Showing papers on "Chromosome 21 published in 1993"

Detection of complete and partial chromosome gains and losses by comparative genomic in situ hybridization

Abstract: Comparative genomic in situ hybridization (CGH) provides a new possibility for searching genomes for imbalanced genetic material. Labeled genomic test DNA, prepared from clinical or tumor specimens, is mixed with differently labeled control DNA prepared from cells with normal chromosome complements. The mixed probe is used for chromosomal in situ suppression (CISS) hybridization to normal metaphase spreads (CGH-metaphase spreads). Hybridized test and control DNA sequences are detected via different fluorochromes, e.g., fluorescein isothiocyanate (FITC) and tetraethylrhodamine isothiocyanate (TRITC). The ratios of FITC/TRITC fluorescence intensities for each chromosome or chromosome segment should then reflect its relative copy number in the test genome compared with the control genome, e.g., 0.5 for monosomies, 1 for disomies, 1.5 for trisomies, etc. Initially, model experiments were designed to test the accuracy of fluorescence ratio measurements on single chromosomes. DNAs from up to five human chromosome-specific plasmid libraries were labeled with biotin and digoxigenin in different hapten proportions. Probe mixtures were used for CISS hybridization to normal human metaphase spreads and detected with FITC and TRITC. An epifluorescence microscope equipped with a cooled charge coupled device (CCD) camera was used for image acquisition. Procedures for fluorescence ratio measurements were developed on the basis of commercial image analysis software. For hapten ratios 4/1, 1/1 and 1/4, fluorescence ratio values measured for individual chromosomes could be used as a single reliable parameter for chromosome identification. Our findings indicate (1) a tight correlation of fluorescence ratio values with hapten ratios, and (2) the potential of fluorescence ratio measurements for multiple color chromosome painting. Subsequently, genomic test DNAs, prepared from a patient with Down syndrome, from blood of a patient with Tcell prolymphocytic leukemia, and from cultured cells of a renal papillary carcinoma cell line, were applied in CGH experiments. As expected, significant differences in the fluorescence ratios could be measured for chromosome types present in different copy numbers in these test genomes, including a trisomy of chromosome 21, the smallest autosome of the human complement. In addition, chromosome material involved in partial gains and losses of the different tumors could be mapped to their normal chromosome counterparts in CGH-metaphase spreads. An alternative and simpler evaluation procedure based on visual inspection of CCD images of CGH-metaphase spreads also yielded consistent results from several independent observers. Pitfalls, methodological improvements, and potential applications of CGH analyses are discussed.

Combinatorial generation of variable fusion proteins in the Ewing family of tumours.

Abstract: Balanced translocations involving band q12 of human chromosome 22 are the most frequent recurrent translocations observed in human solid tumours. It has been shown recently that this region encodes EWS, a protein with an RNA binding homologous domain. In Ewing's sarcoma and malignant melanoma of soft parts, translocations of band 22q12 to chromosome 11 and 12 result in the fusion of EWS with the transcription factors FLI-1 and ATF1, respectively. The present analysis of 89 Ewing's sarcomas and related tumours show that in addition to the expected EWS-FLI-1 fusion, the EWS gene can be fused to ERG, a transcription factor closely related to FLI-1 but located on chromosome 21. The position of the chromosome translocation breakpoints are shown to be restricted to introns 7-10 of the EWS gene and widely dispersed within introns 3-9 of the Ets-related genes. This heterogeneity generates a variety of chimeric proteins that can be detected by immuno-precipitation. On rare occasions, they may be associated with a truncated EWS protein arising from alternate splicing. All 13 different fusion proteins that were evidenced contained the N-terminal domain of EWS and the Ets domain of FLI-1 or ERG suggesting that oncogenic conversion is achieved by the linking of the two domains with no marked constraint on the connecting peptide.

Molecular mapping of twenty-four features of Down syndrome on chromosome 21.

Abstract: To determine which regions of chromosome 21 are involved in the pathogenesis of specific features of Down syndrome, we analysed, phenotypically and molecularly, 10 patients with partial trisomy 21. Six minimal regions for 24 features were defined by genotype-phenotype correlations. Nineteen of these features could be assigned to just 2 regions: short stature, joint hyperlaxity, hypotonia, major contribution to mental retardation and 9 anomalies of the face, hand and foot to the region D21S55, or Down syndrome chromosome region (DCR), located on q22.2 or very proximal q22.3, and spanning 0.4-3 Mb; 6 facial and dermatoglyphic anomalies to the region D21S55-MX1, including the DCR and spanning a maximum of 6 Mb on q22.2 and part of q22.3. Thus, the complex phenotype that constitutes Down syndrome may in large part simply result from the overdosage of only one or a few genes within the DCR and/or region D21S55-MX1.

Homozygous Deletion and Frequent Allelic Loss of Chromosome 8p22 Loci in Human Prostate Cancer

Abstract: Allelic loss studies have been instrumental in identifying tumor suppressor gene loci in a variety of cancers. In this study we analyzed prostate cancer specimens from 52 patients for allelic loss using 8 polymorphic probes for the short arm of chromosome 8. Overall, 32 of 51 (63%) informative tumors showed loss of at least one locus on chromosome 8p. The most frequently deleted region is observed at chromosome 8p22-8p21.2. Loss of one allele is identified in 14 of 23 (61%) tumors at D8S163, in 15 of 32 (47%) tumors at lipoprotein lipase, and in 20 of 29 (69%) tumors at MSR, all on 8p22. Loss of one allele is identified in 16 of 27 (59%) tumors at D8S220 at 8p21.3-8p21.2. In addition to frequent loss of one allele at the MSR locus, one metastatic prostate cancer sample demonstrated homozygous deletion of MSR sequences. Loci telomeric and centromeric to this region are largely retained. A chromosome 8p deletion map is constructed and defines the smallest region of overlap to a 14-cM interval at 8p22 between D8S163 and lipoprotein lipase, flanking the MSR locus. Evidence of chromosome 8q multiplication at locus D8S39 was detected in 5 of 32 (16%) tumors, all of which demonstrated loss with at least one probe on chromosome 8p. This study extends the previous finding of frequent loss of chromosome 8p in prostate cancer by defining a common region of loss of heterozygosity at 8p22 and a homozygous deletion of the MSR locus contained within this region. This is the first homozygous deletion identified in the genome of a human prostate cancer and the highest rate of loss yet reported on chromosome 8p in cancer. These results strongly suggest the presence of a tumor suppressor gene in this region which is frequently inactivated in prostate cancer.

Molecular genetics of Alzheimer's disease.

Abstract: At present it is not clear whether Alzheimer’s disease is a single disease, a complex syndrome, or a heterogeneous ill-defined group of disorders. In the last few years significant progress has been made in identifying and describing its different manifestations, as well as the underlying biological mechanisms. Modern molecular biology techniques have provided new insights into possible etiological mechanisms. Linkage analysis and gene sequencing studies have produced evidence of a possible locus on chromosome 21 in a small group of families with early onset familial Alzheimer’s disease (FAD). It was shown that another small group of early onset FAD families develops the disease as a result of mutations in the gene coding for the s-amyloid precursor protein, and that in a larger subgroup of early onset families the disease appears to be caused by an unidentified gene on chromosome 14. Several other early onset FAD families are clearly not linked to any of these loci, suggesting that other abnormal genes, probably on different chromosomes, might be the cause of the disease in these families. Finally, it was recently shown that the e4 allele of apolipoprotein E (ApoE) gene, which has been mapped to chromosome 19, is associated with an increased risk of developing the disease in late onset FAD families and sporadic cases. These results not only evidence that Alzheimer’s disease is a genetically heterogeneous disorder, but also delineate new approaches in the study of the etiological and pathogenetic mechanisms of Alzheimer’s disease. (Aging Clin. Exp. Res. 5: 417–425, 1993).

Identification of class-mu glutathione transferase genes GSTM1-GSTM5 on human chromosome 1p13.

Abstract: The GSTM1, GSTM2, GSTM3, GSTM4, and GSTM5 glutathione transferase genes have been mapped to human chromosome 1 by using locus-specific PCR primer pairs spanning exon 6, intron 6, and exon 7, as probes on DNA from human/hamster somatic cell hybrids For GSTM1, the assignment was confirmed by Southern blot hybridization to a pair of 125/24-kb HindIII fragments The GSTM1-specific primer pairs can be used to identify individuals carrying non-null GSTM1 alleles The organization of these five genes was confirmed by the isolation of a yeast artificial chromosome clone (GSTM-YAC2) that contains all five genes With this clone, the location of the GSTM1-GSTM5 gene cluster on chromosome 1 was confirmed by fluorescence in situ hybridization Both regional assignment using the fractional length method and examination of probe signal with reference to R-banded chromosomes induced by BrdU places the gene cluster in or near the 1p133 region The close physical proximity of the GSTM1 and GSTM2 loci, which share 99% nucleotide sequence identity over 460 nucleotides of 3'-untranslated mRNA, suggests that the GSTM1-null allele may result from unequal crossing-over

Allelic loss of chromosome 1p36 in neuroblastoma is of preferential maternal origin and correlates with N-myc amplification.

Abstract: Neuroblastomas frequently have deletions of chromosome 1p and amplification of the N-myc oncogene. We analysed 53 neuroblastomas for the N-myc copy number, loss of heterozygosity (LOH) of chromosome 1p36 and the parental origin of the lost alleles. Allelic loss of 1p36 was found in 15 tumours. All N-myc amplified tumours belonged to this subset. In 13/15 tumours with LOH of 1p36 the lost allele was of maternal origin. This non-random distribution implies that the two alleles of the putative neuroblastoma suppressor gene on chromosome 1p36 are functionally different, depending on their parental origin. This is the first evidence as far as we know for genomic imprinting on chromosome 1p.

An ets-related gene, ERG, is rearranged in human myeloid leukemia with t(16;21) chromosomal translocation.

Abstract: The t(16;21)(p11;q22) translocation is a nonrandom chromosomal abnormality found in several types of myeloid leukemia, which show variable cytomorphological features. We constructed rodent-human somatic cell hybrids containing the der(16) chromosome from leukemic cells of a patient with t(16;21). Using these hybrids, we mapped the translocation breakpoint on the Not I restriction map of chromosome 21 which we had previously constructed. The result showed the proximity of the breakpoint to the ERG gene, a member of the ets oncogene superfamily. Polymerase chain reaction and Southern blot analyses of genomic DNA from the hybrids and from peripheral blood cells and bone marrow cells of patients with t(16;21) showed that the breakpoints were clustered within a single intron in the coding region of the ERG gene. This finding and the results obtained by Northern blot analysis suggested the formation of a chimeric product(s) by fusion of the ERG gene and an unknown counterpart gene on chromosome 16.

Mitotic errors in somatic cells cause trisomy 21 in about 4.5% of cases and are not associated with advanced maternal age.

Abstract: The study of DNA polymorphisms has permitted the determination of the parental and meiotic origin of the supernumerary chromosome 21 in families with free trisomy 21. Chromosomal segregation errors in somatic cells during mitosis were recognized after analysis of DNA markers in the pericentromeric region and (in order to identify recombination events) along the long arm of chromosome 21. Mitotic errors accounted for about 4.5% (11 of 238) of free trisomy 21 cases examined. The mean maternal age of mitotic errors was 28.5 years and there was no association with advanced maternal age. There was no preference in the parental origin of the duplicated chromosome 21. The 43 maternal meiosis II errors in this study had a mean maternal age of 34.1 years-the highest mean maternal age of all categories of chromosomal segregation errors.

CSE1 and CSE2, two new genes required for accurate mitotic chromosome segregation in Saccharomyces cerevisiae.

Abstract: By monitoring the mitotic transmission of a marked chromosome bearing a defective centromere, we have identified conditional alleles of two genes involved in chromosome segregation (cse). Mutations in CSE1 and CSE2 have a greater effect on the segregation of chromosomes carrying mutant centromeres than on the segregation of chromosomes with wild-type centromeres. In addition, the cse mutations cause predominantly nondisjunction rather than loss events but do not cause a detectable increase in mitotic recombination. At the restrictive temperature, cse1 and cse2 mutants accumulate large-budded cells, with a significant fraction exhibiting aberrant binucleate morphologies. We cloned the CSE1 and CSE2 genes by complementation of the cold-sensitive phenotypes. Physical and genetic mapping data indicate that CSE1 is linked to HAP2 on the left arm of chromosome VII and CSE2 is adjacent to PRP2 on chromosome XIV. CSE1 is essential and encodes a novel 109-kDa protein. CSE2 encodes a 17-kDa protein with a putative basic-region leucine zipper motif. Disruption of CSE2 causes chromosome missegregation, conditional lethality, and slow growth at the permissive temperature.

Interstitial localization of telomeric DNA sequences in the Indian muntjac chromosomes: further evidence for tandem chromosome fusions in the karyotypic evolution of the Asian muntjacs

Abstract: The Indian muntjac is believed to have the lowest chromosome number in mammals (2n = 6 in females and 2n = 7 in males). It has been suggested that a series of tandem chromosome fusions from an ancestr

Preliminary Mapping of the Deleted Region of Chromosome 9 in Bladder Cancer

Abstract: Inactivation of a suppressor gene by deletion of chromosome 9 is a candidate initiating event in bladder carcinogenesis. We have used 13 polymorphic markers spanning the length of chromosome 9 in order to map the region of deletion in human bladder carcinomas. In the majority of tumors loss of heterozygosity was found at all informative sites along the chromosome, indicating deletion of the entire chromosome. Nine tumors had selective deletions of chromosome 9. Mapping of the deleted region in these tumors suggests that the target gene is located between D9S22 at 9q22 and D9S18 at 9p12-13.

Linkage of Niemann-Pick disease type C to human chromosome 18.

Abstract: We analyzed the involvement of chromosome 18 in Niemann-Pick disease type C (NPC), an autosomal recessive cholesterol-processing disorder. Within affected offspring, the chromosome 18 parental contributions were identified by using allele-specific microsatellite markers. Significant linkage of NPC to an 18p genomic marker, D18S40, was indicated by a two-point lod score of 3.84. Analysis of meiotic chromosomal breakpoint patterns among the affected individuals indicated that the NPC gene is pericentromerically localized on human chromosome 18.

Fine physical mapping of Ph1, a chromosome pairing regulator gene in polyploid wheat.

Abstract: The diploid-like chromosome pairing in polyploid wheat is controlled by the Ph1 (pairing homoeologous) gene that is located on chromosome arm 5BL. By using a combination of cytogenetic and molecular techniques, we report the physical location of the Ph1 gene to a submicroscopic chromosome region (Ph1 gene region) that is flanked by the breakpoints of two deletions (5BL-1 and ph1c) and is marked by a DNA probe (XksuS1). The Ph1 gene region is present distal to the breakpoint of deletion 5BL-1 but proximal to the C-band 5BL2.1. Two other DNA probes (Xpsr128 and Xksu75) flank the region-Xpsr128 being proximal and Xksu75 being distal. The estimated size of the region is less than 3 Mb. The chromosome region around the Ph1 gene is high in recombination as the genetic distance of the region between 5BL-1 breakpoint and C-band 5BL2.1 (not resolved by the microscope) is at least 9.3 cM.

Translocation of BCR to Chromosome 9: A New Cytogenetic Variant Detected by FISH in Two Ph-Negative, BCR-Positive Patients With Chronic Myeloid Leukemia

Abstract: Leukemic cells from two patients with Philadelphia-negative chronic myeloid leukemia (CML) were investigated: I) Cytogenetics showed a normal 46.XY karyotype in both cases, 2) molecular studies revealed rearrangement of the M-BCR region and formation of BCR-ABL fusion mRNA with b2a2 (patient I) or b3a2 (patient 2) configuration, and 3) fluorescence in situ hybridization (FISH) demonstrated relocation of the 5′ BCR sequences from one chromosome 22 to one chromosome 9. The ABL probe hybridized to both chromosomes 9 at band q34, while two other probes which map centromeric and telomeric of BCR on 22q 11 hybridized solely with chromosome 22. For the first time, a BCR-ABL rearrangement is shown to take place on 9q34 instead of in the usual location on 22q 11. A rearrangement in the latter site is found in all Ph-positive CML and in almost all investigated CML with variant Ph or Ph-negative, BCR-positive cases. The few aberrant chromosomal localizations of BCR-ABL recombinant genes found previously were apparently the result of complex and successive changes. Furthermore in patient 2, both chromosomes 9 showed positive FISH signals with both ABL and BCR probes. Restriction fragment length polymorphism (RFLP) analysis indicated that mitotic recombination had occurred on the long arm of chromosome 9 and that the rearranged chromosome 9 was of paternal origin. The leukemic cells of this patient showed a duplication of the BCR-ABL gene, analogous to duplication of the Ph chromosome in classic CML. In addition they had lost the maternal alleles of the 9q34 chromosomal region. The lymphocytes of patient 2 carried the maternal chromosome 9 alleles and were Ph-negative as evidenced by RFLP and FISH analyses, respectively. © 1993 Wiley-Liss, Inc.

Maternal uniparental disomy for human chromosome 14, due to loss of a chromosome 14 from somatic cells with t(13;14) trisomy 14

Abstract: Uniparental disomy (UPD) for particular chromosomes is increasingly recognized as a cause of abnormal phenotypes in humans. We recently studied a 9-year-old female with a de novo Robertsonian translocation t(13;14), short stature, mild developmental delay, scoliosis, hyperextensible joints, hydrocephalus that resolved spontaneously during the first year of life, and hypercholesterolemia. To determine the parental origin of chromosomes 13 and 14 in the proband, we have studied the genotypes of DNA polymorphic markers due to (GT)n repeats in the patient and her parents' blood DNA. The genotypes of markers D14S43, D14S45, D14S49, and D14S54 indicated maternal UPD for chromosome 14. There was isodisomy for proximal markers and heterodisomy for distal markers, suggesting a recombination event on maternal chromosomes 14. In addition, DNA analysis first revealed--and subsequent cytogenetic analysis confirmed--that there was mosaic trisomy 14 in 5% of blood lymphocytes. There was normal (biparental) inheritance for chromosome 13, and there was no evidence of false paternity in genotypes of 11 highly polymorphic markers on human chromosome 21. Two cases of maternal UPD for chromosome 14 have previously been reported, one with a familial rob t(13;14) and the other with a t(14;14). There are several similarities among these patients, and a "maternal UPD chromosome 14 syndrome" is emerging; however, the contribution of the mosaic trisomy 14 to the phenotype cannot be evaluated. The study of de novo Robertsonian translocations of the type reported here should reveal both the extent of UPD in these events and the contribution of particular chromosomes involved in certain phenotypes.

Potential topoisomerase II DNA-binding sites at the breakpoints of a t(9;11) chromosome translocation in acute myeloid leukemia

Abstract: We have examined a t(9;11)(p22;q23) chromosome translocation in an acute myeloid leukemia of an infant. The breakpoints on the two chromosomes occurred within introns of the involved genes: AF-9 on chromosome 9, and ALL-1 on chromosome 11. Sequence analysis identified heptamers flanking the breakpoints on both chromosomes 9 and 11, suggesting that the V-D-J recombinase was involved in the translocation. The presence of an N-region between the two chromosomes supports the hypothesis that a mistake in V-D-J joining was involved in the genesis of the translocation and indicates that terminal deoxynucleotidyl transferase was expressed in the cells from which this acute myeloid leukemia originated. In addition, potential topoisomerase II DNA-binding sites were found near the breakpoints of both chromosomes, suggesting the involvement of altered topoisomerase II activity in this translocation. Altered topoisomerase II activity in the presence of an active V-D-J recombinase may be a pathogenetic mechanism of acute myeloid leukemia with rearrangements at 11q23.

Deletion of chromosome 11 and of 14q sequences in neuroblastoma

Abstract: Restriction fragment length polymorphism (RFLP) analysis carried out on 45 primary neuroblastomas showed deletion of chromosome 11 sequences in 12 of 37 (32%) informative cases. Both 11p and 11q probes were informative in seven tumors; loss of all of chromosome 11, of only 11p sequences, and of only 11q sequences was observed in 4, 1, and 2 tumors, respectively. A cytogenetic abnormality involving translocation of chromosome arm 11q to chromosome arm 1p was observed in a primary tumor. Deletion of 14q was observed in 6 of 27 (22%) informative cases. Deletion of chromosome 11 but not 14q may correlate with regional and metastatic disease. These results suggest a possible role for sequences localized to chromosome 11 and to 14q in the development and/or progression of neuroblastoma.

A cytogenetically based physical map of chromosome 1B in common wheat.

Abstract: We have constructed a cytogenetically based physical map of chromosome 1B in common wheat by utilizing a total of 18 homozygous deletion stocks. It was possible to divide chromosome 1B into 17 subr...

Chapter 16 Molecular pathology of head trauma: altered βAPP metabolism and the aetiology of Alzheimer's disease

Abstract: Publisher Summary Considerable progress has been made in determining the identity of the proteins and molecular events involved in the molecular pathology of Alzheimer's disease (AD), the most widely known of which are the inevitability of Alzheimer's disease in Downs syndrome patients with trisomy of chromosome 21 and the point mutations at codon 717 within exon 17 of the β -amyloid precursor protein gene on chromosome 21. However, these genetic causes of Alzheimer's disease account for a vanishingly small proportion of patients who suffer from the disease. It is probable that the overwhelming majority of cases are caused by a variety of environmental factors, which may be either sufficient to trigger disease by themselves or sufficient when acting synergistically with the patients genotype. One of the best-documented environmental precipitants of Alzheimer's disease is a previous history of head trauma. AD can be caused by a variety of factors. Approximately 20% of AD cases are thought to be familial with almost 5% exhibiting an autosomal dominant pattern of inheritanc. Screening of the amyloid precursor protein ( β APP) gene on chromosome 21, which gives rise to the β -amyloid protein found in plaques, has revealed a mutation in some AD families.

The retinoblastoma-related gene, RB2, maps to human chromosome 16q12 and rat chromosome 19.

Abstract: A retinoblastoma-related human gene, referred to as RB2, has been cloned based on sequence homology of the E1A-binding domain of the retinoblastoma gene. Structural homology with the retinoblastoma gene suggests a possible function of RB2 as a tumor suppressor gene. In this study, we have mapped this gene to human chromosome 16q12.2 and rat chromosome 19, using fluorescence in situ hybridization and somatic hybrid cell analysis, respectively. Based on known syntenic relationships among human, rat and mouse, the data suggest that the mouse homolog resides on chromosome 8. Deletions of chromosome 16q have been found in several human neoplasias (including breast, ovarian, hepatic, and prostatic cancers) which is in support of an involvement of RB2 in human cancer as a tumor suppressor gene.

Physical localization of the flocculation gene FLO1 on chromosome I of Saccharomyces cerevisiae.

Abstract: The genetics of flocculation in the yeast Saccharomyces cerevisiae are poorly understood despite the importance of this property for strains used in industry. To be able to study the regulation of flocculation in yeast, one of the genes involved, FLO1, has been partially cloned. The identity of the gene was confirmed by the non-flocculent phenotype of cells in which the C-terminal part of the gene had been replaced by the URA3 gene. Southern blots and genetic crosses showed that the URA3 gene had integrated at the expected position on chromosome I. A region of approximately 2 kb in the middle of the FLO1 gene was consistently deleted during propagation in Escherichia coli and could not be isolated. Plasmids containing the incomplete gene, however, were still able to cause weak flocculation in a non-flocculent strain. The 3' end of the FLO1 gene was localized at approximately 24 kb from the right end of chromosome I, 20 kb centromere-proximal to PHO11. Most of the newly isolated chromosome I sequences also hybridized to chromosome VIII DNA, thus extending the homology between the right end of chromosome I and chromosome VIII to approximately 28 kb.

A short chromosomal region with major roles in yeast chromosome III meiotic disjunction, recombination and double strand breaks.

Abstract: A multicopy plasmid was isolated from a yeast genomic library, whose presence resulted in a twofold increase in meiotic nondisjunction of chromosome III. The plasmid contains a 7.5-kb insert from the middle of the right arm of chromosome III, including the gene THR4. Using chromosomal fragments derived from chromosome III, we determined that the cloned region caused a significant, specific, cis-acting increase in chromosome III nondisjunction in the first meiotic division. The plasmid containing this segment exhibited high spontaneous meiotic integration into chromosome III (in 2.4% of the normal meiotic divisions) and a sixfold increase (15.5%) in integration in nondisjunctant meioses. Genetic analysis of the cloned region revealed that it contains a "hot spot" for meiotic recombination. In DNA of rad50S mutant cells, a strong meiosis-induced double strand break (DSB) signal was detected in this region. We discuss the possible relationships between meiosis-induced DSBs, recombination and chromosome disjunction, and propose that recombinational hot spots may be "pairing sites" for homologous chromosomes in meiosis.

Paternal nondisjunction in trisomy 21: excess of male patients

Abstract: Paternal nondisjunction accounts for approximately 5% of cases of trisomy 21. We have studied 36 cases of free trisomy 21, in which the supernumerary chromosome was of paternal origin, with DNA markers in the pericentromeric region and along the long arm of chromosome 21. Fifteen of the paternal cases were consistent with meiosis II errors, 8 with mitotic errors and only 7 with meiosis I nondisjunction. This contrasts markedly with maternally derived trisomy 21, in which meiosis I errors predominate. An excess of males was observed in the meiotic cases (21 males:6 females), highly significantly different from a 1.06 ratio. A significant difference in mean maternal age was found between cases of paternal origin (28.1 years) and those of maternal origin (31.8 years, n = 429). This indicates that the maternal age effect is confined to maternal nondisjunction.

Chromosome 14 and late-onset familial Alzheimer disease (FAD)

Abstract: Familial Alzheimer disease (FAD) is genetically heterogeneous. Two loci responsible for early-onset FAD have been identified: the amyloid precursor protein gene on chromosome 21 and the as-yet-unidentified locus on chromosome 14. The genetics of late-onset FAD is unresolved. Maximum-likelihood, affected-pedigree-member (APM), and sib-pair analyses were used, in 49 families with a mean age at onset ≥60 years, to determine whether the chromosome 14 locus is responsible for late-onset FAD. The markers used were D14S53, D14S43, and D14S52. The LOD score method was used to test for linkage of late-onset FAD to the chromosome 14 markers, under three different models: age-dependent penetrance, an affected-only analysis, and age-dependent penetrance with allowance for possible age-dependent sporadic cases. No evidence for linkage was obtained under any of these conditions for the late-onset kindreds, and strong evidence against linkage (LOD score ≤ –2.0) to this region was obtained. Heterogeneity tests of the LOD score results for the combined group of families (early onset, Volga Germans, and late onset) favored the hypothesis of linkage to chromosome 14 with genetic heterogeneity. The positive results are primarily from early-onset families. APM analysis gave significant evidence for linkage of D14S43 and D14S52 to FAD in early-onset kindreds (P < .02). No evidence for linkage was found for the entire late-onset family group. Significant evidence for linkage to D14S52, however, was found for a subgroup of families of intermediate age at onset (mean age at onset ≥60 years and <70 years). These results indicate that the chromosome 14 locus is not responsible for Alzheimer disease in most late-onset FAD kindreds but could play a role in a subset of these kindreds.