1,720,973 research outputs found
Hypercholesterolemia in Childhood: How the Response to Diet could Lead to Diagnosis. Lesson from a Case-Report
No full textSitosterolemia shares clinical and biochemical features with homozygous familial hypercholesterolemia. Nevertheless, it is impressively responsive
to cholesterol-lowering diet. In our report, we demonstrate a rapid reduction of severe hypercholesterolemia in response to dietary
restriction in a young patient leading to the diagnosis of this rare disease. Early identification and treatment may prevent premature atherosclerosis
A novel deletion of BRCA1 gene that eliminates the ATG initiation codon without affecting the promoter region
No full textBackgroundPoint mutations in the highly penetrant cancer susceptibility gene BRCA1 are responsible for the majority of hereditary breast and/or ovarian cancer. We describe a novel large rearrangement of the BRCA1 gene identified in an Italian woman affected by an early onset bilateral breast cancer and a family history of hereditary breast cancer. The proband and her parents were negative for the presence of point mutations in BRCA1 and BRCA2 genes.MethodsMultiplex ligation-dependent probe amplification (MLPA) was used to detect rearrangements in the BRCA1 gene. The breakpoint of the rearrangement identified in the proband was defined by restriction mapping and PCR amplification. BRCA1 mRNA encoded by the mutant allele was isolated from peripheral blood.ResultsThe proband was heterozygous for a 9.1 kb deletion spanning from intron 1 to intron 3 (g.1238_10350del) that eliminates exons 2 and 3 in the mature mRNA. In mutant mRNA exon 1a joins directly to exon 5 with no disruption of the reading frame.ConclusionsThis deletion that eliminates the ATG initiation site in exon 2 and the sequence located in exons 2 and 3 encoding part of the RING finger domain of BRCA1 protein, is expected to abolish the function of this protein
Rearrangements of the ABCC6 gene in Italian patients with PXE
No full textThe objective of this study was to search for the deletion of exon 24 and exons 24-27 that had been previously reported in Italian patients affected by pseudoxanthoma elasticum, anb autosomal recessive disorder characterized by calcification and fragmentation of elastic fibers as a conseguence of mutations in the ABCC6 gene. To detect deletions in the ABCC6 gene the development and use of long range PCR procedure using appropriately designed primers are described
DIAGNOSI MOLECOLARE DELLE IPERTRIGLICERIDEMIE PRIMITIVE ATTRAVERSO “NGS” (NEXT GENERATION SEQUENCING)
No full textL’ipertrigliceridemia severa è
una condizione caratterizzata
da elevati livelli di trigliceridi
(TG) superiori a 1000 mg/dl
ed accumulo di chilomicroni a
digiuno. Questa condizione è
rivelata dalla presenza di
plasma lattescente e può essere
secondaria (es. in corso di
diabete scompensato,
sindrome nefrosica grave etc.)
o primitiva su base genetica. La
forma primitiva prende il
nome di Chilomicronemia
Familiare (CF).
Il quadro clinico della CF può
comprendere: coliche
addominali, pancreatiti
ricorrenti, xantomi eruttivi,
lipemia retinalis, ed
epatomegalia. Questo
disordine ha una modalità di
trasmissione autosomica
recessiva ed è dovuto a
mutazioni in uno dei geni
coinvolti nella cascata lipolitica
intravascolare, il processo
attraverso il quale i trigliceridi
trasportati dai chilomicroni e
dalle VLDL sono idrolizzati nel
plasma.
I principali geni candidati
tradizionalmente considerati
sono cinque: il gene LPL che
codifica per l’enzima lipasi
lipoproteica; il gene APOC2
ed il gene APOA5 che
codificano per due
apolipoproteine che svolgono il
ruolo di attivatori della LPL; il
gene GPIHBP1 che codifica la
piattaforma molecolare per la
LPL, ed infine il gene LMF1
che codifica per una proteina
coinvolta nella maturazione
intracellulare della LP
Clinical and genetic features of 3 patients with familial chylomicronemia due to mutations in GPIHBP1 gene
Full text linkBACKGROUND: Familial chylomicronemia is a recessive disorder that may be due to mutations in lipoprotein lipase (LPL) and in other proteins such as apolipoprotein C-II and apolipoprotein A-V (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface), and LMF1 (a factor required for intracellular formation of active LPL).
METHODS: We sequenced the familial chylomicronemia candidate genes in 2 adult females presenting long-standing hypertriglyceridemia and a history of acute pancreatitis.
RESULTS: Both probands had plasma triglyceride .10 mmol/L but no mutations in the LPL gene. The sequence of the other candidate genes showed that one patient was homozygous for a novel missense mutation p.(Cys83Arg), and the other was homozygous for a previously reported nonsense mutation p.(Cys 89*), respectively, in GPIHBP1. Family screening showed that the hypertriglyceridemic brother of the p.(Cys83Arg) homozygote was also homozygous for this mutation. He had no history of pancreatitis. The p.(Cys83Arg) heterozygous carriers had normal triglyceride levels. The substitution of a cysteine residue in the Ly6 domain of GPIHBP1 is predicted to abolish one of the
disulfide bridges required to maintain the structure of GPIHBP1. The p.(Cys89*) mutation results in a truncated protein devoid of function.
CONCLUSIONS: Both mutant GPIHBP1 proteins are expected to be incapable of transferring LPL from the subendothelial space to the endothelial surface
Leucine 10 allelic variant in signal peptide of PCSK9 increases the LDL cholesterol-lowering effect of statins in patients with familial hypercholesterolaemia.
No full textBACKGROUND AND AIMS: In the normal population, carriers of an additional leucine residue in a stretch of nine leucines in the signal peptide of PCSK9 (L10) have lower total (TC) and low-density lipoprotein cholesterol (LDL-C) than homozygotes for the wild-type allele (L9/L9). A similar effect was detected in familial hypercholesterolaemia (FH) patients with the p.C681X mutation of LDL-receptor (LDLR). We investigated the effect of L10 variant on basal lipid profile and response to statins in molecularly characterised FH patients.METHODS AND RESULTS: Plasma lipids were determined in 322 FH patients screened for the L9/L10/L11 polymorphism and in a subgroup of 54 patients carrying the same LDLR mutation (p.Q474HfsX63). Plasma lipids were also determined in 42 FH patients carrying the L10 variant and in a parallel group of 42 FH patients, L9/L9 homozygotes, matched for gender, age, type of LDLR gene mutation, as well as for type, dose and duration of statin treatment. In FH patients, no difference in the basal plasma TC and LDL-C levels was observed between carriers of L10 variant (L9/L10+L10/L10) and L9/L9 homozygotes. The same was true in FH patients carrying the p.Q474HfsX63 LDLR mutation. In the subgroups of statin-treated patients, the reduction of TC and LDL-C was greater in carriers of L10 (-34.0% and -42.5%, respectively) than in L9/L9 homozygotes (-27.5% and -34.3%, respectively) (P<0.001).CONCLUSION: The variant L10 of the leucine repeats in PCSK9 signal peptide is to be considered as a factor capable of modulating the lipid-lowering effects of statins in FH
Phenotypic variability in 4 homozygous familial hypercholesterolemia siblings compound heterozygous for LDLR mutations
No full textBACKGROUND: Homozygous familial hypercholesterolemia is a rare clinical phenotype with a
variable expression, which is characterized by extremely elevated plasma low-density lipoprotein
(LDL), tendon and skin xanthomas, and a progressive atherosclerosis. In 95% of patients, homozygous
familial hypercholesterolemia is due to mutations in low-density lipoprotein receptor
(LDLR) gene, which abolish (receptor-negative) or greatly reduce (receptor-defective) LDLR
function.
OBJECTIVE: The objective of the study was the molecular and phenotypic characterization of 4
siblings with severe hypercholesterolemia.
METHODS: The major LDL-related genes (LDLR, APOB, PCSK9, ANGPTL3, APOE, and
APOC3) were sequenced. LDLR messenger RNA, isolated from leukocytes, was reverse transcribed
and sequenced.
RESULTS: The index cases were 24-year-old identical twin sisters with long-standing tendon
xanthomas and high low-density lipoprotein cholesterol (LDL-C w10 mmol/L) but no coronary
heart disease. They were carriers of 2 LDLR mutations: (1) a previously reported mutation
[p.(G335S)] inherited from the mother who had LDL-C level within normal range; (2) a novel
24 bp deletion in exon 8/intron 8 junction inherited from the hypercholesterolemic (LDL-C
6.1 mmol/L) father. The deletion allele encodes an messenger RNA with a partial deletion of
exon 8, whose translation product has an in-frame deletion of 17 amino acids [p.(Glu380_Gly396-
del)]. Family screening revealed that the 2 siblings of the twin sisters were also compound heterozygotes
but had much lower LDL-C levels (8.2 and 7.1 mmol/L). The sequence of potential
modifying genes showed that the 2 siblings and the mother of the twin sisters were heterozygous
for a rare missense variant of apoB [p.(S2429T)], which might have an LDL-lowering effect
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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