Translocation(X;Y)(p22.33;p11.2) in XX males: Etiology of male phenotype

Summary Analysis of G-banded prometaphase chromosomes from three XX males revealed extra bands on the distal end of one X short arm. These bands were similar both in size and staining properties to the distal Y short arm of their fathers (in the two cases examined) and also to other chromosomally normal males. The extra material on the abnormal X chromosomes was not C-or G-11 positive in the two cases examined, suggesting that the proximal Y long arm was not present.Previous karyotype-phenotype correlations with structurally altered Y chromosomes provided evidence for localization of male determinants on the Y short arm. The present findings in XX males provide support for more precise localization, to bands p11.2pter of Y short arm.     

Symmetrical replication patterns and sex chromatin bodies formation of an idic(X)(p22.3::p22.3) chromosome

Summary The morphologic and staining characteristics of the sex chromatin bodies and the DNA replication patterns were studied in a patient with a 45,X/46,X,idic(X)(p22.3::p22.3) karyotype and in a normal woman. The analysis showed a relatively high frequency of bipartite Barr bodies as well as some variation of the distance, staining intensity, and size relationship between their halves. Regarding the DNA replication studies, in 71% of the cells the abnormal X chromosome showed a synchronous pattern, and in the remaining 29%, in which a slight asynchrony was present, an almost equal proportion of early and late functional and nonfunctional centric halves was observed. Furthermore, the atypical chromosome had a quite similar replication pattern to the late replicating X chromosome of the normal woman, suggesting that its sequence of DNA synthesis was not altered.Supported in part by grant No. 1479 from the Programa Nacional de la Salud, Conacyt (México)     

On telomere replication and fusion in eukaryotes: apropos of a case of 45,X/46,X,ter rea(X;X)(p22.3;p22.3)

A Mexican 181/2-year-old girl with short stature, primary amenorrhea, and mild Turner stigmata was found to have a 45,X/46,X,ter rea(X;X)(p22.3;p22.3) karyotype in her lymphocytes. The rearranged chromosome was twice the size of a normal X, appeared to be attached head-to-head, had no detectable chromatin loss, only one primary constriction, constitutive heterochromatin at both the centromere and pseudocentromere regions, was mitotically stable, and always showed late replication. From the analysis of this and other X;X terminal rearrangements we draw four conclusions: (1) Terminal rearrangements may arise either by telomeric fusion (tel fus) without loss of genetic material or from a conventional telomeric translocation. (2) Telomeric fusions between homologous chromosomes (the commonest type) can be secondary to impaired telomeric replication. (3) Phenotypically, patients with an X;X terminal rearrangement show great variability which depends mainly on whether or not chromatin has been lost in the rejoining process and a 45,X clone. (4) Patients with an X;X telomeric fusion without mosaicism are likely to have an XXX phenotype, whereas turneroid features are expected in mixoploidies that include an X monosomic clone and in cases of translocations involving the short arms.     

Del(X)(p21.1) in a mother and two daughters: genotype-phenotype correlation of Turner features

We report a mother and two daughters with partial Xp monosomy. Clinical assessment for Turner phenotype revealed that the three females manifested low-normal to mild short stature (-1.6 to approximately -2.3 SD) and variable degrees of skeletal features, such as cubitus valgus, short 4th matacarpals, and Madelung deformity, but no soft tissue or visceral anomalies or gonadal dysfunction. Cytogenetic studies for lymphocytes showed that the karyotype was 45,X[3]/46,X,del(X)(p21.1)[27] in the mother and non-mosaic 46,X,del(X)(p21.1) in the two daughters. Fluorescence in situ hybridization and microsatellite analyses for 19 loci/regions on the X chromosome demonstrated that the del(Xp) chromosome was missing SHOX and had the breakpoint between DMD and CYBB. The results are consistent with the recently proposed notion that haploinsufficiency of SHOX results in not only short stature, but also Turner skeletal features in association with maturational effects of gonadal estrogens. The lack of soft tissue or visceral anomalies suggests the presence of the putative lymphogenic gene on the del(Xp) chromosome; the preservation of ovarian function appears to be compatible with meiotic pairing failure being relatively mild.     

The CaaX proteases, Afc1p and Rce1p, have overlapping but distinct substrate specificities

Many proteins that contain a carboxyl-terminal CaaX sequence motif, including Ras and yeast a-factor, undergo a series of sequential posttranslational processing steps. Following the initial prenylation of the cysteine, the three C-terminal amino acids are proteolytically removed, and the newly formed prenylcysteine is carboxymethylated. The specific amino acids that comprise the CaaX sequence influence whether the protein can be prenylated and proteolyzed. In this study, we evaluated processing of a-factor variants with all possible single amino acid substitutions at either the a(1), the a(2), or the X position of the a-factor Ca(1)a(2)X sequence, CVIA. The substrate specificity of the two known yeast CaaX proteases, Afc1p and Rce1p, was investigated in vivo. Both Afc1p and Rce1p were able to proteolyze a-factor with A, V, L, I, C, or M at the a(1) position, V, L, I, C, or M at the a(2) position, or any amino acid at the X position that was acceptable for prenylation of the cysteine. Eight additional a-factor variants with a(1) substitutions were proteolyzed by Rce1p but not by Afc1p. In contrast, Afc1p was able to proteolyze additional a-factor variants that Rce1p may not be able to proteolyze. In vitro assays indicated that farnesylation was compromised or undetectable for 11 a-factor variants that produced no detectable halo in the wild-type AFC1 RCE1 strain. The isolation of mutations in RCE1 that improved proteolysis of a-factor-CAMQ, indicated that amino acid substitutions E139K, F189L, and Q201R in Rce1p affected its substrate specificity.     

Turner syndrome mosaicism: an unusual case with a de novo large dicentric marker chromosome: mos 45,X/46,X, ter rea(X;X)(p22.3;p22.3)

X/X translocations are quite rare in humans. The effect of this anomaly on the phenotype is variable and depends on the amount of deleted material and whether the chromosomes are joined by their long or short arms. We report an unusual case of Turner syndrome mosaicism in a 16-year-old girl, who was referred to our Institute for primary amenorrhoea associated with short stature. Endocrine evaluation revealed hypergonadotropic hypogonadism, which required a study of the karyotype. Cytogenetic analysis, performed on peripheral blood leucocytes, showed a mos 45,X/46,X,ter rea (X;X)(p22.3;p22.3) de novo karyotype. The prevalent cell line was 45,X (90% cells). A second cell line (10% cells) showed a very large marker chromosome, similar to a large metacentric chromosome. FISH (fluorescent in situ hybridisation) and molecular analysis revealed that the marker chromosome was dicentric and totally derived from the paternal X chromosome.     

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.     

Cri du chat and Turner syndrome features in a newborn girl with an unbalanced 45,X,psu dic(5;X)(p15.2;p22.1) karyotype: FISH and replication banding studies.

A newborn girl with features of Turner and Cri du chat syndromes was found to have a pseudodicentric 5;X chromosome. Her karyotype was 45,X, psu dic(5;X)(p15.2;p22.1). The net result was monosomy for 5p15.2-pter and Xp22.1-pter. Fluorescence in situ hybridization (FISH) showed the Cri du chat region was deleted. Replication banding studies to assess the X-inactivation pattern found only the X portion of the pseudodicentric chromosome to be late replicating without any apparent spread of inactivation into chromosome 5 segment. There are only two cases reported with a dicentric X; autosome. In this paper, we compare the cytogenetics of the present case and those in the literature.     

A role for NF-kappa B subunits p50 and p65 in the inhibition of lipopolysaccharide-induced shock

To evaluate the possibility that NF-kappaB subunits p50 and p65 have a role in limiting the systemic inflammatory response induced by endotoxin, we compared the susceptibility of wild-type (WT), p65+/-, p50-/-, and p50-/-p65+/- (3X) mice to LPS-induced shock. Interestingly, whereas p65+/- mice were no more sensitive than WT mice to LPS-induced shock, 3X mice were exquisitely sensitive to the toxic effects of LPS. Mice lacking p50 alone displayed an intermediate phenotype. Sensitivity to LPS was a property of the innate immune system and was characterized by elevated circulating levels of TNF in both p50-/- and 3X mice. The ability of LPS to induce shock depended upon TNF, and 3X mice were significantly more sensitive to the toxic effects of TNF than were p50-deficient mice. The expression of several LPS-inducible proinflammatory genes, including IFN-gamma, was significantly higher within the spleens of p50-/- mice than in the spleens of WT mice, and interestingly, the expression of IFN-gamma was augmented still further within the spleens of 3X mice. These results demonstrate that NF-kappaB subunits p50 and p65 have critical inhibitory functions during the systemic response to LPS and raise the possibility that these functions could be essential in preventing mortality associated with systemic inflammatory response syndromes.     

"Pure" partial trisomy 3p due to the malsegregation of a balanced maternal translocation t (X;3) (p22.3;p21)

The authors present the clinical and cytogenetic studies of a white malformed baby with dup (3p) secondary to the malsegregation of a maternal balanced (X;3) (p22.3;p21) translocation. Besides the typical clinical features he also presented polydactyly of both hands. X-replication findings of the mother's lymphocytes did not strictly follow the usual inactivation pattern of balanced X;A translocations.     

p53 reactivation

Comment on: Yu X, et al. Cancer Cell 2012; 21:614-25.     

A case of ambiguous genitalia presenting with a 45,X/46,Xr(Y)(p11.2;q11.23)/47,X,idic(Y)(p11.2),idic(Y)(p11.2) karyotype

An infant with ambiguous genitalia was found to have a karyotype 45,X/46,X,r(Y)(p11.2;q11.23)/47,X,idic(Y)(p11.2),idic(Y)(p11.2) using G-banding, C-banding and FISH. Examination of the genitalia revealed a phallus measuring 1.5 cm in length and 0.5 cm wide with perineal orifice. Subtle phenotypic features consistent with Turner syndrome were not present. Genital ultrasonography revealed the presence of an infantile uterus. Endoscopy of the vagina, uterus and cervix appeared normal.     

A Turner patient with a 45,X,t(1;2) (q41;p11.2) karyotype

The most common chromosomal anomaly is 45,X in the Turner syndrome. In addition to this, anomaly, mosaicism such as structural 46,X,i(Xq), 46,X,del(Xp), 46,X,r(X), 46,X,t(X;Y) and numerical 46XO/46,XX/47XXX are seen rather frequently. An infant with the Turner syndrome was found to have a karyotype 45X,t(1;2) (q41;p16) using high resolution banding. Based on our knowledge, we present the first case of 45X,t(1;2) (q41;p11.2), a karyotype in Turner's syndrome in the literature.     

del(X)(p22.1)/r(X)(p22.1q28) Dynamic mosaicism in a Turner syndrome patient

We report on a 16-year-old patient with Turner syndrome who presented a mos 46,X,del(X)(p22.1)[35]/45,X [19]/46,X,r(X)(p22.1q28)[6]GTG-band karyotype. The R-banding showed that the abnormal X-chromosome was inactive in all 61 cells analyzed. Fluorescence in situ hybridization with a Xp/Yp subtelomeric probe revealed that both abnormal chromosomes lacked the complementary sequences, a fact consistent with a terminal deletion. Besides, the molecular analysis of the human androgen receptor gene showed that the rearranged chromosome was paternal in origin. Since the deleted and the ring chromosomes had the same size and banding pattern, and because the former was the predominant cell line, it was inferred that the Xp- formed a ring in some cells apparently without further loss of genetic material. However, the reverse sequence and even a simultaneous origin due to a complex intrachromosomal exchange are also conceivable. The mild Turner syndrome phenotype is explained by the mosaicism and by the size of the deleted segment.     

P2X7 receptor mediated phosphorylation of p38MAP kinase in the hippocampus

This study was designed to explore the effect of P2X7 receptor (P2X7R) activation on the expression of p38 MAP kinase (p38 MAPK) enzyme in hippocampal slices of wild-type (WT) and P2X7R^−/− mice using the Western blot technique and to clarify its role in P2X7 receptor mediated [³H]glutamate release. ATP (1 mM) and the P2X7R agonist BzATP (100 μM) significantly increased p38 MAPK phosphorylation in WT mice, and these effects were absent in the hippocampal slices of P2X7R^−/− mice. Both ATP- and BzATP-induced p38 MAPK phosphorylations were sensitive to the p38 MAP kinase inhibitor, SB203580 (1 μM). ATP elicited [³H]glutamate release from hippocampal slices, which was significantly attenuated by SB203580 (1 μM) but not by the extracellular signal-regulated kinase (ERK1/2) inhibitor, PD098095 (10 μM). Consequently, we suggest that P2X7Rs and p38 MAPK are involved in the stimulatory effect of ATP on glutamate release in the hippocampal slices of WT mice.     

Karyotyp-Phenotyp-Lorrelation bei einem 46,Xdel(X)(p22)-Befund

Summary In a patient with a height of 1.46 m, short neck and cubitus valgus the unbalanced karyotype 46,Xdel(X)(p22) was found. The mother of the proband has the balanced karyotype 46,Xt(X;15)(p22;p1). The mother is 1.56 m tall and has a short neck and cubitus valgus too. For this reason the deletion of the Xp22 band seems to cause the short stature of Turner patients. Our proband has had 2 pregnancies which ended as abortions in the 2nd and 4th month.As Giraud et al. (1974) have shown the deletion of the dark middle bande of the short X chromosome arm induces a slight dysgenesie of the gonade.     

Women heterozygous for deficiency of the (p21 leads to pter) region of the X chromosome are fertile

A woman balanced carrier of a X/15 translocation gave birth to a balanced infertile son and three unbalanced Xp--fertile daughters. This family and the other eleven cases of Xp--fertile women found in the literature demonstrate that loss of the p21 leads to pter region of the X chromosome is compatible with fertility, probably because it leaves on Xp the region which is never inactivated.     

Translocation (X;13)(p11.21;q12.3) in a girl with incontinentia pigmenti and bilateral retinoblastoma

A de novo t(X;13)(p11.21;q12.3) translocation is described in an 19-month-old girl with incontinentia pigmenti (IP) and bilateral retinoblastoma. Based on previously reported two girls and this patient, each with a structural X chromosome abnormality and IP, it was assumed that the locus for IP is at Xp11.21. Q-banding analysis revealed that the translocated chromosomes were of paternal origin. The derivative X chromosome was late-replicating in 9% of cultured peripheral blood lymphocytes and in 1% of skin fibroblasts. The erythrocyte esterase D activity in the patient was normal. Several possibilities were considered for possible causative relationship between the X/13 translocation and the development of retinoblastoma. One possibility involved functional monosomy of 13q14 in a minority of retinoblasts due to the spreading of inactivation of the translocated X chromosome segment.     

PKC, p42/p44 MAPK, and p38 MAPK are required for HGF-induced proliferation of H441 cells

In this paper, we studied the signaling pathway used by hepatocyte growth factor/scatter factor (HGF) to stimulate mitosis. We show, using H441 cells, that 1) HGF activates membrane-associated protein kinase C (PKC); the activity is transient and peaks within 30 min; 2) HGF activates p42/p44 and p38 mitogen-activated protein kinases (MAPKs); maximum activity in both is within 10 min; and 3) the activation of neither p38 nor p42/p44 MAPK is dependent on PKC, indicating that HGF uses separate and nonintersecting pathways to activate these two classes of kinase. However, phorbol 12-myristate 13-acetate also activates both MAPKs as well as PKC, but this activation is abolished in cells pretreated with the PKC inhibitor GF-109203X. HGF was found to significantly increase [(3)H]thymidine incorporation within 5 h; peak thymidine incorporation was observed at 16 h. However, when cells were pretreated with inhibitors of p42/p44 (PD-98059), p38 (SB-203580), or PKC (GF-109203X, G?-6983, or myristoylated inhibitor peptide(19-27)), HGF-induced thymidine uptake was diminished in a dose-dependent manner. Taken together, these results demonstrate that HGF activates PKC and both MAPKs simultaneously through parallel pathways and that the activation of the MAPKs does not depend on PKC. However, p38 and p42/p44 MAPKs and PKC may all be essential for HGF-induced proliferation of H441 cells.     

Janus-faced Enzymes Yeast Tgl3p and Tgl5p Catalyze Lipase and Acyltransferase Reactions

In the yeast, mobilization of triacylglycerols (TAGs) is facilitated by the three TAG lipases Tgl3p, Tgl4p, and Tgl5p. Motif search analysis, however, indicated that Tgl3p and Tgl5p do not only contain the TAG lipase motif GXSXG but also an H-(X)₄-D acyltransferase motif. Interestingly, lipid analysis revealed that deletion of TGL3 resulted in a decrease and overexpression of TGL3 in an increase of glycerophospholipids. Similar results were obtained with TGL5. Therefore, we tested purified Tgl3p and Tgl5p for acyltransferase activity. Indeed, both enzymes not only exhibited lipase activity but also catalyzed acylation of lysophosphatidylethanolamine and lysophosphatidic acid, respectively. Experiments using variants of Tgl3p created by site-directed mutagenesis clearly demonstrated that the two enzymatic activities act independently of each other. We also showed that Tgl3p is important for efficient sporulation of yeast cells, but rather through its acyltransferase than lipase activity. In summary, our results demonstrate that yeast Tgl3p and Tgl5p play a dual role in lipid metabolism contributing to both anabolic and catabolic processes.