Direct duplication of 9p22→p24 in a child with duplication 9p syndrome

A de novo direct duplication of 9p22→p24 was shown in a child with a duplication 9p phenotype by GTG banding and fluorescence in situ hybridization (FISH) using a chromosome-9 specific painting probe as well as 6 YAC DNA probes localized to the 9p13–9p23 region. The breakpoints in this patient and previously reported patients suggest that 9p22 may be the critical region for duplication 9p syndrome. Am. J. Med. Genet. 77:268–271, 1998. © 1998 Wiley-Liss, Inc.     

Sotos syndrome and de novo balanced autosomal translocation (t(3;6)(p21;p21))

In this report we describe a 6-year-old boy with Sotos syndrome and a de novo apparently balanced 3/6 translocation (karyotype: 46,XY,t(3;6)(p21;p21)). Pre- and postnatal overgrowth are observed in an increasing number of conditions of variable etiology. In the Sotos syndrome autosomal dominant inheritance with variable expression has been documented. Here we discuss the importance of the cytogenetic findings and postulate a relationship between the invisible loss of chromosomal material at 3p21 and/or 6p21 and the expression of the autosomal dominant gene.     

Disruption of the ARF–Mdm2–p53 tumor suppressor pathway in Myc-induced lymphomagenesis

Transgenic mice expressing the c-Myc oncogene driven by the immunoglobulin heavy chain enhancer (Emu) develop B-cell lymphoma and exhibit a mean survival time of approximately 6 months. The protracted latent period before the onset of frank disease likely reflects the ability of c-Myc to induce a p53-dependent apoptotic program that initially protects animals against tumor formation but is disabled when overtly malignant cells emerge. In cultured primary mouse embryo fibroblasts, c-Myc activates the p19(ARF)-Mdm2-p53 tumor suppressor pathway, enhancing p53-dependent apoptosis but ultimately selecting for surviving immortalized cells that have sustained either p53 mutation or biallelic ARF deletion. Here we report that p53 and ARF also potentiate Myc-induced apoptosis in primary pre-B-cell cultures, and that spontaneous inactivation of the ARF-Mdm2-p53 pathway occurs frequently in tumors arising in Emu-myc transgenic mice. Many Emu-myc lymphomas sustained either p53 (28%) or ARF (24%) loss of function, whereas Mdm2 levels were elevated in others. Its overexpression in some tumors lacking p53 function raises the possibility that Mdm2 can contribute to lymphomagenesis by interacting with other targets. Emu-myc transgenic mice hemizygous for ARF displayed accelerated disease (11-week mean survival), and 80% of these tumors lost the wild-type ARF allele. All ARF-null Emu-myc mice died of lymphoma within a few weeks of birth. About half of the tumors arising in ARF hemizygous or ARF nullizygous Emu-myc transgenic mice also overexpressed Mdm2. Therefore, Myc activation strongly selects for spontaneous inactivation of the ARF-Mdm2-p53 pathway in vivo, cancelling its protective checkpoint function and accelerating progression to malignancy.     

SNP fine mapping of chromosome 8q24 in bipolar disorder.

We previously reported linkage to chromosome 8q24 in bipolar disorder (BP) with a LOD of 3.32. We fine mapped the locus with SNPs and tested for association with BP in families with evidence of linkage to the region. We genotyped 249 informative SNPs over 3.4 Mb in an initial sample of 155 nuclear families (352 affected offsprings), and followed up the best findings by genotyping six of the most significantly associated SNPs in a replication sample of 103 nuclear families (231 affected offsprings). We used FBAT and GIST for association tests. Two clusters of SNPs emerged with the strongest evidence of association. The first consisted of three SNPs, approximately 3 kb 5' from the gene ST3GAL1. These SNPs were associated with BP in the initial sample by FBAT (best P = 0.001) and GIST (best P = 0.05) and associated in the replication sample by FBAT (best P = 0.04). The second cluster consisted of four SNPs (one of which was not genotyped in the replication sample), approximately 480 kb 5' of ST3GAL1 in a relative gene desert. These SNPs were associated with BP in the initial sample by FBAT (best P = 0.007) and GIST (best P = 0.03), and marginally associated in the replication sample by FBAT (best P = 0.07) and GIST (P = 0.04). ST3GAL1 belongs to a family of glycosyltransferase proteins, several members of which are highly expressed in the brain and involved in neurogenesis. Several other interesting candidate genes are also located nearby. The congruence of findings across methods and samples suggests further investigation is warranted in these two targeted regions.     

Linkage analysis in blepharophimosis-ptosis syndrome confirms localisation to 3q21-24

Blepharophimosis-ptosis is an autosomal dominant disorder in which previous chromosome rearrangements have suggested a putative gene location on the long arm of chromosome 3. This paper confirms the location at 3q21-24 with linkage studies in two large families. A lod score of 3·2 was found with D3S1237.     

Beckwith-Wiedemann syndrome and uniparental disomy 11p: fine mapping of the recombination breakpoints and evaluation of several techniques

Beckwith-Wiedemann syndrome (BWS) is a phenotypically and genotypically heterogeneous overgrowth syndrome characterized by somatic overgrowth, macroglossia and abdominal wall defects. Other usual findings are hemihyperplasia, embryonal tumours, adrenocortical cytomegaly, ear anomalies, visceromegaly, renal abnormalities, neonatal hypoglycaemia, cleft palate, polydactyly and a positive family history. BWS is a complex, multigenic disorder associated, in up to 90% of patients, with alteration in the expression or function of one or more genes in the 11p15.5 imprinted gene cluster. There are several molecular anomalies associated with BWS and the large proportion of cases, about 85%, is sporadic and karyotypically normal. One of the major categories of BWS molecular alteration (10-20% of cases) is represented by mosaic paternal uniparental disomy (pUPD), namely patients with two paternally derived copies of chromosome 11p15 and no maternal contribution for that. In these patients, in addition to the effects of IGF2 overexpression, a decreased level of the maternally expressed gene CDKN1C may contribute to the BWS phenotype. In this paper, we reviewed a series of nine patients with BWS because of pUPD using several methods with the aim to evaluate the percentage of mosaicism, the methylation status at both loci, the extension of the pUPD at the short arm and the breakpoints of recombination. Fine mapping of mitotic recombination breakpoints by single-nucleotide polymorphism-array in individuals with UPD and fine estimation of epigenetic defects will provide a basis for understanding the aetiology of BWS, allowing more accurate prognostic predictions and facilitating management and surveillance of individuals with this disorder.     

Refined FISH characterization of a de novo 1p22–p36.2 paracentric inversion and associated 1p21–22 deletion in a patient with signs of 1p36 microdeletion syndrome

We report on a 10‐year‐old boy presenting with obesity, moderate mental retardation, large anterior fontanelle at birth, mild physical anomalies including mid‐face hypoplasia, deep‐set eyes, long philtrum, and small mouth. He was found to carry a paracentric inversion inv(1)(p22p36.2) associated with a 10 cM deletion at the proximal breakpoint. By YAC FISH, the boundaries of the deletion were established at IB1028 (1p21) and WI‐5166 (1p22) STSs contained in YACs 781E8 and 954F6, respectively. This large region, covering about 10 cM, contains the COL11A1 and AMY2B genes, whose haploinsufficiency does not seem to contribute significantly to the clinical phenotype. On the other hand, the patient's clinical manifestations, also including visual problems and moderate mental retardation, are those typically observed in the 1p36 deletion syndrome. Refined mapping of the telomeric 1p36.2 inversion breakpoint was obtained by FISH of a PAC contig constructed to encompass this subinterval of the 1p36 microdeletion syndrome region. PACs 1024B10 and 884E7 were found to span the breakpoint, suggesting that the clinical signs of the 1p36 microdeletion syndrome might be due to disruption of a sequence lying at 1p36.2. © 2001 Wiley‐Liss, Inc.     

Contribution of microRNA 24–3p and Erk1/2 to interleukin‐6‐mediated plasma cell survival

Plasma cells can survive for long periods and continuously secrete protective antibodies, but plasma cell production of autoantibodies or transformation to tumor cells is detrimental. Plasma cell survival depends on exogenous factors from the surrounding microenvironment, and largely unknown intracellular mediators that regulate cell homeostasis. Here we investigated the contribution of the microRNA 24–3p (miR‐24–3p) to the survival of human plasma cells under the influence of IL‐6 and SDF‐1α (stromal cell derived factor 1), both of which are bone marrow survival niche mediators. Deep sequencing revealed a strong expression of miR‐24–3p in primary B cells, plasma blasts, plasma cells, and in plasmacytoma cells. In vitro studies using primary cells and the plasmacytoma cell line RPMI‐8226 revealed that (i) expression of miR‐24–3p mediates plasma cell survival, (ii) miR‐24–3p is upregulated by IL‐6 and SDF‐1α, (iii) IL‐6 mediates cell survival under ER stress conditions via miR‐24–3p expression, and (iv) IL‐6‐induced miR‐24–3p expression depends on the activity of the MAP kinase Erk1/2. These results suggest a direct connection between an external survival signal and an intracellular microRNA in regulating plasma cell survival. miR‐24–3p could therefore be a promising target for new therapeutic strategies for autoimmune and allergic diseases and for multiple myeloma.     

Duplication of 7p21.2→pter due to maternal 7p;21q translocation: Implications for critical segment assignment in the 7p duplication syndrome

We describe a 1-year-old boy with mental and physical retardation, a large anterior fontanel, brachycephaly with flat occiput, short and stubby fingers, generalized hypotonia, ocular hypertelorism, low-nasal bridge, long philtrum, high-narrow palate, apparently low-set ears, and a small mandible. Cytogenetic analysis utilizing high resolution chromosome banding technique showed an unbalanced karyotype consisting of 46,XY,add(21)(q22.3) that originated from maternal balanced translocation between chromosomes 7 and 21. Fluorescence in situ hybridization (FISH) using micro-dissected library probe pool from chro-mosome 7 confirmed the additional material on 21q was derived from chromosome 7. Our results indicated that the patient had an unbalanced translocation, 46,XY,der(21)t(7;21)(p21.2;q22.3)mat, which resulted in duplication for distal 7p. Our patient is similar to reported cases with a 7p15→pter or larger duplication of 7p, suggesting that the critical segment causing the characteristic phenotype of 7p duplication syndrome, including large anterior fontanel, exists at 7p21.2 or 7p21.2→pter. Am. J. Med. Genet. 86:305–311, 1999. © 1999 Wiley-Liss, Inc.     

The CDK domain of p21 is a suppressor of IL‐1β‐mediated inflammation in activated macrophages

Significant morbidity and mortality can be attributed to inflammatory diseases; therefore, a greater understanding of the mechanisms involved in the progression of inflammation is crucial. Here, we demonstrate that p21^(WAF1/CIP1), an established suppressor of cell cycle progression, is a inhibitor of IL‐1β synthesis in macrophages. Mice deficient in p21 (p21^?/?) display increased susceptibility to endotoxic shock, which is associated with increased serum levels of IL‐1β. Administration of IL‐1 receptor antagonist reduces LPS‐induced lethality in p21^?/? mice. Analysis of isolated macrophages, which are one of the central producers of IL‐1β, reveals that deficiency for p21 led to more IL‐1β mRNA and pro‐protein synthesis following TLR ligation. The increase in IL‐1β pro‐protein is associated with elevated secretion of active IL‐1β by p21^?/? macrophages. siRNA‐mediated knockdown of p21 in human macrophages results in increased IL‐1β secretion as well. A peptide mapping strategy shows that the cyclin‐dependent‐kinase (CDK)‐binding domain of p21 is sufficient to reduce the secretion of IL‐1β by p21^?/? macrophages. These data suggest a novel role for p21 and specifically for the CDK‐binding domain of p21^(WAF1/CIP1) in inhibiting inflammation.     

A case of myelodysplastic syndrome with abnormal megakaryocytes and ins(8;3)(q24;q21q26)

We report a 56-year-old male patient with refractory anemia with excess of blasts in transformation (RAEB-T) who had an ins(8;3)(q24;q21q26) as the sole chromosome abnormality in bone marrow (BM) cells. The findings of disturbed thrombocytopoiesis with numerous micromegakaryocytes suggest that it could be a variant of the classic ins(3;3)(q26;q21q26) described in hematologic malignancies with abnormal thrombopoiesis.     

A 12-Mb Complete Coverage BAC Contig Map in Human Chromosome 16p13.1–p11.2

We have constructed a complete coverage BAC contig map that spans a 12-Mb genomic segment in the human chromosome 16p13.1-p11.2 region. The map consists of 68 previously mapped STSs and 289 BAC clones, 51 of which-corresponding to a total of 7.721 Mb of genomic DNA-have been sequenced, and provides a high resolution physical map of the region. Contigs were initially built based mainly on the analysis of STS contents and restriction fingerprint patterns of the clones. To close the gaps, probes derived from BAC clone ends were used to screen deeper BAC libraries. Clone end sequence data obtained from chromosome 16-specific BACs, as well as from public databases, were used for the identification of BACs that overlap with fully sequenced BACs by means of sequence match. This approach allowed precise alignment of clone overlaps in addition to restriction fingerprint comparison. A freehand contig drawing software tool was developed and used to manage the map data graphically and generate a real scale physical map. The map we present here is approximately 3.5 x deep and provides a minimal tiling path that covers the region in an array of contigous, overlapping BACs.