Partial trisomy 9q: a new syndrome.

Two unrelated patients with a strikingly similar phenotype (low birth weight and poor thriving; mental retardation; dolichocephaly; beaked nose; deeply set eyes; prominent maxilla and receding small chin; long fingers with a peculiar clench) were partially trisomic for two different segments of 9q. The segment found to be trisomic in both patients is small and corresponds to the q31q32 region. This new syndrome is compared to observations of trisomy 9 reported in the literature.     

Cytogenetic findings in a prospective series of patients with DiGeorge anomaly.

High-resolution cytogenetics analysis of peripheral blood lymphocytes was done prospectively on 27 of 28 patients with features of DiGeorge anomaly. Twenty-two patients (81%) had normal chromosome studies with no detectable deletion in chromosome 22. Five patients (18%) had demonstrable chromosome abnormalities. Three patients had monosomy 22q11, one due to a 4q;22q translocation, one due to a 20q;22q translocation, and one due to an interstitial deletion of 22q11. One patient had monosomy 10p13, and one patient had monosomy 18q21.33, although the latter had subsequent resolution of T-cell defects. These findings are consistent with the heterogeneity of DiGeorge anomaly but confirm the association with monosomy 22q11 in some cases. However, monosomy 10p13 may also lead to this phenotype. Because of these associated chromosome findings, cytogenetic analyses should be done on patients with suspected DiGeorge anomaly. This is particularly important since many of the abnormalities involving chromosome 22 are translocations that can be familial with a higher recurrence risk. Since only one subtle, interstitial deletion of chromosome 22 was observed, it is not clear whether high-resolution cytogenetic analysis is cost beneficial for all such patients.     

The assembly of ionic currents in a thalamic neuron. I. The three-dimensional model

We have previously discussed qualitative models for bursting and thalamic neurons that were obtained by modifying a simple two-dimensional model for repetitive firing. In this paper we report the results of making a similar sequence of modifications to a more elaborate six-dimensional model of repetitive firing which is based on the Hodgkin-Huxley equations. To do this we first reduce the six-dimensional model to a two-dimensional model that resembles our original two-dimensional qualitative model. This is achieved by defining a new variable, which we call q. We then add a subthreshold inward current and a subthreshold outward current having a variable, z, that changes slowly. This gives a three-dimensional (v,q,z) model of the Hodgkin-Huxley type, which we refer to as the z-model. Depending on the choice of parameter values this model resembles our previous models of bursting and thalamic neurons. At each stage in the development of these models we return to the corresponding seven-dimensional model to confirm that we can obtain similar solutions by using the complete system of equations. The analysis of the three-dimensional model involves a state diagram and a stability diagram. The state diagram shows the projection of the phase path from v,q,z space into the v,z plane, together with the projections of the curves z = 0 and v = q = 0. The stability of the points on the curve v = q = 0, which we call the v, q nullcurve, is determined by the stability diagram. Taken together the state and stability diagrams show how to assemble the ionic currents to produce a given firing pattern.     

Molecular characterization of a 130-kb terminal microdeletion at 22q in a child with mild mental retardation.

We have analyzed a recently described 22q13.3 microdeletion in a child with some overlapping features of the cytologically visible 22q13.3 deletion syndrome. Patient NT, who shows mild mental retardation and delay of expressive speech, was previously found to have a paternal microdeletion in the subtelomeric region of 22q. In order to characterize this abnormality further, we have constructed a cosmid/P1 contig covering the terminal 150 kb of 22q, which encompasses the 130-kb microdeletion. The microdeletion breakpoint is within the VNTR locus D22S163. The cloning of the breakpoint sequence revealed that the broken chromosome end was healed by the addition of telomeric repeats, indicating that the microdeletion is terminal. This is the first cloned terminal deletion breakpoint on a human chromosome other than 16p. The cosmid/P1 contig was mapped by pulsed-field gel electrophoresis analysis to within 120 kb of the arylsulfatase A gene, which places the contig in relation to genetic and physical maps of the chromosome. The acrosin gene maps within the microdeletion, approximately 70 kb from the telomere. With the distal end of chromosome 22q cloned, it is now possible to isolate genes that may be involved in the overlapping phenotype of this microdeletion and 22q13.3 deletion syndrome.     

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.     

Cytogenetics of neuroblastoma: a study using fine needle aspiration cultures.

Neuroblastoma is associated with chromosomal aberrations of 1p and 1q in a majority of cases. Some nonrandom secondary changes were observed in this study. The role of these changes in the development and progression of neuroblastoma is examined. Chromosomal analysis was performed on 33 children with neuroblastoma using fine needle aspiration cultures. Metaphases were observed in 57.5% of cases. 86.6% showed the involvement of chromosome 1. Double minutes and unidentifiable markers was also observed. The most frequent secondary changes included add(4)(q35), add(11)(p13), add(14)(q32), add(16)(q12). add(17)(p13), add(19)(q12) and add(21)(q22). Minority of cases showed deletions and translocations. Ploidy pattern ranged from diploid to hypotetraploid. The present study substantiates aberration of chromosome 1 in the form of deletions, additions, duplications and iso-chromosome with some notable secondary abnormalities.     

Translocation/duplication of 9p onto a duplicated 4q.

A 5-month-old girl with the classical dysmorphism of the 9p trisomy syndrome and a severe heart defect was found to have an unbalanced translocation of 9pter-->p22 onto q35 of a chromosome 4 with an inverted duplication of q32-->q35. This concurrence of two de novo rearrangements suggests that the breakpoint at 4q35 not only participated in the translocation but also predisposed to the segmental duplication of 4q.     

11q- syndrome: three cases and a review of the literature.

We report on three children with de novo terminal deletions of the long arm of chromosome 11 (11q-) and breakpoints in 11q23-q24. Eighty-nine other patients with partial monosomy 11q have been reported and were reviewed by us. Salient features of 11q- syndrome are psychomotor retardation, trigonocephaly, telecanthus/hypertelorism, broad depressed nasal bridge, micrognathia, low set abnormal ears, cardiac anomalies and hand/foot anomalies. Renal agenesis and anal atresia are reported first here. Supratentorial white matter abnormality on CT and MRI present in our second patient was reported in three patients. Increased mortality is caused by cardiac anomalies. A third of all patients with partial monosomy 11q had thrombocytopenia or pancytopenia and this seems to be related to the absence of band 11q23-q24. Seventy-six percent of patients have de novo deletions with breakpoints in 11q21-q25. There is no obvious correlation between the length of the deleted segment and the severity of the symptoms. In unbalanced chromosomal patterns with deletions of 11q involving bands 11q23-q24 the typical phenotype of 11q- syndrome remains recognizable. Deletions distal to 11q24.1 do not produce the typical 11q- syndrome.     

Trisomy 13 with a 13q14q translocation.

A sporadic case of Patau syndrome with 46,XY,14-,t(13q14q)+ karyotype is reported in a 2-month-old child. Dermatoglyphic and cytogenetic findings of the propositus and cytogenetic study of his parents are presented.     

Characterization of a partial trisomy 16q with FISH. Report of a patient and review of the literature.

Characterization of a partial trisomy 16 q with FISH: Report of a patient and literature review: We report on a 28-year-old male patient with severe growth and mental retardation, severe behavioural problems, especially automutilation, and a spastic quadriplegia. He showed no specific dysmorphism. The karyotype was 46, XY, dir dup(16) (q11.2-q13). The clinical and cytogenetical findings are compared with 3 previously reported cases with proximal duplication 16q.     

Characterization of the C1q receptor on a human macrophage cell line, U937.

The binding of C1q to the human macrophage cell line U937 has been studied. Fluorescence microscopy with fluorescein-conjugated F(ab')2 anti-C1q antibody showed that 100% of the cell population is able to bind exogenous C1q. Monomeric C1q binding to U937 cells is very weak at normal ionic strength (I0.15) and was therefore investigated at I0.07, conditions which stabilize the binding. However, aggregation of C1q on dextran sulphate or a lipid A-rich lipopolysaccharide allowed a firm, binding at I0.15. Quantitative binding studies with monomeric 125I-C1q showed a concentration-dependent, saturable, specific and reversible binding involving specific membrane receptors. Scatchard plots of C1q binding indicated [1.6 +/- 0.7 (1 S.D.)] X 10(6) sites per cell with an equilibrium constant of (2.9 +/- 1.8) X 10(7) M-1 at I0.07. The location of the molecule region mediating C1q binding was established with collagen-like fragments prepared by partial pepsin digestion, confirming earlier results obtained by inhibition studies.     

STK25 is a candidate gene for pseudopseudohypoparathyroidism.

We determined the chromosomal location of the mouse gene Stk25, encoding a member of the Ste20/PAK family of serine/threonine kinases, by interspecific backcross analysis. We mapped Stk25 to the central region of mouse chromosome 1 linked to Chrng (formerly Acrg) and En1. This central region of mouse chromosome 1 shares a region of homology with the long arm of human chromosome 2, suggesting that the human homologue of Stk25 would also map to 2q. We proved this prediction of syntenic homology correct by mapping human STK25 to 2q37. Deletion of the 2q37 region has been implicated in the expression of pseudopseudohypoparathyroidism (PPHP), a disease which shares features of the Albright hereditary osteodystrophy (AHO) phenotype. To investigate a pathogenetic relationship between STK25 and PPHP, we carried out fluorescence in situ hybridization (FISH) using an STK25 gene probe and chromosomes from PPHP patients characterized as having small deletions near the distal end of 2q. PPHP patient DNA showed no hybridization to STK25 genomic DNA, indicating that STK25 is contained within the deleted chromosomal region. This finding, in conjunction with previous studies demonstrating the role of Ste20/PAK kinases in heterotrimeric G protein signaling, suggests that STK25 is a positional candidate gene for PPHP.     

Secretion of a 107 K dalton polypeptide into the medium from a haemolytic E. coli K12 strain

Summary Certain E. coli K12 strains are able to secrete a plasmid encoded 107 K protein into the culture medium. During exponential growth of the cells this protein represents approximately 1% of total cell protein.The presence of the 107 K polypeptide was demonstrated through the fortuitous use of strain MC4100. This gave a largely protein-free culture supernatant, presumably due to minimal lysis of whole cells. Pulse-labelling experiments showed that the secretion of the 107 K polypeptide reached a maximum during the stationary phase of growth, where it represented substantially more than 1% of total cell protein. The 107 K polypeptide is coded by the haemolytic plasmid pHly167, and appears to be related to a previously reported intracellular precursor form of the -haemolysin (Goebel and Hedgpeth 1982). However, additional extracellular factors appear to be required for -haemolysin activity since several nonhaemolytic mutants still secrete this protein.     

Construction of a GT polymorphism map of human 9q.

To construct a framework map of human chromosome 9 consisting of highly informative markers, we identified 36 cosmid clones from chromosome 9 that contained long GT repeat sequences. The cosmids were found to cluster on the long arm of the chromosome, particularly in the q32-34 region. Thirteen highly informative polymorphisms from 9q were identified, with median observed heterozygosity 0.75 and median calculated heterozygosity based upon allele frequencies of 0.75. These new GT repeat polymorphisms (D9S56, D9S58-67), as well as anchor GT polymorphisms for D9S15 (MCT112, 9q13), and ABL and ASS (both 9q34.1) were utilized to construct a linkage map of human 9q by the typing of the Venezuelan Reference Pedigree. Care was taken to avoid errors, including analysis of the data with CHROMLOOK and verification of all double crossover events detected within a 30 cM interval by repetition of the marker analysis. The map was generated using the MAPMAKER program. All positions in the resulting map are favored by odds of greater than 10(4):1. The map has a sex-averaged length of 90 cM (Kosambi function) with a single maximum intermarker recombination fraction of 26%. All other intermarker recombination fractions are less than 15%. As D9S15 is known to be closely linked to markers on proximal 9p, and ASS/ABL are in band 34.1, this set of GT polymorphisms spans the length of 9q and provides a useful panel for linkage analysis of disease genes to this region. The marker order was confirmed by in situ hybridization of the cosmid clones to metaphase spreads of normal human chromosomes, which indicated an excess of recombination in the telomeric region in comparison to centromeric 9q, in agreement with previous chiasmata distribution observations. Two spontaneous new mutations for these GT repeat markers were identified, giving an overall observed spontaneous mutation rate of 0.00045 per locus per gamete. Direct observation of new mutations has not been previously reported for dinucleotide polymorphisms, but the observed rate is consistent with frequencies observed for other VNTR polymorphisms.     

A t(4;22) in a meningioma points to the localization of a putative tumor-suppressor gene.

Cytogenetic analysis of meningioma cells from one particular patient (MN32) displayed the stem-line karyo-type 45, XY, -1, 4p+, 22q-, 22q+, which thus had rearrangements of both chromosomes 22. The 22q+ marker appeared as a dicentric: 22 pter----q11::1p11----qter. The reciprocal product of this translocation has presumably been lost because it lacked a centromere. The 22q- chromosome also appeared to have lost sequences distal to band q11. We assumed that this marker could have been the result of a reciprocal translocation between chromosomes 4 and 22. To investigate the 4p+ and 22q- chromosomes in more detail, human-hamster somatic cell hybrids were constructed that segregated the 22q- and 4p+ chromosomes. Southern blot analysis with DNA from these hybrids showed that sequences from 22q were indeed translocated to 4p+ and that reciprocally sequences from 4p were translocated to 22q-, demonstrating a balanced t(4;22)(p16;q11). On the basis of these results we presume that in this tumor a tumor-suppressor gene is deleted in the case of the 22q+ marker and that the t(4;22) disrupts the second allele of this gene. The latter translocation was mapped between D22S1 and D22S15, a distance of 1 cM on the linkage map of this chromosome. The area in which we have located the translocation is within the region where the gene predisposing to neurofibromatosis 2 has been mapped.     

Mutations in the carboxyl-terminal domain of phospholipase C-beta 1 delineate the dimer interface and a potential Galphaq interaction site.

The carboxyl-terminal domain of phospholipase C-beta is required for its stimulation by Galpha(q) and for its Galpha(q)-specific GTPase-activating protein (GAP) activity. We subjected this domain to a combination of deletion and alanine/glycine scanning mutagenesis to detect mutations that would inhibit either responsiveness to G(q) or G(q) GAP activity. Most mutations that altered either response or GAP activity diminished both in parallel. Many of these mutations map at the interface at which the carboxyl-terminal domain was recently shown to form a dimer (Singer, A. U., et al. (2001) Nat. Struct. Biol., 9, 32-36). Most others clustered in an area that is a plausible Galpha(q) binding site. In addition, one mutation that differentially inhibited GAP activity relative to responsiveness to Galpha(q) mapped in this region at a location modeled to be in close contact with the switch II region of Galpha(q). This is the site at which RGS proteins are thought to exert their GAP activity. Last, a deletion mutation differentially inhibited the response of phospholipase C-beta1 to Galpha(q) without blocking GAP activity. Its location in the molecule suggests that moving the attachment point of the catalytic domain can disrupt its ability to be activated by Galpha(q).     

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.     

A new type of inversion of a human Y chromosome.

Using chromosome banding techniques, a phenotypically normal male was found to have an abnormal banding pattern of the Y chromosome. By the constitutive heterochromatin staining method, a darkly stained band was located on the short arm and the proximal region of the long arm. The quinacrine staining method also showed a similar abnormal banding pattern: a brightly fluorescing band was seen on the short arm and the proximal region of the long arm. By the conventional Giemsa staining method, however, no specific morphological abnormality was detected in the aberrant Y. On detailed karyotype analyses no recognizable abnormality of banding patterns of any other chromosome was found aside from the abnormal Y. The abnormality was determined to be a complex inversion of the Y chromosome, which is described as 46,X,inv(Y)(pter leads to p11::q11 leads to q12::cen::q12 leads to qter).