Assignment of human phosphoribosylglycinamide synthetase locus to region 21q221

Summary The enzymatic activity of phosphoribosylglycinamide synthetase (GARS) has been studied in several cases of partial monosomies and full and partial trisomies 21. An excess of GARS activity was found in regular trisomy 21 with a trisomy 21/normal ratio equal to 1.55. A 0.99 ratio was found in 21q2121pter monosomy; a 0.54 ratio was found in 21qter21q22 monosomy; a 0.88 ratio, in 21q2121pter trisomy, and a 1.46 ratio, in 21q22.1 trisomy. Consequently, the GARS gene locus, assigned to chromosome 21, could be localized in subband 21q22.1.     

Submicroscopic duplication of chromosome 21 and trisomy 21 phenotype (Down syndrome)

Summary A patient with the phenotype of trisomy 21 (Down syndrome) was found to have a normal karyotype in blood lymphocytes and fibroblasts. Assessment of the chromosome 21 markers SOD1, CBS, ETS2, D21S11, and BCEI showed partial trisomy by duplication of a chromosome segment carrying the SOD1, CBS, and ETS2 loci and flanked by the BCEI and D21S11 loci, which are not duplicated. This submicroscopic duplication at the interface of 21q21 and 21q22.1 reduces to about 2000–3000kb the critical segment the trisomy of which is responsible for the phenotype of trisomy 21.     

Phosphofructokinase activity in fibroblasts aneuploid for chromosome 21

Summary Although the gene for the liver type (L) subunit of phosphofructokinase (PDK) is located on human chromosome 21 and PFKL subunits predominate in fibroblasts, an increase in PFK activity has not been reported in trisomy 21 fibroblasts. However, using well-matched pairs of trisomy 21 and diploid fibroblast strains, we observed an almost 1.5-fold increase in mean PFK activity of trisomic cells. In monosomy 21 fibroblasts we found an almost 0.5-fold decrease in mean PFK activity. Thus there appears to be a gene-dosage effect for the PFKL gene, as for other loci on chromosome 21. PFK activity in a cell strain deleted for the distal part of band 21q22.3 was not decreased, suggesting with other data that PFKL is located in the midportion of band 21q22.3.     

Reciprocal syndromes caused by deficiency duplication resulting from maternal t(10;18)(p12;q22) translocation

The detection of a familial translocation, t(10;18)(p12;q22), has made possible the observation in type and countertype of two related persons with opposite chromosomal imbalance: trisomy 18q22----18qter with monosomy 10p12----10pter in one of the two and monosomy 18q22----10pter in the other. In each case the abnormalities attributable to monosomy overrule those attributable to monosomy overrule those attributable to the associated trisomy.     

Complete monosomy mosaic of chromosome 21: Case report and review of literature

Complete monosomy mosaic of chromosome 21 is a rare disorder. The syndromic features are highly variable. This study describes a girl of Mexican origin with complete monosomy 21 in mosaicism with novel findings, including cortical atrophy, macrostomia, pectum excavatum and immune deficiencies. Parental karyotypes were normal. FISH analysis with probes from 21q22.1–q22.2 region and centromere of X DNA probe was performed on peripheral blood lymphocytes whereas 21q22.1–q22.2 and 21q, 4p, 4q subtelomeric DNA probes were tested in fibroblasts. We propose that the monosomy 21 mosaicism is the cause of the survival of children with more than 4 months of age.     

Polymorphism of restriction fragment length in the detection of the precise status of monosomy 21 in a deformed retarded girl

The authors used genomic single copy DNA fragments cloned from chromosome 21 to study cytogenetic abnormalities in patients not easily defined by conventional cytogenetic means. Ten restriction fragment length polymorphisms (RLFP) detected by 8 independent probes were used to detect homologous sequences from chromosome 21 in genomic digests of DNA from one patient and her parents. The proband is a 3 1/2-year-old girl who was referred to us at 1 month of age because of hypertonia, hirsutism, flattened nasal bridge, antimongoloid slant of palpebral fissures, high arched palate and bilateral hip dysplasia. The karyotype of the proband was: 46, XX, -3, -21, + ? del (3) (3 pter----3q1:) +? (3qter----3q1:: 21q21----21 pter). GTG banding and the karyotype of her parents were normal (in peripheral blood and skin fibroblasts). She was re-examined by us every three months, because she showed physical and psychomotor retardation. We traced the inheritance of RFLPs from her parents, and familial molecular studies showed in contrast to the cytogenetic analysis that the patient is disomic for all regions of 21q tested by our collection of probes. The use of molecular technology has resulted in a more precise definition of 21 chromosome abnormalities and especially the "complete" monosomy 21 which is extremely rare in live born infants.     

Possible localization of the glutathione reductase (EC 1.6.4.2) on the 8p21 band]

Glutathione reductase (EC 1.6.4.2.) (GSR) activity was measured in the red cells of patients with different rearrangements of chromosome 8. Of three patients with mosaic trisomy 8, two had a high GSR activity. The lack of correlation between GSR levels and the degree of mosaicism in lymphocytes is discussed. In six patients with trisomy 8qter the mean value of GSR activities was normal. In one patient with trisomy pter leads to q22.1 and in two with trisomy p11 leads to p22, a significant increase (+60%) of GSR activity was observed. In two patients with monosomy p22 leads to pter and p21 leads to pter, respectively, the GSR levels were normal. It is concluded that the gene locus of GSR can be assigned to the 8p11 leads to p22 segment. A comparison of these results with one other case from the literature suggests a more precise assignment of the GSR locus to band p21.     

Assignment of the gene for cystathionine β-synthase to human chromosome 21 in somatic cell hybrids

Summary Among several established mouse, rat, and Chinese hamster cell lines that were screened for cystathionine -synthase (CBS) activity, mouse 3T3 and Chinese hamster Don fibroblasts were found to contain no detectable activity. Somatic cell hybrids between human fibroblasts KG-7 with normal CBS activity and Don/a23TK^- cells (series XXI) were examined for CBS activity and for human chromosome content. Only chromosome 21 cosegregated with CBS activity. Because the activities measured could represent either Chinese hamster or human gene products, we have prepared a new series of hybrids between Don/a23TK^- cells and mutant human fibroblasts from a patient with homocystinuria due to deficiency of functional CBS mRNA. None of these (series XXV) hybrids contained detectable CBS activity, although collectively all human chromosomes were represented. Our results suggest that the human gene for CBS, called CBS, and thus for the most common form of homocystinuria, is located on chromosome 21.     

Moderate Down's syndrome in three siblings having partial trisomy 21q22.2→qter and therefore no SOD-1 excess

Summary Three mentally retarded siblings with moderate stigmata of Down's syndrome were found to have a partial trisomy 21q22.2qter resulting from a maternal translocation t(4q+;21q-). By the exclusion of any excess of SOD-1 in them, we can confirm the nonessentiality of the sub-band 21q22.1 and of the SOD-1 excess for most of the Down's syndrome stigmata including the mental retardation. However, the sub-band 21q22.1 in triplicate might be required for the completion of the full syndrome, as for example is shown by the incomplete dermatoglyphic pattern on the palms in the patients.     

Regional mapping of liver type 6 phosphofructokinase isoenzyme on chromosome 21

Summary Among several cases of partial monosomies and full and partial trisomies 21, the enzymatic activity of phosphofructokinase (PFK) is increased only in 21q2121pter trisomy with a (T₂₁/N) ratio equal to 1.35 and decreased in monosomy 21q2121pter. These results suggest that the human gene for liver-type PFK is located between 21q21 and 21pter.     

YAC and cosmid FISH mapping of an unbalanced chromosomal translocation causing partial trisomy 21 and Down syndrome

Most cases of Down syndrome (DS) result from a supernumerary chromosome 21; however, there are rare cases in which DS is due to partial trisomy of chromosome 21, involving various segments of the chromosome. The characterization of cases of DS that are due to partial trisomy 21 allows the phenotype to be correlated with the genotype. We present a case with features of DS and a partial trisomy of chromosome 21 inherited from a paternal balanced translocation involving chromosomes 13 and 21. Fluorescence in situ hybridization analysis using yeast artificial chromosome (YAC) probes mapped the breakpoint to 21q22.1, within YAC 230E8, which contains markers CBR, D21S333 and D21S334. Further mapping using cosmids positioned the breakpoint proximal to CBR. The patient was also monosomic for the distal portion of chromosome 13 (q33–qter). Many phenotypic features of DS were present including hypotonia, flat occiput, flat facies, up-slanted palpebral fissures, epicanthic folds, flat nasal bridge, macroglossia, open mouth, small ears and a heart murmur. This case further supports the contention that the majority of the phenotypic features of DS map to 21q22–qter and further refines the location of some of them. In addition to the DS phenotype, the patient had a prominent upper maxilla with protruding upper incisors, and low levels of the coagulation factors VII and X, consistent with a syndrome resulting from monosomy 13q33–qter. Since some features overlap between the two syndromes, including severe mental retardation, it is unclear to what extent monosmy for 13q33–qter, trisomy for 21q22.1–qter, or a combination of both, contributed to the common features of the phenotype. Received: 27 March 1996 / Revised: 15 May 1996     

Down syndrome with duplication of a region of chromosome 21 containing the CuZn superoxide dismutase gene without detectable karyotypic abnormality

Summary We report the case of an 18-month-old boy with many typical Down syndrome features but a normal cytogenetic analysis. High-resolution banding techniques on lymphocytes and fibroblasts of the propositus and his parents did not show any detectable abnormality including that of trisomy 21 mosaicism. However, CuZn superoxide dismutase (CuZn SOD) in the patient's red cells was increased as in trisomy 21. DNA analysis (Southern blots) using a human CuZn SOD probe showed that the genotype of the propositus contained three CuZn SOD genes. In situ hybridization on metaphase chromosomes with the same probe confirmed the gene location in a segment enclosing the distal part of 21q21 and 21q22.1. There was no significant labeling on other chromosomes of the patient. These results indicate that the Down syndrome phenotype of this patient is due to microduplication of a chromosome 21 fragment containing the CuZn SOD gene.     

Anonymous DNA probes to human chromosome 16 derived from a flow-purified library.

Anonymous DNA probes specific for human chromosome 16 were isolated from a flow-purified human chromosome 16 library. The library was constructed at the Lawrence Livermore National Laboratory. Twenty-nine clones containing a unique or low-copy DNA insert were isolated. Of these, six were assigned to chromosome 16 and regionally mapped and 12 were shown not to map to chromosome 16. One clone mapped to 16pter----16p13.1, one clone to 16p11.1----16q13, one clone to 16q13----16q22.1, and three clones to 16q22.1----16q24. An additional clone from the same library was mapped to 16q13----16q22.1.     

Partial trisomy 17q and monosomy 9p due to a familial translocation.

Described is an infant with partial trisomy 17q and monosomy 9p [46,XX,-9,+der(9)t(9;17)(p21;q23)] due to adjacent-1 segregation of a maternal balanced reciprocal translocation. Characteristic clinical features of both partial 17q trisomy and monosomy 9p are present, but the former syndrome is less recognisable in this infant than in previously reported cases due to the concomitant 9p monosomy.     

Presumptive monosomy 21 with neuronal migration disorder re-diagnosed as de novo unbalanced translocation t(18p;21q) by fluorescence in situ hybridisation

We present clinical and cytogenetic data of a one year old boy with partial monosomy for both 21q and 18p, resulting from a de novo unbalanced translocation. The initial diagnosis of a seemingly full monosomy 21 was revised after fluorescence in situ hybridisation (FISH) with whole chromosome painting probes and a locus-specific chromosome 21 probe. The karyotype was reinterpreted as 45,XY,der(18)t(18;21)(p11.2;q22.1),-21. This karyotype, to our knowledge, has not been previously described. The boy presented with a spectrum of clinical features previously described for (partial) monosomy 18p only, for monosomy 21q only, or for both of these aneusomies. The radiological finding of a neuronal migration disorder with localised polymicrogyria (cortical dysplasia) has not been described for either monosomy before.     

Opposite Phenotypes of Muscle Strength and Locomotor Function in Mouse Models of Partial Trisomy and Monosomy 21 for the Proximal Hspa13-App Region

The trisomy of human chromosome 21 (Hsa21), which causes Down syndrome (DS), is the most common viable human aneuploidy. In contrast to trisomy, the complete monosomy (M21) of Hsa21 is lethal, and only partial monosomy or mosaic monosomy of Hsa21 is seen. Both conditions lead to variable physiological abnormalities with constant intellectual disability, locomotor deficits, and altered muscle tone. To search for dosage-sensitive genes involved in DS and M21 phenotypes, we created two new mouse models: the Ts3Yah carrying a tandem duplication and the Ms3Yah carrying a deletion of the Hspa13-App interval syntenic with 21q11.2-q21.3. Here we report that the trisomy and the monosomy of this region alter locomotion, muscle strength, mass, and energetic balance. The expression profiling of skeletal muscles revealed global changes in the regulation of genes implicated in energetic metabolism, mitochondrial activity, and biogenesis. These genes are downregulated in Ts3Yah mice and upregulated in Ms3Yah mice. The shift in skeletal muscle metabolism correlates with a change in mitochondrial proliferation without an alteration in the respiratory function. However, the reactive oxygen species (ROS) production from mitochondrial complex I decreased in Ms3Yah mice, while the membrane permeability of Ts3Yah mitochondria slightly increased. Thus, we demonstrated how the Hspa13-App interval controls metabolic and mitochondrial phenotypes in muscles certainly as a consequence of change in dose of Gabpa, Nrip1, and Atp5j. Our results indicate that the copy number variation in the Hspa13-App region has a peripheral impact on locomotor activity by altering muscle function.     

Partial trisomy and monosomy 21 in an infant with an unusual de novo 21/21 translocation

A 3-month-old boy with a 46,XY,--21,+t(21;21)(pter leads to q22.3::q22.3 leads to q11::p11 leads to pter) karyotype, implicating trisomy for the 21q11 leads to 21q22.2 segment and monosomy for the 21q22.3 sub-band, is described. Most of the clinical features corresponded to Down syndrome ; other signs such as large ears, prominent nasal bridge and retromicrognathia were interpreted as the expression of 21q22.3 monosomy. The abnormal monocentric chromosome had satellites and stalks on both ends as a result of a 21q;21q translocation followed by deletion of one centromere region. Despite similar stalk size and NOR-Ag positiveness a significantly higher association frequency of the centrometric end as compared to the acentric end was found. This observation suggests that the satellite association phenomenon is not exclusively NOR-dependent, but that the centromeric and/or p11 regions of acrocentrics also play an important role.     

Assignment of human porphobilinogen deaminase to 11q24.1----q24.2 by in situ hybridization and gene dosage studies

In situ hybridization and gene dosage-effect studies were conducted to determine the detailed chromosomal location of the gene encoding human porphobilinogen deaminase (PBGD). Red cell PBGD activity was normal in one patient with monosomy for 11q24.2----qter but was increased 1.5 times in another patient with trisomy for 11q22.2----qter. The cDNA probe for PBGD was found to be specifically hybridized to band 11q24. These results suggest that the gene for PBGD is localized within the region 11q24.1----q24.2.     

Familial translocation t(10;21)(q22;q22)

Summary A family is described with a translocation t(10;21)(q22;q22) transmitted through three generations. This family was studied for the apparition of several miscarriages and two sisters with multiple malformations. Both children had a probably partial trisomy of chromosome 10 and a monosomy of chromosome 21 due to a maternal adjacent-2 meiotic segregation.