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An SNP array-based genome-wide linkage analysis is conducted to explain the molecular basis and symptoms of the adducted thumb-clubfoot syndrome. The results demonstrate that a particular defect of dermatan sulfate biosynthesis is the main factor that leads to the onset of the autosomal-recessive disorder.

A genome-wide SNP scan is used to study the characteristics and causes of the syndromic form of the autosomal-recessive congenital sodium diarrhea (CSD). The classic CSD is shown to be distinct from the syndromic CSD, which is shown to be caused by the mutations caused in SPINT2.

Studies reveal a genetic migrational pattern among populations along the Nile River Valley. Using first hypervariable segment sequences of the control region of the mtDNA, coupled with a polymorphic Hpa1 site, researchers were able to determine the migrations to be between a few hundred to a few thousand years old, and predominantly from south to north.

The Smith-Lemli-Opitz syndrome (SLOS) is an inborn disorder of sterol metabolism with characteristic congenital malformations and dysmorphias. All patients suffer from mental retardation. Here we identify the SLOS gene as a [Delta]7-sterol reductase (DHCR7, EC 1.3.1.21) required for the de novo biosynthesis of cholesterol. The human and murine genes were characterized and assigned to syntenic regions on chromosomes 11q13 and 7F5 by fluorescense in situ hybridization. Among the mutations found in patients with the SLOS, are missense (P51S, T93M, L99P, L157P, A247V, V326L, R352W, C380S, R404C, and G410S), nonsense (W151X), and splice site (IVS8-1G>C) mutations as well as an out of frame deletion (720-735 del). The missense mutations L99P, V326L, R352W, R404C, and G410S reduced heterologous protein expression by >90%. Our results strongly suggest that defects in the DHCR7 gene cause the SLOS.

A study was conducted to examine possible intracellular metabolism of human liver cell's apolipoprotein(a) which can be found in lipoproteins. The subcellular localization and fate of apolipoprotein(a) in stably transfected HepG2cells were analyzed. Results revealed that apolipoprotein(a) was synthesized as a precursor with a lower molecular mass that was processed into secreted, mature form which was observed at low levels in the Golgi apparatus. Such results suggested that apolipoprotein which was dependent on its isoform was retained due to extensive maturation process.

Blood lipoprotein(a) (Lp(a)) levels appear to be the most important risk factor for target-organ damage in patients with hypertension. Lipoprotein(a) is low-density lipoprotein (LDL) attached to a protein called apolipoprotein(a). Researchers analyzed Lp(a) levels in 277 patients with untreated hypertension and 102 people with normal blood pressure. Lp(a) was the best predictor of target-organ damage. Blood pressure, duration of hypertension and LDL cholesterol levels were also associated with target-organ damage. Low molecular weight forms of apolipoprotein(a) were also associated with target-organ damage., Objective. -- To investigate the association between lipoprotein(a) [Lp(a)] and other plasma lipids and apolipoproteins and target-organ damage (TOD) in patients with arterial hypertension. Design. -- Cross-sectional study of a case series. Setting. -- University medical center. Participants. -- Lipoprotein(a) and apolipoproteins were analyzed in 277 untreated patients with mild to moderate essential hypertension and in 102 healthy controls. Apolipoprotein(a) [apo(a)] phenotypes were additionally analyzed in an independent sample set of 106 hypertensive and 105 control subjects. Main Outcome Measures. -- Staging of TOD obtained according to World Health Organization guidelines by clinical evaluation, and laboratory tests including measurements of creatinine clearance, proteinuria, ophthalmoscopy, electrocardiography, echocardiography, and ultrasound examination of major arteries; levels of lipids, apolipoproteins, Lp(a), fibrinogen, and apo(a) phenotypes. Results. -- Blood pressure, duration of hypertension, and levels of total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, Lp(a), and fibrinogen were significantly related to the presence and severity of TOD in univariate analysis. Stepwise multivariate analysis showed Lp(a) levels (P [is less than].001) to be the best discriminator of the presence of TOD, followed by systolic blood pressure P [is less than] .001), duration of hypertension (P = .01), and low-density lipoprotein cholesterol (P =. 04). The Lp(a) levels were related to TOD independent of the level of blood pressure. We confirmed this association between Lp(a) concentrations and severity of TOD in a second independent sample set and observed a significantly higher frequency of low-molecular-weight apo(a) isoforms with increasing severity of TOD (P = .02). Conclusions. - Lipoprotein(a) and apo(a) phenotype are sensitive indicators of the severity of TOD in patients with essential hypertension, and their evaluation might permit identification of hypertensive subjects liable to the development of organ damage. The higher frequency of low-molecular-weight apo(a) isoforms in patients with TOD demonstrates a genetically determined risk for the development of TOD in hypertensive patients.

A 'transferrinfection' apolipoprotein a (apo(a)) system involving transferrin receptor- and adenovirus receptor-mediated DNA influx into cells allows the characterization of the function of kringle IV sequence during the extracellular attachment of low-density lipoprotein (LDL) and indicates that several kringle IV sequences are essential for the attachment other than kringle IV-36. Mixing of normal human plasma LDL and 18, 15 or 9 kringle IV repeats results in stable complexes, while site-directed mutagenesis of Arg residue results in the inhibition of extracellular attachment. The r-apo(a) carbohydrate moiety has no effect on the extracellular attachment of LDL, implicating the occurrence of protein-protein interactions between apoB and r-apo(a).

Human hepatocarcinoma cell line, HepG2, is used for analyzing the role of Cys4057 in the lipoprotein(a) (Lp(a)) assembly, containing one copy of apolipoprotein B-100 and apolipoprotein (a). Analyses of cDNA plasmid expression in human hepatocarcinoma line HepG2 reveal the transformation of the amino acid sequence of apolipoprotein from Cys4057 to either serine or glycine. Experimental results corroborate the presence of a disulfide bond between Cys4057 of apolipoprotein (a) and apolipoprotein B-100, located within recombinant lipoprotein (a) particles. This bridge is vital to the integrity of lipoprotein (a)-like complex assembly which is synthesized by HepG2 cells.

Familial hypercholesterolemia is an inherited condition in which levels of low-density lipoprotein (LDL) cholesterol are unusually high because the body cannot break down LDL cholesterol normally. Persons with this disorder are at increased risk for developing coronary artery disease (CAD), yet not all these individuals do develop CAD. This suggests that there are other important risk factors involved. One such factor may be elevated lipoprotein(a), a substance found in the blood which appears to contribute to the accumulation of fatty plaques in the arteries serving the heart, much as LDL cholesterol does. A group of 115 persons with familial hypercholesterolemia was studied to evaluate whether lipoprotein(a) level was correlated with occurrence of CAD. The blood level of lipoprotein(a) in the 54 subjects with CAD was significantly higher than in the other 61 subjects who did not have CAD. Of all the factors studied, including age, sex, smoking habits, and all other blood lipids, lipoprotein(a) was the variable that best distinguished between the CAD group and the group without this disease. Genetic analysis of most subjects was also performed to identify different types of the compound apolipoprotein(a), which affects lipoprotein(a) level. Differences were found between the groups with and without CAD in the genetic varieties of apolipoprotein(a) that were present. It is concluded that a high level of lipoprotein(a) is a strong risk factor for CAD in persons with familial hypercholesterolemia, and that the high lipoprotein(a) levels in the patients with CAD were inherited. (Consumer Summary produced by Reliance Medical Information, Inc.)