of neuropeptide Y in the arcuate nucleus.

Neuropeptide Y is one of the most powerful neurochemical stimulants of food intake known. The neuronal substrate for this action is believed to be the neuropeptide Y-expressing cell population in the hypothalamic arcuate nucleus. In this study, mice homozygous for the anorexia mutation (anx) were investigated histochemically; anx is a recessive mutation that causes decreased food intake and starvation, leading to death 22 days after birth.

Effect of in vitro promoter methylation and CGG repeat expansion on FMR-1 expression.

Fragile X syndrome is associated with a CGG repeat expansion in the 5'-untranslated region of the FMR-1 gene. Within the FMR-1 promoter a CpG island is frequently methylated in fragile X patients. To identify the effect of methylation on FMR-1 expression, we transfected methylated and unmethylated constructs containing the FMR-1 promoter in front of the CAT gene (pFXCAT) into COS-1 cells.

A high ratio of insulin-like growth factor II/insulin-like growth factor binding protein 2 messenger RNA as a marker for anaplasia in meningiomas.

Insulin-like growth factors (IGFs) I and II have been implicated as autocrine or paracrine growth promoters. These growth factors bind to specific receptors, and the response is modulated by interaction with IGF-binding proteins (IGFBPs). We observed a strong correlation between anaplastic/atypical histopathology and a high IGF-II/IGFBP-2 mRNA ratio in a set of 68 sporadic meningiomas.

Leptin secretion from adipose tissue in women. Relationship to plasma levels and gene expression.

The role of expression and secretion of the ob gene product, leptin, for the regulation of plasma leptin levels has been investigated in vitro using abdominal subcutaneous adipose tissue of 20 obese, otherwise healthy, and 11 nonobese women. Body mass index (BMI, mean+/-SEM; kg/m2) in the two groups was 41+/-2 and 23+/-1, respectively. Fat cell volume was 815+/-55 pl in the obese and 320+/-46 pl in the nonobese group.

Schizophrenia and neurotrophin-3 alleles.

Studies of brain anatomy and premorbid functioning indicate that schizophrenia may be of neurodevelopmental origin. In the neurotrophic factor neurotrophin-3 (NT-3) gene, the A3/147-bp allele in a dinucleotide repeat polymorphism located in the promoter region was found to be associated with schizophrenia in a Japanese study. Another NT-3 polymorphism (Glu63Gly) indicated an association with schizophrenic patients with a putative neurodevelopmental form of the disease.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a recently described genetic disease characterized by recurrent subcortical infarcts and dementia. Based on linkage analysis its gene has been assigned to chromosome 19p13. We report an Australian kindred with typical clinical features of CADASIL, the diagnosis being supported by linkage analysis.