Partial duplication 8p due to interstitial duplication: inv dup(8)(p21.1----p22). Further delineation of the phenotype from birth to adulthood

We report on 2 patients, less than age 5 years, and one adult patient with partial duplication 8p, due to interstitial duplication of bands 8p21.1-22. The phenotype in young and adult patients with this chromosomal unbalance syndrome is further documented. In young patients the craniofacial manifestations are very similar to trisomy 8 mosaicism. However, mental retardation is much more pronounced in 8p21-22 duplication than in trisomy 8 mosaicism. The phenotypic changes observed in adult patients are probably secondary and they are due to the great neurologic deficit with generalized spasticity and hypertonia.     

Phenotypic and cytogenetic spectrum of 9p trisomy

Trisomy 9p is one of the most frequent autosomal anomalies compatible with long survival rate. The spectrum of clinical severity in trisomy 9 roughly correlates with the extent of trisomic chromosome material. Trisomy 9p is a clinically well delineated syndrome and of all stigmata craniofacial dysmorphism is most specific. In this study we report five cases with de novo trisomy 9p. The study aimed at the identification of the genotype/phenotype correlations in patients with different breakpoints. GTG banding, DAPI stain, whole chromosome paint, centromere, telomere and 9p21 specific locus probes demonstrated that partial trisomy 9p in case 1 was due to isochromosome 9p with translocation of the long arm of re-arranged chromosome 9 onto the short arm of chromosome 13, cases 2 and 3 had intrachromosomal duplication of the short arm of chromosome 9 [dup(9)(p21p24)], case 4 had "classical" 9p trisomy and case 5 had duplication of whole short arm and part of the long arm of chromosome 9 (partial 9 trisomy). Although cases 1 to 4 had trisomy involving 9p, cases 1 and 2 exhibited the classical clinical manifestations of 9p trisomy, while cases 3 and 4 had additional features overlapping with Coffin-Siris syndrome. The present study strengthens the association of Coffin-Siris syndrome and 9p, the significance of such observations may point to possible gene location of Coffin-Siris syndrome on 9p. Case 5 had additional manifestations more than those typical of trisomy 9p which could be due to duplication of 9q21 region. Wide gap between 1st and 2nd toes, observed in the studied cases, can be added to the phenotype of this trisomy. Three of our cases had brain malformations, case 3 had dilated ventricles with hypogenesis of corpus callosum, case 4 had agenesis of corpus callosum, and case 5 had Dandy-Walker malformation. We also suggest that dosage effects of genes located in 9pter-q22 contribute to the etiology of Dandy-Walker syndrome. We recommend MRI studies as a routine in all cases with trisomy 9p.     

Karyotype-phenotype analysis: 9p deletion versus 10q2 duplication

An analysis of karyotype-phenotype correlations was carried out on a male infant with 46,XY, -9, +der(9)t(9;10)(p22;q25.2)mat. Cytogenetically, the patient had a 9p deletion and a concurrent 10q2 duplication. Clinically, he manifested predominantly the features of 9p deletion syndrome. An epistasis of 9p deletion over 10q2 duplication was evident in this patient. Possible explanations for this epistatic phenomenon are discussed.     

The application of region-specific probes for the resolution of duplication 8p: a case report and a review of the literature

The structural rearrangement in the short arm of a chromosome 8 in a clinically affected patient has been reinvestigated by FISH using whole chromosome painting and region specific YAC probes. An inverted duplication of the segment p22-->p11.2 and a deletion of the subtelomeric region were demonstrated. By this approach, a more detailed resolution of the duplication/deletion 8p was possible. With the application of molecular cytogenetic methods the existence of different duplication segments within the clinical entity of duplication/deficiency 8p can be shown.     

H2O2 production downstream of FLT3 is mediated by p22phox in the endoplasmic reticulum and is required for STAT5 signalling

The internal tandem duplication (ITD) of the juxtamembrane region of the FLT3 receptor has been associated with increased reactive oxygen species (ROS) generation in acute myeloid leukemia (AML). How this elevated level of ROS contributes to the leukemic phenotype, however, remains poorly understood. In this work we show that ROS in the FLT3-ITD expressing AML cell line MV4-11 is reduced by treatment with PKC412, an inhibitor of FLT3, DPI, a flavoprotein inhibitor, and VAS2870, a Nox specific inhibitor, suggesting that ROS production is both FLT3 and NADPH oxidase dependent. The majority of these ROS co-localize to the endoplasmic reticulum (ER), as determined with the H(2)O(2)-specific aryl-boronate dye Peroxyorange 1, which also corresponds to co-localization of p22phox. Moreover, knocking down p22phox dramatically reduces H(2)O(2) after 24 hours in the ER, without affecting mitochondrial ROS. Significantly, the FLT3 inhibitor PKC412 reduces H(2)O(2) in FLT3-ITD expressing cell lines (MV4-11, MOLM-13) through reduction of p22phox over 24 hours. Reduced p22phox is achieved by proteasomal degradation and is prevented upon GSK3-β inhibition. Knockdown of p22phox resulted in reduced STAT5 signalling and reduced Pim-1 levels in the cells after 24 hours. Thus, we have shown that FLT3 driven H(2)O(2) production in AML cells is mediated by p22phox and is critical for STAT5 signalling.     

Cloning and expression of CIS6, chromosome assignment to 3p22 and 2p21 by in situ hybridization

A family of negative regulators of JAK signaling pathway referred to as suppressor of cytokines signaling (SOCS) or cytokine-inducible SH2 protein (CIS) has been recently identified. In order to find additional members of this family, we have used a consensus amino acid sequence contained in the well-conserved central SH2 domain to search DNA databases. We isolated cDNA coding for the human homologue of SOCS-5, referred to as CIS6. Northern blot analysis revealed CIS6 mRNA expression in various tissues such as heart, muscle, spleen, and thymus and in all myeloma cell lines examined. The gene was assigned to human chromosome bands 2p21 and 3p22 by in situ hybridization. CIS6 is structurally related to other members of the CIS family and therefore could act as a negative regulator of signal transduction.     

A 9p13→p24 duplication coupled with a whole 22q translocation onto 9p24

We report on a 3-year-old girl with a typical 9p trisomy syndrome, whose 45-chromosome karyotype includes a 9p+. As assessed by G, C and Ag-NOR bands, the rearranged chromosome resulted from a 9p13-->p24 direct duplication coupled with a translocation of the whole 22q onto 9pter, had heterochromatin at the junction site, lacked both nucleolar organizing regions (NORs) and centromere dots at the unconstricted fusion point, and was present in all metaphases scored. FISH results: a 9p subtelomere probe gave a diminished signal on the 9p+ precisely at the duplication junction 9p24::9p13, but no labeling was observed at the 9;22 translocation site; a pancentromeric alphoid probe labeled all centromeres, and gave a distinct signal at the 9pter;22cen junction. Hence, her karyotype was 45,XX,rea(9;22)(9qter-->9p24::9p13-->9p24::22p10-->22qter).ish rea(9;22) (9psubtel+dim,pancen+). Parental chromosomes were normal. The distinctiveness of the present centromere-telomere fusion rests on the coupling of an intrachromosomal distal duplication with a whole-arm translocation including alphoid DNA onto the duplicated segment. The centromeric inertia of the residual alphoid DNA in the present case compares with the variable functional status of the chromosome 22 centromere in true heterodicentrics involving such a chromosome.     

Regional assignment of two genes of the human branched-chain alpha-keto acid dehydrogenase complex: the E1 beta gene (BCKDHB) to chromosome 6p21-22 and the E2 gene (DBT) to chromosome 1p31

Maple syrup urine disease (MSUD) is caused by the deficiency of the mitochondrial branched-chain alpha-keto acid dehydrogenase complex. The multienzyme complex is a macromolecule (Mr 4 X 10(6] consisting of at least six distinct subunits. In this study, the human E1 beta gene (BCKDHB) has been localized to human chromosome 6 by hybrid somatic cell analysis, and regionally assigned to chromosome bands 6p21-22 by in situ hybridization. The E2 gene (DBT), which was previously localized to chromosome 1, is regionally assigned to the chromosome band 1p31 also by in situ hybridization. Localization of the E1 beta gene to chromosome 6p21-22 assigns another major human disease locus to a region that contains several important genes, including the major histocompatability complex, tumor necrosis factor, and heat-shock protein HSP70. Mapping of the E1 beta and the E2 genes may provide information for the linkage analysis of MSUD families with mutations in these two loci.     

Interstitial deletion 1p as a result of a de novo reciprocal 1p;2p translocation

A 5-month-old female patient with psychomotor retardation and minor dysmorphisms is described. Cytogenetic analysis using high-resolution banding technique revealed an interstitial deletion of the short arm of one chromosome 1 (p21----p22.2) resulting from a de novo translocation t(1;2)(p22;p25).     

Sex reversal due to Xp disomy by t(X;Y)(p21;q11).

A 20-month-old infant exhibiting psychomotor retardation, dysmorphisms and ambiguous external genitalia was found to have a 46-chromosome karyotype including a normal X chromosome and a marker Y with most of Yq being replaced by an extra Xp21-->pter segment. The paternal karyotype (G and C bands) was 46,XY. The marker Y composition was verified by means of FISH with a chromosome X painting, an alphoid repeat and a DMD probe. Thus, the final diagnosis was 46,X,der(Y)t(X;Y)(p21;q11)de novo.ish der(Y)(wcpX+,DYZ3+,DMD+). The patient's phenotype is consistent with the spectrum documented in 13 patients with similar Xp duplications in whom sex reversal with female or ambiguous genitalia has occurred in spite of an intact Yp or SRY gene. A review of t(X;Y) identifies five distinct exchanges described two or more times: t(X;Y)(p21;q11), t(X;Y)(p22;p11), t(X;Y)(p22;q11-12), t(X;Y) (q22;q12), and t(X;Y)(q28;q12). These translocations probably result from a recombination secondary to DNA homologies within misaligned sex chromosomes in the paternal germline with the derivatives segregating at anaphase I.     

The Saccharomyces cerevisiae spindle pole body (SPB) component Nbp1p is required for SPB membrane insertion and interacts with the integral membrane proteins Ndc1p and Mps2p

The spindle pole body (SPB) in Saccharomyces cerevisiae functions to nucleate and organize spindle microtubules, and it is embedded in the nuclear envelope throughout the yeast life cycle. However, the mechanism of membrane insertion of the SPB has not been elucidated. Ndc1p is an integral membrane protein that localizes to SPBs, and it is required for insertion of the SPB into the nuclear envelope during SPB duplication. To better understand the function of Ndc1p, we performed a dosage suppressor screen using the ndc1-39 temperature-sensitive allele. We identified an essential SPB component, Nbp1p. NBP1 shows genetic interactions with several SPB genes in addition to NDC1, and two-hybrid analysis revealed that Nbp1p binds to Ndc1p. Furthermore, Nbp1p is in the Mps2p-Bbp1p complex in the SPB. Immunoelectron microscopy confirmed that Nbp1p localizes to the SPB, suggesting a function at this location. Consistent with this hypothesis, nbp1-td (a degron allele) cells fail in SPB duplication upon depletion of Nbp1p. Importantly, these cells exhibit a "dead" SPB phenotype, similar to cells mutant in MPS2, NDC1, or BBP1. These results demonstrate that Nbp1p is a SPB component that acts in SPB duplication at the point of SPB insertion into the nuclear envelope.     

The salt tolerant yeast Zygosaccharomyces rouxii possesses two plasma-membrane Na+/H+-antiporters (ZrNha1p and ZrSod2-22p) playing different roles in cation homeostasis and cell physiology

Antiporters exporting Na(+) and K(+) in exchange for protons are conserved among yeast species. The only exception so far has been Zygosaccharomyces rouxii, an osmotolerant species closely related to Saccharomyces cerevisiae. Z. rouxii was described as possessing one plasma-membrane antiporter transporting only Na(+) (ZrSod2-22p in the CBS 732(T) type strain). We report the characterization of a second gene, ZrNHA1, encoding a new K(+)(Na(+))/H(+)-antiporter capable of both K(+) and Na(+) export. Synteny analyses suggested that ZrSOD2-22 originated by single duplication of the ZrNHA1 gene. Substrate specificities and transport properties of ZrNha1p and ZrSod2-22p were compared upon heterologous expression in S. cerevisiae, and then directly in Z. rouxii. Deletion mutants and phenotype analyses revealed that ZrSod2-22 antiporter is important for Na(+) detoxification, probably together with ZrEna1 ATPase; ZrNha1p is indispensable to maintain potassium homeostasis and ZrEna1p is not, in contrast to the situation in S. cerevisiae, involved in this function.     

Chromosomes 17 and 22 involved in marker formation in neurofibrosarcoma in von Recklinghausen disease

Summary We describe the cytogenetic findings in a recurrent neurofibrosarcoma in a patient with nonfamilial von Recklinghausen disease. The composite karyotype was: 40,Y,-X,+dic r(X;20)(:Xp22.2q26::20p13 q13:), -1, +der(1)t(1;3) (p21;p24),-3,-4,-5,+der(5) t(5;?)(q31;?),-9,-9,+der(9)t(3;9)(q21 or q13;p24 or p22), -11,+der(11)t(11;?)(q22.2;?), -17,+der(17)t(17; 22;?)(q21;q13.1;?), -20, -21, -22, -22, +der(22)t(17; 22;?)(q21;q13.1;?),t(2;10)(q37;q22). The derivative chromosomes were demonstrated at the 500 band level. Chromosomes 17 and 22 were shown to be involved in an unbalanced three-way translocation: t(17;22;?)(q21;q13.1;?). This event was confirmed by in situ hybridization, using two probes mapped to chromosome 17. Hill H is a probe derived from the novel oncogene TRE and is located at 17q12–22. The second probe, derived from the granulocyte colony-stimulating factor (G-CSF), is located at 17q11–q21. The rearrangement between chromosomes 17 and 22 showed breakpoints similar or close to the gene loci for neurofibromatosis 1 (NF-1) and NF-2. Based on our observations we recommend that genetic studies on NF-1 tumors include both gene sites (NF-1 and NF-2) rather than focus on one gene locus.     

Partial 3q duplication syndrome and assignment of D3S5 to 3q25–3q28

Summary We report a girl with a de novo duplication of the distal part of the long arm of chromosome 3 and review the literature. Our patient had the facial characteristics and many other anomalies of the partial 3q duplication syndrome. As a hitherto undescribed symptom in partial 3q trisomy syndrome, she had microphthalmia. The karyotype of this girl was interpreted as an inverse duplication of the terminal portion of chromosome 3: 46,XX,inv dup (3)(pter-q28::q28–q25::q28-qter). Quantitative hybridisation studies with 3p and 3q probes gave a consistent 32 ratio of the relative intensities of the q bands in relation to the p bands between patient and control. This confirmed the presence of a 3q duplication and delineated the location of D3S5 to 3q25–3q28.     

From p63 to p53 across p73

Most genes are members of a family. It is generally believed that a gene family derives from an ancestral gene by duplication and divergence. The tumor suppressor p53 was a striking exception to this established rule. However, two new p53 homologs, p63 and p73, have recently been described [1, 2, 3, 4, 5 and 6]. At the sequence level, p63 and p73 are more similar to each other than each is to p53, suggesting the possibility that the ancestral gene is a gene resembling p63/p73, while p53 is phylogenetically younger [1 and 2].

The complexity of the family has also been enriched by the alternatively spliced forms of p63 and p73, which give rise to a complex network of proteins involved in the control of cell proliferation, apoptosis and development [1, 2, 4, 7, 8 and 9].

In this review we will mainly focus on similarities and differences as well as relationships among p63, p73 and p53.