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Biomedical subjects

J Horst

Publications and source records attributed to J Horst.

At least 19 recordsLinked to original sources
PubMed1995

Factor VIII gene inversions in severe hemophilia A: results of an international consortium study.

Twenty-two molecular diagnostic laboratories from 14 countries participated in a consortium study to estimate the impact of Factor VIII gene inversions in severe hemophilia A. A total of 2,093 patients with severe hemophilia A were studied; of those, 740 (35%) had a type 1 (distal) factor VIII inversion, and 140 (7%) showed a type 2 (proximal) inversion. In 25 cases, the molecular analysis showed additional abnormal or polymorphic patterns. Ninety-eight percent of 532 mothers of patients with inversions were carriers of the abnormal factor VIII gene; when only mothers of nonfamilial cases were studied, 9 de novo inversions in maternal germ cells were observed among 225 cases (approximately 1 de novo maternal origin of the inversion in 25 mothers of sporadic cases). When the maternal grandparental origin was examined, the inversions occurred de novo in male germ cells in 69 cases and female germ cells in 1 case. The presence of factor VIII inversions is not a major predisposing factor for the development of factor VIII inhibitors; however, slightly more patients with severe hemophilia A and factor VIII inversions develop inhibitors (130 of 642 [20%]) than patients with severe hemophilia A without inversions (131 of 821 [16%]).

Blotting, Southern↗
PubMed1995

Parental origin of the extra haploid chromosome set in triploidies diagnosed prenatally.

The parental origin of the additional chromosome complement in a total of 17 cases of triploidy was determined mainly using highly polymorphic microsatellites. Maternal origin of the triploidy was demonstrated in most cases. To the best of our knowledge, this is the first systematic evaluation of the parental origin of chromosome sets in fetuses who survived until a cytogenetic diagnosis was established. In contrast to previous investigations this study documented a predominance of maternal origin of the extra haploid set mainly due to longer survival time for digynic triploidies. The concept of 2 distinct fetal phenotypes in triploidy is clearly supported by this study.

Adult↗
PubMed1995

Two polymorphic dinucleotide repeats in intron 44 of the dystrophin gene.

Duchenne muscular dystrophy (DMD) is one of the most common and severe X-linked disorders with an incidence of approximately 1 in 3500 newborn males. In more than 60% of DMD patients, deletions of part or all of the dystrophin gene have been shown. Despite this, carrier detection still poses a problem in some cases, because of the enormous size of the gene and the lack of sufficient numbers of informative markers. Here, we report the isolation and characterization of two additional microsatellite markers (IVS44SK12 and IVS44SK21) in intron 44 of the dystrophin gene. Both markers are useful for carrier detection either by indirect DNA analysis or by direct proof of loss of heterozygosity.

Base Sequence↗
PubMed1995

Genetic heterogeneity of polycystic kidney disease in Bulgaria.

Linkage analysis was performed on 22 Bulgarian families with polycystic kidney disease (PKD) ascertained through the hemodialysis centers of two medical schools. A total of 128 affected and 59 unaffected individuals, and 54 spouses have been investigated using eight polymorphic markers linked to PKD1 and nine markers to PKD2. The results demonstrate locus heterogeneity with 0.67 as the maximum likelihood value of alpha, i.e., the proportion of families linked to PKD1. In five families, the results suggest linkage to PKD2 and observed recombinants place the gene between loci D4S1544 and D4S1542. In one family, two double recombinants for closely linked markers on chromosome 16 and on chromosome 4 give evidence for the lack of linkage to either PKD1 or PKD2, thus suggesting the involvement of a third locus. Analysis of clinical data in the PKD1 group versus the unlinked group shows no significant differences in the severity of the disease.

Adult↗
PubMed1995

Congenital heart disease in the 48,XXYY syndrome.

We report on an infant with severe tetralogy of Fallot, bilateral preauricular pits, and a 48,XXYY chromosomal complement. This case and evidence collected from the literature suggest that congenital heart disease may occur in the 48,XXYY syndrome more frequently than currently appreciated.

Heart Defects, Congenital↗
PubMed1995

Smith-Lemli-Opitz syndrome diagnosed by using time-of-flight secondary-ion mass spectrometry.

We describe a rapid and sensitive method involving time-of-flight secondary-ion mass spectrometry (TOF-SIMS) for specific laboratory diagnosis of the Smith-Lemli-Opitz syndrome, which is characterized by massive (approximately 1000-fold) accumulation of the biosynthetic cholesterol precursor 7-dehydrocholesterol. Minute amounts of blood (1-50 microL) were extracted with n-hexane, and aliquots were analyzed by TOF-SIMS. 7-Dehydrocholesterol and its isomers were detected at 491.3 mass units ([M + 107Ag]+) and cholesterol at 495.3 mass units ([M + 109Ag]+). Quantitation of 7-dehydrocholesterol and cholesterol was achieved after saponification and addition of stigmasterol as internal standard. Whereas 7-dehydrocholesterol and isomeric dehydrocholesterol were not detectable in controls, the patients revealed concentrations ranging between 0.84 and 1.25 mmol/L. Comparison with results obtained by gas chromatography indicated that quantitation by TOF-SIMS yielded the sum of 7-dehydrocholesterol, isomeric dehydrocholesterol II, and sterol III, the latter two also being increased in the patients. Consistent with quantitation by gas chromatography, the cholesterol concentrations in the patients ranged between 1.54 and 2.12 mmol/L (controls: 6.10 +/- 1.37 mmol/L).

Cholesterol↗
PubMed1994

Nonisotopic detection of mutations using a modified single-strand conformation polymorphism analysis.

This report describes a rapid convenient screening system with improved sensitivity to detect mutations in the cystic fibrosis transmembrane regulator (CFTR) gene based on nonisotopic SSCP analysis. Because conventional SSCP analysis is often hampered by poor yield of single-stranded DNA, we applied the well-established solid-phase technique in which streptavidin-coated magnetic beads are used to immobilize biotinylated polymerase chain reaction (PCR) products. High yield of single-stranded DNA can be eluted from the solid phase by denaturation and used for SSCP analysis. An additional advantage of this procedure is that the immobilized single strand is available without any further purification steps for solid-phase sequencing.

Base Sequence↗
PubMed1994

Frequencies of the most common mutations responsible for phenylketonuria in Poland.

We screened 91 Polish phenylketonuric (PKU) children for the presence of 18 common mutations in the phenylalanine hydroxylase (PAH) gene, and 75.7% of PAH alleles were identified. The R408W mutation accounted for 54.9% of PAH mutant alleles. In the other 20.8%, eight mutations were detected: R158Q (6.6%), IVS10 (4.9%), IVS12 (2.7%), R261Q (2.2%), G272ter (1.65%), Y414C (1.1%), R252W (1.1%) and P281L (0.54%). Correlations between genotype and clinical phenotype were described.

Alleles↗
PubMed1994

Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells.

The factor VIII gene, which is defective in hemophilia A, is located in the last megabase of the long arm of the X chromosome. Inversions due to intrachromosomal homologous recombination between mispaired copies of gene A located within intron 22 of the gene and about 500 kb telomeric to it account for nearly half of all cases of severe hemophilia A. We hypothesized that pairing of Xq with its homolog inhibits the inversion process, and that, therefore, the event originates predominantly in male germ cells. In all 20 informative cases in which the inversion originated in a maternal grandparent, DNA polymorphism analysis determined that it occurred in the male germline. In addition, all but one of 50 mothers of sporadic cases due to an inversion were carriers. Thus, these data support the hypothesis and indicate that factor VIII gene inversions leading to severe hemophilia A occur almost exclusively in male germ cells.

Blotting, Southern↗
PubMed1992

Distal limb deficiency following chorionic villus sampling?

We have reviewed the follow-up of almost 3000 completed pregnancies in the Münster CVS Program and identified 4 children with distal limb deficiencies. Two cases involved only minor anomalies of distal digital phalanges. One child had a Hanhart anomaly (hypoglossia hypodactylia). We also reviewed 24 cases of limb defects following CVS reported previously. With the exception of a single series, neither the overall incidence of affected children nor cases reported from larger series provide unambiguous evidence of an increased risk of distal limb deficiency caused by CVS.

Child, Preschool↗
PubMed1992

Two missense mutations causing mild hyperphenylalaninemia associated with DNA haplotype 12.

The genetic defects responsible for most phenylketonuria (PKU) and hyperphenylalaninemia (HPA) cases are located in the phenylalanine hydroxylase (PAH) gene. Approximately 50-60 mutations have been reported in Caucasians and are reflected in a wide range of clinical severities. Most mutations are linked to specific haplotypes, as defined by eight polymorphic restriction sites in the PAH gene. We hypothesized that there is at least one mild mutation linked to haplotype 12 in the Swedish PKU/HPA population, since 7 of 8 patients carrying haplotype 12 had mild HPA. Sequence analysis revealed a C-to-G transversion at the second base of codon 322, resulting in a substitution of glycine for alanine, in four mutant haplotype 12 genes, and a G-to-A transition at the second base of codon 408, resulting in a substitution of glutamine for arginine, in another three mutant haplotype 12 genes. These mutations segregated with mutant haplotype 12 alleles in nuclear families but were not present on normal or other mutant alleles. Both mutations were tested in a eukaryotic expression system in which enzyme activities of different mutant PAH enzymes reflect the relative severities of the mutations, although these in vitro activities cannot be translated directly into in vivo hepatic activities. The A322G mutant PAH had about 75% and the R408Q mutant PAH about 55% of the wild-type PAH enzyme activity. These in vitro activities are the highest reported for mutant PAH enzymes produced in the same expression system.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Metabolism, Inborn Errors↗