BACKGROUND X-linked dominant chondrodysplasia punctata, also known as Conradi-H ünermann-Happle syndrome, is a rare skeletal dysplasia characterized by short stature, craniofacial defects, cataracts, ...ichthyosis, coarse hair, and alopecia. Conradi-H ünermann-Happle syndrome is caused by mutations in the gene EBP encoding Δ8- Δ7 sterol isomerase emopamil-binding protein. Random X-inactivation could account for the intrafamilial variability of the phenotype of X-linked dominant chondrodysplasia punctata. OBSERVATIONS We describe a girl with clinical features of X-linked dominant chondrodysplasia punctata. Biochemical analysis showed an abnormal sterol profile consistent with a defect in Δ8- Δ7 sterol isomerase. Molecular studies confirmed the diagnosis by identifying a novel heterozygous missense EBP mutation (c.199C>T; p.Cys67Arg). The mutation was not detectable on genomic DNA extracted from blood lymphocytes in both parents. The mother presented with an erythematous and ichthyosiform skin lesion. EBP analysis of DNA extracted from a lesional skin biopsy revealed the presence of p.Cys67Arg mutation. CONCLUSION To our knowledge, we report the first molecular confirmation of postzygotic mosaicism on an ichthyosiform skin lesion in the mother of a girl with X-linked dominant chondrodysplasia punctata associated with a novel EBP mutation.
The 18th Annual Meeting of the European Lipoprotein Club Stalenhoef, Anton F.H; Aalto-Setala, Katriina; Armstrong, Victor W ...
Arteriosclerosis, thrombosis, and vascular biology,
1996-July, 1996-07-00, 19960701, Volume:
16, Issue:
7
Journal Article
Our purpose was to search for mutations in the apolipoprotein E (apoE) gene and to evaluate the role of apoE polymorphisms in the occurrence of autosomal dominant retinitis pigmentosa (ADRP). The ...ApoE gene coding sequence was analyzed in 51 unrelated patients affected with ADRP. A screening for mutations by SSCP and an analysis of the apoE polymorphisms were performed using PCR and restriction enzymatic digestion . No abnormal patterns of migration were observed by SSCP analysis. No significant statistical difference was seen between our ADRP population and the French general population for apoE allele frequency. From these results we report that the apoE gene does not seems to be involved in our ADRP population.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Familial defective apo B-100 (FDB) is an autosomal dominant condition resulting in hypercholesterolemia. It is generally observed in 1–6% of hypercholesterolemic subjects in Caucasian populations ...studied. There are, thus far, no reports characterizing the frequency and phenotype of FDB in a Chinese population. We report on the frequency of the FDB (Arg
(3500)→Gln) mutation and the associated haplotype among 160 hypercholesterolemic (TC≥6.2 mmol/l) Chinese Canadians including 36 subjects with a clinical diagnosis of familial hypercholesterolemia (FH). Screening for the FDB mutation was done using a mutagenic polymerase chain reaction and haplotype analysis was undertaken using eight diallelic markers and the 3′HVR marker. One Chinese Canadian clinical FH heterozygote was positive for the FDB Arg
(3500)→Gln mutation while none of the remaining non-FH hypercholesterolemic subjects (
n=124) were carriers of this mutation. Haplotype analysis in the patient positive for this mutation revealed a unique haplotype which differed from both the common haplotype of this mutation observed in Caucasians and from the only other haplotype reported in a Chinese individual. The associated haplotype included a 9-base pair deletion in the signal peptide region and the presence of three restriction sites absent in previously reported haplotypes. These data suggest that the apo B-100 Arg
(3500)→Gln mutation does not appear to be a significant factor contributing to moderate hypercholesterolemia in a Chinese population residing in Canada. However, this mutation was rarely observed among Chinese individuals with a clinical diagnosis of FH. The presence among Chinese individuals of two different haplotypes associated with this mutation, which are different from what has been described among Caucasians is compatible with multiple recurrent origins for this mutation in the Chinese population.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, UL, UM, UPCLJ, UPUK
BACKGROUND: X-linked dominant chondrodysplasia punctata, also known as Conradi-Huenermann-Happle syndrome, is a rare skeletal dysplasia characterized by short stature, craniofacial defects, ...cataracts, ichthyosis, coarse hair, and alopecia. Conradi-Huenermann-Happle syndrome is caused by mutations in the gene EBP encoding Delta 8- Delta 7 sterol isomerase emopamil-binding protein. Random X-inactivation could account for the intrafamilial variability of the phenotype of X-linked dominant chondrodysplasia punctata. OBSERVATIONS: We describe a girl with clinical features of X-linked dominant chondrodysplasia punctata. Biochemical analysis showed an abnormal sterol profile consistent with a defect in Delta 8- Delta 7 sterol isomerase. Molecular studies confirmed the diagnosis by identifying a novel heterozygous missense EBP mutation (c.199C>T; p.Cys67Arg). The mutation was not detectable on genomic DNA extracted from blood lymphocytes in both parents. The mother presented with an erythematous and ichthyosiform skin lesion. EBP analysis of DNA extracted from a lesional skin biopsy revealed the presence of p.Cys67Arg mutation. CONCLUSION: To our knowledge, we report the first molecular confirmation of postzygotic mosaicism on an ichthyosiform skin lesion in the mother of a girl with X-linked dominant chondrodysplasia punctata associated with a novel EBP mutation.
The year 1997 celebrated the 20th anniversary of the European Lipoprotein Club. Sessions explored topics in the line of classical concepts and forthcoming advances in the field of basic and clinical ...research on lipoproteins. Participants from 18 European countries attended the conference. Recent Developments in Lipoprotein Research, were reviewed by Thomas Olivecrona (Umea, Sweden), who gave a perspective on lipolysis; and Gerd Assmann (Münster, Germany), who overviewed epidemiological data of the PROCAM study and focused on the biochemical and genetic components of reverse cholesterol transport.
Session I, chaired by Katriina Aalto Setälä (Tampere, Finland) and Marten Hofker (Leiden, Netherlands) was dedicated to `Lipoprotein receptors (old and new)'. Various structural and functional aspects were reported for the newcomers in the ever enriching LDL receptor gene family (VLDLR, LR7/8B, LR11, Megalin, RAP-related proteins). However, a decade of identification of LDL receptors gene defects reveals now that phenocopies of familial hypercholesterolemia may be linked to a third, yet unknown locus. Identification of pathways which clear HDL is underway.
Session II, chaired by David Bowyer (Cambridge, United Kingdom) and Richard W James (Geneva, Switzerland), was entitled `Significance of lipoprotein heterogeneity (metabolic and pathological aspects)'. Factors involved in lipoprotein modification (dense LDL, oxidation), transient production (post prandial, VLDL synthesis) or degradation (complement activation) and controversial hypotheses on their links with atherosclerosis were discussed.
Session III on `Novel methodologies for lipoprotein research' was chaired by Rudolph Poledne (Prague, Czech Republic) and Armin Steinmetz (Marburg, Germany). Simple technologies for routine assessment of lipoprotein metabolism, as well as the most sophisticated ones, to study lipid and free radical exchanges between particles, were presented.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, UL, UM, UPCLJ, UPUK
Major genetic factors for age-related macular degeneration (AMD) have recently been identified as susceptibility risk factors, including variants in the CFH gene and the ARMS2 LOC387715/HTRA1locus. ...Our purpose was to perform a case-control study in two populations among individuals who did not carry risk variants for CFHY402H and LOC387715 A69S (ARMS2), called ‘‘study’’ individuals, in order to identify new genetic risk factors. Based on a candidate gene approach, we analyzed SNP rs5888 of the SCARB1 gene, coding for SRBI, which is involved in the lipid and lutein pathways. This study was conducted in a French series of 1241 AMD patients and 297 controls, and in a North American series of 1257 patients with advanced AMD and 1732 controls. Among these individuals, we identified 61 French patients, 77 French controls, 85 North American patients and 338 North American controls who did not carry the CFH nor ARMS2 polymorphisms. An association between AMD and the SCARB1 gene was seen among the study subjects. The genotypic distribution of the rs5888 polymorphism was significantly different between cases and controls in the French population (p,0.006). Heterozygosity at the rs5888 SNP increased risk of AMD compared to the CC genotypes in the French study population (odds ratio (OR) = 3.5, CI95%: 1.4–8.9, p,0.01) and after pooling the 2 populations (OR = 2.9, 95% CI: 1.6–5.3, p,0.002). Subgroup analysis in exudative forms of AMD revealed a pooled OR of 3.6 for individuals heterozygous for rs5888 (95% CI: 1.7–7.6, p,0.0015). These results suggest the possible contribution of SCARB1, a new genetic factor in AMD, and implicate a role for cholesterol and antioxidant micronutrient (lutein and vitamin E) metabolism in AMD
The activity of Na–Ca-exchange and ATP-dependent Na and Ca transport by heart sarcolemmal membranes from male 3–4-week-old spontaneously hypertensive rats (SHR) and their normotensive controls (WKY) ...were compared. Differences in active Ca and Na transport between the two substrains were suppressed by addition of exogenous calmodulin. Calmodulin was active only in the presence of Ca. The rate of the Na-dependent Ca efflux, reflecting the activity of the Na–Ca exchange, was significantly higher in SHR than in WKY vesicles. An alteration of the intracellular calmodulin activity or content might thus be responsible for the modifications in Ca handling, and limit the activity of the Na pump in SHR membranes. The platelet cytosolic free Ca concentration of young SHR and WKY was measured by using the fluorescent indicator Quin-2/AM, In the absence or presence of added external Ca, no difference in the intracellular concentration of Ca was observed between platelets of either origin. The intraerythrocytic sodium content, measured by flame spectrophotometry, was similar in SHR and WKY. This study, performed before the onset of hypertension, shows that membrane mechanisms controlling the intracellular ion content were already modified, whereas the resulting intracellular concentrations remained within the normal range.
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