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91.
Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice 总被引:4,自引:3,他引:4
Lamb BT; Call LM; Slunt HH; Bardel KA; Lawler AM; Eckman CB; Younkin SG; Holtz G; Wagner SL; Price DL; Sisodia SS; Gearhart JD 《Human molecular genetics》1997,6(9):1535-1541
Missense mutations in the beta-amyloid precursor protein gene (APP) co-
segregate with a small subset of autosomal dominant familial Alzheimer's
disease (FAD) cases wherein deposition of the 39-43 amino acid beta-amyloid
(A beta) peptide and neurodegeneration are principal neuropathological
hallmarks. To accurately examine the effect of missense mutations on APP
metabolism and A beta production in vivo, we have introduced yeast
artificial chromosomes (YACs) containing the entire approximately 400 kbp
human APP gene encoding APP harboring either the asparagine for lysine and
leucine for methionine FAD substitution at codons 670 and 671
(APP(K670N/M671L)), the isoleucine for valine FAD substitution at codon 717
(APP(V7171)) or a combination of both substitutions into transgenic mice.
We demonstrate that, relative to YAC transgenic mice expressing wild-type
APP, high levels of A beta peptides are detected in the brains of YAC
transgenic mice expressing human APP(K670N/M671L) that is associated with a
concomitant diminution in the levels of apha-secretase-generated soluble
APP derivatives. Moreover, the levels of longer A beta peptides (species
terminating at amino acids 42/43) are elevated in YAC transgenic mice
expressing human APP(V7171). These mice should prove valuable for detailed
analysis of the in vivo effects of the APP FAD mutations in a variety of
tissues and throughout aging and for testing therapeutic agents that
specifically alter APP metabolism and A beta production.
相似文献
92.
Cloning and characterization of DXS6673E, a candidate gene for X-linked mental retardation in Xq13.1 总被引:3,自引:0,他引:3
van der Maarel SM; Scholten IH; Huber I; Philippe C; Suijkerbuijk RF; Gilgenkrantz S; Kere J; Cremers FP; Ropers HH 《Human molecular genetics》1996,5(7):887-897
In several families with non-specific X-linked mental retardation (XLMR)
linkage analyses have assigned the underlying gene defect to the
pericentromeric region of the X chromosome, but none of these genes have
been isolated so far. Here, we report on the cloning and characterization
of a novel gene, DXS6673E, that maps to Xq13.1, is subject to
X-inactivation and is disrupted in the 5' untranslated region by a balanced
X;13 translocation in a mentally retarded female. The DXS6673E gene is
highly conserved among vertebrates and its expression is most abundant in
brain. It encodes a hydrophilic protein of 1358 amino acids (aa) that does
not show sequence homology to other known proteins. A segment of this
protein consisting of neutral and hydrophobic aa with a proline residue in
every second position may represent a transmembrane domain. Almost complete
sequence identity was found between the 3' end of the DXS6673E gene and two
expressed sequence tags (ESTs) and between the 5' end of the DXS6673E gene
and a third EST. Moreover, weaker sequence similarity was observed between
coding regions and two other ESTs.
相似文献
93.
Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitor 总被引:3,自引:1,他引:3
Bienvenu T; des Portes V; Saint Martin A; McDonell N; Billuart P; Carrie A; Vinet MC; Couvert P; Toniolo D; Ropers HH; Moraine C; van Bokhoven H; Fryns JP; Kahn A; Beldjord C; Chelly J 《Human molecular genetics》1998,7(8):1311-1315
Non-specific X-linked mental retardation (MRX) is a very common disorder
which affects approximately 1 in 600 males. Despite this high frequency,
little is known about the molecular defects underlying this disorder,
mainly because of the clinical and genetic heterogeneity which is evident
from linkage studies. Recently, a collaborative study using the candidate
gene approach demonstrated the presence of mutations in GDIalpha, a Rab
GDP-dissociation inhibitor encoded by a gene localized in Xq28, associated
with non-specific mental retardation. GDIalpha is mainly a brain-specific
protein that plays a critical role in the recycling of Rab GTPases involved
in membrane vesicular transport. The study presented here was designed to
assess the prevalence of mutations in the GDIalpha in mentally retarded
patients and to discuss the clinical phenotypes observed in affected
individuals. Mutation screening of the whole coding region of the GDIalpha
gene, using a combination of denaturing gradient gel electrophoresis and
direct sequencing, was carried out in 164 patients found negative for
expansions across the FRAXA GCC repeat. In addition to the nonsense
mutation recently reported in MRX48, we have identified a novel missense
mutation in exon 11 of the GDIalpha gene in one familial form of
non-specific mental retardation. In this family (family R), all affected
males show moderate to severe mental retardation, and the X-linked
semidominant inheritance is strongly suggested by the severe phenotypes in
males with respect to mildly affected females or unaffected obligatory
carriers. This study showed that the prevalence of GDIalpha mutations in
non-specific mental retardation could be estimated to be 0.5-1%, and
molecular diagnosis and genetic counselling in some cases of non-specific
mental handicap can now be provided.
相似文献
94.
Denoyelle F; Weil D; Maw MA; Wilcox SA; Lench NJ; Allen-Powell DR; Osborn AH; Dahl HH; Middleton A; Houseman MJ; Dode C; Marlin S; Boulila-ElGaied A; Grati M; Ayadi H; BenArab S; Bitoun P; Lina-Granade G; Godet J; Mustapha M; Loiselet J; El-Zir E; Aubois A; Joannard A; Petit C 《Human molecular genetics》1997,6(12):2173-2177
Prelingual non-syndromic (isolated) deafness is the most frequent
hereditary sensory defect. In >80% of the cases, the mode of
transmission is autosomal recessive. To date, 14 loci have been identified
for the recessive forms (DFNB loci). For two of them, DFNB1 and DFNB2, the
genes responsible have been characterized; they encode connexin 26 and
myosin VIIA, respectively. In order to evaluate the extent to which the
connexin 26 gene (Cx26) contributes to prelingual deafness, we searched for
mutations in this gene in 65 affected Caucasian families originating from
various countries, mainly tunisia, France, New Zealand and the UK. Six of
these families are consanguineous, and deafness was shown to be linked to
the DFNB1 locus, 10 are small non consanguineous families in which the
segregation of the trait has been found to be compatible with the
involvement of DFNB1, and in the remaining 49 families no linkage analysis
has been performed. A total of 62 mutant alleles in 39 families were
identified. Therefore, mutations in Cx26 represent a major cause of
recessively inherited prelingual deafness since according to the present
results they would underlie approximately half of the cases. In addition,
one specific mutation, 30delG, accounts for the majority (approximately
70%) of the Cx26 mutant alleles. It is therefore one of the most frequent
disease mutations so far identified. Several lines of evidence indicate
that the high prevalence of the 30delG mutation arises from a mutation hot
spot rather than from a founder effect. Genetic counseling for prelingual
deafness has been so far considerably impaired by the difficulty in
distinguishing genetic and non genetic deafness in families presenting with
a single deaf child. Based on the results presented here, the development
of a simple molecular test could be designed which should be of
considerable help.
相似文献
95.
G. Grossmann M. Schwentikowski F.S. Keck M. Hher G. Steinbach H. Osterhues V. Hombach 《Diabetic medicine》1997,14(5):364-369
The purpose of this study was to investigate the presence of ventricular late potentials derived from signal-averaged ECG in patients with IDDM with and without diabetic neuropathy. Eighty patients with IDDM but without evidence of cardiac disease and 80 age-matched healthy control subjects were investigated. The corrected QT interval was measured from the standard surface electrocardiogram. Ventricular late potentials were derived from signal-averaged electrocardiogram. Out of the 80 diabetic patients, 20 had an autonomic neuropathy, 20 had an isolated peripheral neuropathy, and 40 had no symptoms of neuropathy. The corrected QT interval was significantly prolonged in patients with an autonomic neuropathy as compared with the control group (436 ± 23 ms.5 vs 384 ± 23 ms.5, p < 0.001). In the other patient groups there was no significant prolongation of the corrected QT interval. Ventricular late potentials were present in 3 diabetic patients with an isolated peripheral neuropathy and in 1 control subject (NS). No diabetic patient with an autonomic neuropathy had ventricular late potentials. Our data did not indicate an increased incidence of ventricular late potentials derived from signal-averaged electrocardiogram in diabetic patients independent of a coexisting diabetic neuropathy or a prolonged corrected QT interval. © 1997 by John Wiley & Sons, Ltd. 相似文献
96.
HH Miozzari M Tönz RO von Vigier MG Bianchetti 《Acta paediatrica (Oslo, Norway : 1992)》2001,90(5):511-514
The purpose of this analysis was to investigate biochemical disturbances at presentation and initial fluid resuscitation before surgery in infantile pyloric stenosis. The charts of 139 consecutive infants (113 boys and 26 girls) between 7 d and 20 wk of age with hypertrophic pyloric stenosis were reviewed. The infants were treated at the Department of Pediatric Surgery, University of Bern, Switzerland, in the period between 1987 and 1997. A trend towards hypokalaemia (13 of the 139 patients), hypochloraemia (39 patients) and especially metabolic alkalosis (98 patients) was frequently noted on admission. In 84 patients, data on fluid management and on circulating sodium, potassium, chloride and the acid-base balance immediately before surgery were also available. In these patients a significant correlation was found between the parenteral chloride dose given for fluid repair (y = 0.310 x; r = 0.54; p < 0.001) and the changes in plasma bicarbonate. The equation indicates that a chloride dose of 10 mmol/kg body weight is required to reduce plasma bicarbonate on average by 3 mmol/. CONCLUSION: Since assessment of the fluid volume stated by physical examination and history is inaccurate in infants with vomiting, the severity of metabolic alkalosis helps to define the amount of fluid required for repair. 相似文献
97.
E Bailly ; JP Kleim ; KE Schneweis ; B van Loo; U Hammerstein ; HH Brackmann 《Transfusion》1992,32(2):104-108
To detect latent infection with human immunodeficiency virus (HIV), specimens of peripheral blood leukocytes from HIV-seronegative hemophiliacs and from sexual partners of HIV-seropositive hemophiliacs were examined by polymerase chain reaction (PCR). The primer pair SK 38/39 derived from the gag region and/or the primer pair SK 68/69 corresponding to a conserved region of the env gene were used. Whereas HIV proviral DNA was detected by PCR in samples from 86 (97%) of 89 HIV-seropositive hemophiliacs, no HIV-DNA was found in blood samples of 198 HIV-seronegative hemophiliacs at risk. Of 40 HIV-seronegative sexual partners of HIV-infected hemophiliacs, none was PCR positive. Thus, PCR is proving to be a sensitive method by which to confirm infection in seropositive hemophiliacs, while the negative results in HIV-seronegative hemophiliacs and HIV-seronegative sexual partners of HIV-seropositive hemophiliacs suggest that a prolonged seronegative period of latent HIV infection is the exception. 相似文献
98.
Blood pressure independent effects of nitrendipine on cardiac structure in patients after renal transplantation 总被引:2,自引:2,他引:0
Rockstroh JK; Schobel HP; Vogt-Ladner G; Hauser I; Neumayer HH; Schmieder RE 《Nephrology, dialysis, transplantation》1997,12(7):1441-1447
Left ventricular hypertrophy is well established as a blood pressure
independent cardiovascular risk factor in patients on renal replacement
therapy. The effects of antihypertensive treatment on myocardial structure
and function in renal transplant recipients have been so far only rarely
investigated. In a double-blind, placebo-controlled study patients were
randomized to the calcium channel blocker nitrendipine or placebo if the
transplanted kidney had developed a stable phase. Normotensive patients
received nitrendipine 2 x 5 mg daily or placebo, hypertensive patients
received 2 x 10 mg up to 2 x 20 mg nitrendipine daily or placebo. To
achieve adequate blood pressure control, all patients with still elevated
blood pressure on study medication received antihypertensive drugs other
than calcium channels blockers. Ambulatory blood pressure recording and
2D-guided M-mode echocardiography were performed at baseline and upon
completion of the study. In addition, laboratory workup (including serum
creatinine and lipids) was done, and serum aldosterone, plasma renin
activity, plasma angiotensin II and blood glucose levels were measured in
all patients at baseline and after at least 12 months of therapy.
Ambulatory blood pressure was almost identical between both groups at study
baseline and follow-up. In renal transplant patients on nitrendipine,
posterior wall thickness (-0.10 +/- 1.77 mm) and septal wall thickness
(-0.83 +/- 2.23 mm) did not change significantly from baseline. In
contrast, posterior wall thickness (0.71 +/- 0.92 mm, P < 0.01) and
septal wall thickness (0.97 +/- 2.20 mm, P < 0.05) increased in patients
on placebo, which differed from the observed changes on nitrendipine
(ANOVA: P = 0.093 and P = 0.048, respectively). Relative wall thickness, a
parameter for concentric left ventricular hypertrophy, became numerically
smaller on nitrendipine therapy from 0.46 +/- 0.07 to 0.44 +/- 0.09 (-0.02
+/- 0.09, NS) but increased from 0.42 +/- 0.08 to 0.48 +/- 0.08 in the
placebo arm (+0.04 +/- 0.08, P < 0.02), which was also significant
between the two groups (ANOVA: P = 0.036). Endocrine parameters, lipids and
blood glucose were not different between the two groups. We conclude from
these data that the calcium channel blocker nitrendipine exerted beneficial
effects on cardiac structure in patients after renal transplantation
independent of blood pressure.
相似文献
99.
In industrialized countries the rate of sudden cardiac death remains unchanged. The most frequently encountered structural heart disease in these patients is coronary artery disease. Despite the era of thrombolytic therapy of acute myocardial infarction patients carry an increased risk of sudden cardiac arrhythmogenic death within a time period of one to two years following the acute event. Therefore, risk stratification post-MI before patient discharge is furthermore mandatory. The spectrum of non-invasive techniques for risk stratification includes the clinical risk profile, measurement of left ventricular global function (LV ejection fraction), the resting ECG (QT dispersion), an ECG stress test (detection and severity of myocardial ischemia), ambulatory ECG monitoring (number and type of ventricular arrhythmias), surface high resolution ECG (detection of ventricular late potentials), measurement of T wave alternans (TWA, alternans ratio), and measurements of the activity and balance of the autonomous nervous system (heart rate variability, baroreflex sensitivity = BRS). Programmed ventricular stimulation (PVS) serves as an invasive risk stratification technique (detection of an arrhythmogenic substrate). The prognostic power of the non-invasive techniques is limited; in general, the prognostic value of a negative test is reasonably high (90 to 100% depending on the test used), whereas the prognostic value of a positive test is rather low (4 to 42% depending on the test used). Combining several non-invasive tests may significantly improve the positive predictive value above 50%, but this goes along with a significant decreases of sensitivity below 50%. Therefore, a combination of several non-invasive tests (detection and exclusion of a large number of low-risk individuals) with the invasive method of PVS (detection of an arrhythmogenic substrate, i.e. a high-risk patient) seems reasonable, as has been convincingly shown by several smaller prognostic studies. 相似文献
100.