Masturzo P

Analysis of LDL Receptor Gene Mutations in Italian Patients With Homozygous Familial Hypercholesterolemia

The aim of this study was the characterization of mutations of the LDL receptor gene in 39 Italian patients with homozygous familial hypercholesterolemia, who were examined during the period 1994 to 1996. The age of the patients ranged from 1 to 64 years; one third of them were older than 30. Plasma LDL cholesterol level ranged from 10.8 to 25.1 mmol/L. The residual LDL receptor activity, measured in cultured fibroblasts of 32 patients, varied from <2% to 30% of normal and was inversely correlated with the plasma LDL cholesterol level (r=-0.665; P<0.003). The most severe coronary atherosclerosis was observed in those patients with the lowest residual LDL receptor activity (</=5% of normal) and the highest plasma LDL cholesterol levels. Twenty-nine patients (23 of whom were unrelated) were found to be homozygotes at the LDL receptor locus. In this group we discovered 2 major rearrangements and 12 different point mutations (9 in the coding region and 3 in splice sites). Some mutations (D200G, C358R, V502M, G528D, and P664L) were found in 3 or more unrelated patients. Patients with the same mutation shared the same haplotype at the LDL receptor gene locus and came from the same geographic area. Ten patients (9 of whom were unrelated) were found to be compound heterozygotes. The mutations found in this group consisted of one large deletion and 12 point mutations (11 in the coding sequence and one in a splice site). In 3 compound heterozygotes we failed to identify the second mutant allele at the LDL receptor locus. These observations confirm the allelic heterogeneity underlying familial hypercholesterolemia in the Italian population and indicate that the variability of phenotypic expression of homozygous familial hypercholesterolemia is, to a large extent, related to the type of mutation of the LDL receptor gene.

Influence of β0-Thalassemia on the Phenotypic Expression of Heterozygous Familial Hypercholesterolemia

One of the genetic features of the Sardinian population is the high prevalence of hemoglobin disorders. It has been estimated that 13% to 33% of Sardinians carry a mutant allele of the alpha-globin gene (alpha-thalassemia trait) and that 6% to 17% are beta-thalassemia carriers. In this population, a single mutation of beta-globin gene (Q39X, beta(0) 39) accounts for >95% of beta-thalassemia cases. Because previous studies have shown that Sardinian beta-thalassemia carriers have lower total and low density lipoprotein (LDL) cholesterol than noncarriers, we wondered whether this LDL-lowering effect of the beta-thalassemia trait was also present in subjects with familial hypercholesterolemia (FH). In a group of 63 Sardinian patients with the clinical diagnosis of FH, we identified 21 unrelated probands carrying 7 different mutations of the LDL receptor gene, 2 already known (313+1 g>a and C95R) and 5 not previously reported (D118N, C255W, A378T, T413R, and Fs572). The 313+1 g>a and Fs572 mutations were found in several families. In cluster Fs572, the plasma LDL cholesterol level was 5.76+/-1.08 mmol/L in subjects with beta(0)-thalassemia trait and 8.25+/-1.66 mmol/L in subjects without this trait (P<0.001). This LDL-lowering effect was confirmed in an FH heterozygote of the same cluster who had beta(0)-thalassemia major and whose LDL cholesterol level was below the 50th percentile of the distribution in the normal Sardinian population. The hypocholesterolemic effect of beta(0)-thalassemia trait emerged also when we pooled the data from all FH subjects with and without beta(0)-thalassemia trait, regardless of the type of mutation in the LDL receptor gene. The LDL-lowering effect of beta(0)-thalassemia may be related to (1) the mild erythroid hyperplasia, which would increase the LDL removal by the bone marrow, and (2) the chronic activation of the monocyte-macrophage system, causing an increased secretion of some cytokines (interleukin-1, interleukin-6, and tumor necrosis factor-alpha) known to affect the hepatic secretion and the receptor-mediated removal of apolipoprotein B-containing lipoproteins. The observation that our FH subjects with beta(0)-thalassemia trait (compared with noncarriers) have an increase of blood reticulocytes (40%) and plasma levels of interleukin-6 (+60%) supports these hypotheses. The lifelong LDL-lowering effect of beta(0)-thalassemia trait might slow the development and progression of coronary atherosclerosis in FH.

Pseudodominance of lipoprotein lipase (LPL) deficiency due to a nonsense mutation (Tyr302>Term) in exon 6 of LPL gene in an Italian family from Sardinia (LPLOlbia)

We analyzed the molecular defect in the lipoprotein lipase (LPL) gene of a young boy from Sardinia who had primary hyperchylomicronemia, pancreatitis, and a complete LPL deficiency in post‐heparin plasma. Analysis of LPL gene was performed by using single strand conformation polymorphism (SSCP) and direct sequencing of SSCP‐positive region. The proband was homozygous for a C>A transversion in exon 6, which converts the codon for tyrosine at position 302 into a termination codon and eliminates an RsaI restriction site; this allowed the rapid screening of the probands family members, among whom nine heterozygotes and one additional homozygote were identified. The homozygote was the probands paternal grandmother who had shown the first clinical manifestation (recurrent pancreatitis) of LPL deficiency at the age of 54 years. LPL mutation carriers showed a mild dyslipidemic phenotype characterized by a reduction of high density lipoprotein‐cholesterol (HDL‐C) levels, HDL‐C/total cholesterol ratio, and low density lipoprotein (LDL) size, associated with a variable increase of triglyceride levels. Five of these carriers were also heterozygotes for β°‐thalassemia (Q39X mutation). In these double mutation carriers, plasma HDL‐C levels were higher and plasma triglycerides tended to be lower than in carriers of LPL mutation alone. The Tyr302>Term mutation encodes a truncated protein of 301 amino acids that is probably not secreted by the LPL producing cells. This is the first mutation of LPL gene found in Sardinians.

Circadian rhythmicity of prolactin secretion in elderly subjects: changes during bromocriptine treatment

Prolactin has been taken as an index of neuroendocrine function in aging, where dopaminergic neurotransmission in considered to be impaired. The mean concentration of the hormone in the 24 h is higher in the aged men than in the adult controls. A sleep entrained periodicity is present in both aged subjects and controls, but a harmonic analysis of rhythmicity shows that secretory episodes have in aged men a slower periodicity than in adults. In aged men bromocriptine decreases the mean PRL values in the 24 h and the periodicity analysis shows the occurrence of harmonics with shorter period.

Changes in Pituitary Hormones Serum Levels in Bromocryptine-Treated Parkinsonian Patients

In the course of a clinical trial with 2alpha-bromoergocryptin in Parkinsons disease, the serum levels of several pituitary hormones have been studied in the assumption that the drug active on nigro-striatal dopaminergic system might also interfere with hypothalamus-protuberantial neurotransmission, and have effects on the function of the pituitary. No changes in serum levels of FSH, LH, STH and TSH were detected for every dose of the drug employed. Only prolactin serum levels diminished since the beginning of the treatment, the decrease being significant (p less than 0.05 and p less than 0.01). This effect on prolactin does not change in the dose range considered. Clinical improvement was observed for doses of drugs above 15 mg/day, whereas the effect on prolactin secretion occurred with the dose of 7.5 mg/day.

Thyroid-stimulating hormone and prolactin responses to thyrotropin-releasing hormone in common migraine

Intravenous administration of 50 μg or 200 μg thyrotropin-releasing hormone (TRH) to men with common migraine elicited blunted prolactin (PRL) responses, when compared with healthy controls. The thyroid-stimulating hormone (TSH) response was enhanced after 50 μg TRH in the migraineurs, but not after 200 μg. The physiologic TSH dose-response relationship was abolished in migraine sufferers. The data may be interpreted in the light of dopaminergic and noradrenergic supersensitivity, for PRL and TSH, respectively. The TSH response in migraine differs from the one that occurs in depression.

Circadian rhythmicity of prolactin secretion in Huntington's Chorea

Abstract Prolactin circadian secretion has been studied in 16 males and in 8 females with Huntingtons Chorea, in order to evaluate changes of the hormones titres and of their periodicity in a condition where alterations of neurotransmission have been documented. Prolactin levels have been found normal, enhanced and low levels have been observed in one male case. Sleep connected surge has been found to be present in all cases. A harmonic analysis of periodical changes has been performed by a Fouriers cosines series. The changes in the occurence of different harmonic frequencies in respect to normal controls are not significant. No correlation could be drawn among clinical indices, hormone levels and the feature of the occurring harmonics.

Chorionic DNA analysis for the prenatal diagnosis of familial hypercholesterolaemia

Prenatal diagnosis for familial hypercholesterolaemia (FH) was performed by using restriction fragment length polymorphisms (RFLPs) of the LDL receptor gene on chorionic villi DNA taken during the 10th week of pregnancy. Both parents were FH heterozygotes and had previously had a healthy son and an FH homozygous son. Two RFLPs were informative in this family and revealed that the fetus was unaffected by FH. At birth the child was found to have an LDL cholesterol level of 30 mg/dl and a normal LDL receptor activity in cultured umbilical cord fibroblasts. RFLP analysis on chorionic villi DNA is highly recommended for all heterozygous FH couples in whom the LDL receptor gene mutation/s is/are still to be characterized.

Lack of Counteracting Effect of Liposomes on Benserazide-Induced Hyperprolactinemia

Benserazide induces an increase of serum prolactin in man, possibly as the result of an impairment of the dopamine effect on the pituitary and/or on the outer median eminence caused by the inhibition on L-dopa decarboxylase. On the other hand, liposomes obtained from bovine brain cortex phospholipids reduced serum prolactin possibly through an effect of phosphatidylserine on dopamine biosynthesis at the level of tyrosine hydroxylase. Benserazide, given orally (125 mg) to 5 normal subjects, induced an increase of serum prolactin that did not change when 300 mg of phospholipid liposomes were given intravenously 60 min later. An increase of L-dopa synthesis does not seen to be capable to overcome the effects of the decarboxylase inhibition.

Sleep-wake differences in serum prolactin levels in children

Sleep-wake differences in prolactin serum levels have been studied in 47 prepubertal children of both sexes, aged 1 to 12 years. Sampling has been made in each subject once during wake and once during sleep. The serum levels of prolactin were found to be higher during sleep than during wake (p >0.01). When the children were divided into age groups, a statistically significant difference between wake and sleep was observed in all groups considered, including that with children aged 1 to 2 years. This indicates that the sleep connected rise of prolactin levels occurs very early in childhood. No sex related difference either in absolute hormone serum levels or in wake-sleep changes is apparent.