Showing papers by "Stylianos E. Antonarakis published in 1994"

Sequential strategy to identify a susceptibility gene for schizophrenia: Report of potential linkage on chromosome 22q12‐q13.1: Part 1

Abstract: We describe four infants with a novel subtype of an isolated deficiency of one of the peroxisomal beta-oxidation enzymes with detectable enzyme protein. The patients showed characteristic clinical and biochemical abnormalities, including hypotonia, psychomotor retardation, hepatomegaly, typical facial appearance, accumulation of very-long-chain fatty acids, and decreased lignoceric acid oxidation. However, beta-oxidation enzyme proteins were detected by immunoblot analyses, and large peroxisomes were identified by immunofluorescence staining. In order to identify the underlying defect in these patients, complementation analysis was introduced using fibroblasts from these patients and patients with an established deficiency of either acyl-CoA oxidase or bifunctional enzyme, as identified by immunoblotting. In the complementing combinations, fused cells showed increased lignoceric acid oxidation, resistance against 1-pyrene dodecanoic acid/UV selection, and normalization of the size and the distribution of peroxisomes. The results indicate that two patients with a more severe clinical course were suffering from bifunctional enzyme deficiency and that the other two infants, who were siblings and had a less severe clinical presentation, were the first patients with acyl-CoA oxidase deficiency with detectable enzyme protein.

Follow‐up of a report of a potential linkage for schizophrenia on chromosome 22q12‐q13.1: Part 2

Abstract: A collaboration involving four groups of investigators (Johns Hopkins University/Massachusetts Institute of Technology; Medical College of Virginia/The Health Research Board, Dublin; Institute of Psychiatry, London/University of Wales, Cardiff; Centre National de la Recherche Scientifique, Paris) was organized to confirm results suggestive of a schizophrenia susceptibility locus on chromosome 22 identified by the JHU/MIT group after a random search of the genome. Diagnostic, laboratory, and analytical reliability exercises were conducted among the groups to ensure uniformity of procedures. Data from genotyping of 3 dinucleotide repeat polymorphisms (at the loci D22S268, IL2RB, D22S307) for a combined replication sample of 256 families, each having 2 or more affected individuals with DNA, were analysed using a complex autosomal dominant model. This study provided no evidence for linkage or heterogeneity for the region 22q12-q13 under this model. We conclude that if this region confers susceptibility to schizophrenia, it must be in only a small proportion of families. Collaborative efforts to obtain large samples must continue to play an important role in the genetic search for clues to complex psychiatric disorders such as schizophrenia

Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene, second edition

Abstract: A large number of different mutations in the factor VIII (F8) gene have been identified as a cause of haemophilia A. This compilation lists known single base-pair substitutions, deletions and insertions in the F8 gene and reviews the status of the inversional events which account for a substantial proportion of mutations causing severe haemophilia A.

Understanding the mechanism(s) of mosaic trisomy 21 by using DNA polymorphism analysis

Abstract: In order to investigate the mechanism(s) underlying mosaicism for trisomy 21, we genotyped 17 families with mosaic trisomy 21 probands, using 28 PCR-detectable DNA polymorphic markers that map in the pericentromeric region and long arm of chromosome 21. The percentage of cells with trisomy 21 in the probands' blood lymphocytes was 6%-94%. There were two classes of autoradiographic results: In class I, a "third allele" of lower intensity was detected in the proband's DNA for at least two chromosome 21 markers. The interpretation of this result was that the proband had inherited three chromosomes 21 after meiotic nondisjunction (NDJ) (trisomy 21 zygote) and subsequently lost one because of mitotic (somatic) error, the lost chromosome 21 being that with the lowest-intensity polymorphic allele. The parental origin and the meiotic stage of NDJ could also be determined. In class II, a "third allele" was never detected. In these cases, the mosaicism probably occurred either by a postzygotic, mitotic error in a normal zygote that followed a normal meiosis (class IIA mechanism); by premeiotic, mitotic NDJ yielding an aneusomic zygote after meiosis, and subsequent mitotic loss (class IIB mechanism); or by a meiosis II error with lack of crossover in the preceding meiosis I, followed by mitotic loss after fertilization (class IIC mechanism). Among class II mechanisms, the most likely is mechanism IIA, while IIC is the least likely. There were 10 cases of class I and 7 cases of class II results.(ABSTRACT TRUNCATED AT 250 WORDS)

Homologous loci DXYS156X and DXYS156Y contain a polymorphic pentanucleotide repeat (TAAAA)n and map to human X and Y chromosomes.

Abstract: We report the isolation and characterization of a polymorphic pentanucleotide repeat (TAAAA)n, which was mapped to human chromosomes X and Y (loci DXYS156X and DXYS156Y) by PCR amplification of DNA from a monochromosomal somatic cell hybrid panel (NIGMS panel 2). The (TAAAA)n repeat of loci DXYS156 occurs within a human LINE element at a position where the consensus sequence contains a single TAAAA motif. In 72 unrelated CEPH individuals seven alleles were detected which ranged in size from 125 to 165 bp in 5 bp intervals. The two largest alleles (160 and 165 bp) were observed only in males, which suggests that they were amplified from the Y chromosome DXYS156Y locus. The other 5 alleles were present in two copies in females and in a single copy in males, which suggests that they were amplified from the X chromosome DXYS156X locus. Locus DXYS156X was polymorphic in CEPH families with an observed heterozygosity in females of 46% (27 of 59). Linkage analysis with DNA markers on the X chromosome revealed significant lod scores for a location of DXYS156X close to markers DXS1002 (theta = 0.000; zeta = 8.43), DXYS1X (theta = 0.015; zeta = 17.3), DXS3, and PGK1 in the region of chromosome Xq13. The sequence of DXYS156Y derived from the 165 bp allele has been deposited in Genbank with accession number X71600.

"Compensatory" uniparental disomy of chromosome 21 in two cases.

Abstract: Two cases of growth failure, microcephaly, facial dysmorphism, muscular hypertonia, and severe psychomotor retardation are described. At birth, both cases had cytogenetic mosaicism in lymphocytes and skin fibroblasts, in case 1 ring chromosome 21 and monosomy 21 and in case 2, deletion of chromosome 21 and monosomy 21. At a later age the lymphocyte karyotype changed almost completely to 46,XX, but the fibroblast karyotype remained as before. DNA polymorphism analysis described elsewhere indicated that the 46,XX lymphocytes contained two identical chromosomes 21 (isodisomy), in case 1 inherited from the father and in case 2 from the mother. The isodisomy was the result of duplication of a chromosome in mitosis after the loss of the homologous abnormal chromosome ("compensatory isodisomy"). We report here that this cytogenetic mechanism can result in false normal cytogenetic findings. The phenotypes were attributed to the cells with monosomy 21 in case 1 and to the deletion and monosomy of chromosome 21 in case 2.

Biparental inheritance of chromosome 21 polymorphic markers indicates that some Robertsonian translocations t(21;21) occur postzygotically

Abstract: Robertsonian translocations between acrocentric chromosomes are the most common structural chromosomal rearrangements in humans and many other organisms, and several mechanisms for their formation have been proposed. We have analyzed highly informative DNA polymorphisms in a family with a non-mosaic de novo Robertsonian translocation 21q;21q, to determine the parental origin of the two 21q arms of the rearranged chromosome. The genotypes indicated a biparental origin, i.e. one 21q was paternal and the other maternal. These results imply that in some cases the formation of the rob(21q;21q) occurs in the zygote or in the first few postzygotic mitotic divisions.

No uniparental disomy for chromosome 3 in Brachmann-De Lange syndrome.

Abstract: Brachmann-De Lange syndrome (BDLS, MIM No. 122470) is a well-described genetic syndrome of mental retardation and multiple congenital anomalies, with an estimated birth prevalence of 1/10,000. The authors set out to test the hypothesis that some cases of BDLS are associated with uniparental disomy for chromosome 3, especially for 3q21-qtre. The following DNA polymorphic markers were used to test for uniparental disomy:SST maps on 3q28; GLUT2 on 3q26.1-q26.3; D3S196 on 3q24-q26, D3S1101 on 3p21-cen and D3S1206 on 3q21-q24. The order of these loci in the linkage map of chromosome 3 is pter-D3S1101-cen-D3S1206-D3S196-GLUT2-SST [NIH/CEPH Collaborative Mapping Group, 1992]. All of these polymorphisms are due to dinucleotide repeats and genotypes in the families were obtained as described. In 22 families UPD3q has been excluded. Four families were not informative for the markers used. There were no families with UPD3q. The authors concluded that UPD3q is not associated with most cases of BDLS; however, this study does not exclude the possibility of UPD for a small portion of 3q, that has not been examined with the markers used.

Exon skipping associated with A→G transition at +4 of the IVS33 splice donor site of the neurofibromatosis type 1 (NF1) gene

Abstract: Von Recklinghausen neurofibromatosis (neurofibromatosis type 1, NF1, McKusick no. 162200) is one of the most common human genetic disorders, with an incidence of approximately 1 in 3500 in all ethnic groups (1). The mutation rate is close to 1 in 10 meioses, and about half the cases result from new mutations (2). The clinical hallmarks of the disease are cutaneous or subcutaneous neurofibromas and hyperpigmented cafe\"-au-lait skin patches, but the disorder presents a remarkable phenotypic variability, with many other clinical signs such as axillary freckling, Lisch nodules, bone deformities, or learning disabilities. In addition, NF1 patients show an increased frequency of nervous system tumors, such as malignant neurofibrosarcomas, optic nerve gliomas, and pheochromocytomas. The NF1 locus was mapped by linkage analysis to chromosome 17qll.2 (3-5), and subsequently the NF1 gene was identified by positional cloning (6-8). The gene, which consists of 51 exons extending over a genomic distance of approximately 350 kilobases, produces a ubiquitously-expressed mRNA of 13 kilobases (kb) (6-8). The gene codes for the protein neurofibromin, which contains a domain related to GAP (GTPase-activating protein) (9), and is capable of down-regulating ras by stimulating its intrinsic GTPase activity (10, 11). Many germline mutations have been identified in patients with NF1 (see ref. 12 for review). The observation of loss of heterozygosity in at least one patient (13) supports a tumor suppressor gene hypothesis for NF1.

Highly polymorphic repeat marker within the β-amyloid precursor protein gene

Abstract: We have identified a polymorphic compound dinucleotide repeat sequence in intron 1 of the β-amyloid precursor protein (APP) gene on chromosome 21. Using polymerase chain reaction (PCR) amplification of the locus, designated APPivsl, we detected 13 alleles in the CEPH family members (heterozygosity = 0.69). Lod score analysis showed complete linkage of the marker to the loci D21S210 and D21221.