Genomic structure of karyopherin ?2 ( KPNA2 ) within a low-copy repeat on chromosome 17q23-q24 and mutation analysis in patients with Russell-Silver syndrome

Dörr, Sylvia; Schlicker, Mike; Hansmann, I.

doi:10.1007/s004390100605

Cited by 16 publications

(13 citation statements)

References 36 publications

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“…Several studies indicated that KPNA2 extensive expression in breast cancer patients was associated with a short overall patient survival and recurrence-free survival [20], [28], and may warrant consideration as a potential marker for chemoresistance in advanced breast cancer [24]. Our study indicated that KPNA2 extensive expression strongly associates with poor prognosis and recurrence rates of OMGCT patients, as consistent with previous reports.…”

Section: Discussionsupporting

confidence: 91%

“…KPNA2 has been known to play an important role in regulating epidermal proliferation and differentiation, and activating cellular signaling in blood lymphocytes [17], [27]. KPNA2 has also been associated with the Russell-Silver syndrome [28] and possess tumorigenic activity [18], [29]. A series of reports suggest that KPNA2 expression is linked to breast carcinogenesis and acts as a potential prognostic marker for breast carcinomas [20]–[23].…”

Section: Discussionmentioning

confidence: 99%

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Overexpression of Karyopherin 2 in Human Ovarian Malignant Germ Cell Tumor Correlates with Poor Prognosis

Wang

Zhou

et al. 2012

PLoS ONE

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BackgroundThe aim of this study was to identify a biomarker useful in the diagnosis and therapy of ovarian malignant germ cell tumor (OMGCT).MethodsThe karyopherin 2 (KPNA2) expression in OMGCT and normal ovarian tissue was determined by standard gene microarray assays, and further validated by a quantitative RT-PCR and immunohistochemistry. The correlation between KPNA2 expression in OMGCT and certain clinicopathological features were analyzed. Expression of SALL4, a stem cell marker, was also examined in comparison with KPNA2.ResultsKPNA2 was found to be over-expressed by approximately eight-fold in yolk sac tumors and immature teratomas compared to normal ovarian tissue by microarray assays. Overexpression was detected in yolk sac tumors, immature teratomas, dysgerminomas, embryonal carcinomas, mature teratomas with malignant transformation and mixed ovarian germ cell tumors at both the transcription and translation levels. A positive correlation between KPNA2 and SALL4 expression at both the transcription level (R = 0.5120, P = 0.0125), and the translation level (R = 0.6636, P<0.0001), was presented. Extensive expression of KPNA2 was positively associated with pathologic type, recurrence and uncontrolled, ascitic fluid presence, suboptimal cytoreductive surgery necessity, resistance/refraction to initial chemotherapy, HCG level and SALL4 level in OMGCT patients. KPNA2 was found to be an independent factor for 5-year disease-free survival (DFS) of OMGCT (P = 0.02). The 5-year overall survival (OS) and DFS rate for KPNA2-low expression patients (88% and 79%, n = 48) were significantly higher than the OS and DFS rate for KPNA2-high expression patients (69% and 57.1%, n = 42)(P = 0.0151, P = 0.0109, respectively). The 5-year OS and DFS rate for SALL4-low expression patients (84% and 74%, n = 62) was marginally significantly higher than the high expression patients (78.6% and 71.4%, n = 28)(P = 0.0519, P = 0.0647, respectively).ConclusionsKPNA2 is a potential candidate molecular marker and important prognostic marker in OMGCT patients.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Overexpression of Karyopherin 2 in Human Ovarian Malignant Germ Cell Tumor Correlates with Poor Prognosis

Wang

Zhou

et al. 2012

PLoS ONE

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“…Furthermore, the translocation breakage has affected KPNA2 involved in the nuclear transport of proteins [46]–[48]. Thus, KPNA2 has been regarded as a candidate gene for SRS, although mutation analysis of KPNA2 has failed to detect a disease-causing mutation in SRS patients [49].…”

Section: Discussionmentioning

confidence: 99%

Molecular and Clinical Studies in 138 Japanese Patients with Silver-Russell Syndrome

et al. 2013

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BackgroundRecent studies have revealed relative frequency and characteristic phenotype of two major causative factors for Silver-Russell syndrome (SRS), i.e. epimutation of the H19-differentially methylated region (DMR) and uniparental maternal disomy 7 (upd(7)mat), as well as multilocus methylation abnormalities and positive correlation between methylation index and body and placental sizes in H19-DMR epimutation. Furthermore, rare genomic alterations have been found in a few of patients with idiopathic SRS. Here, we performed molecular and clinical findings in 138 Japanese SRS patients, and examined these matters.Methodology/Principal FindingsWe identified H19-DMR epimutation in cases 1–43 (group 1), upd(7)mat in cases 44–52 (group 2), and neither H19-DMR epimutation nor upd(7)mat in cases 53–138 (group 3). Multilocus analysis revealed hyper- or hypomethylated DMRs in 2.4% of examined DMRs in group 1; in particular, an extremely hypomethylated ARHI-DMR was identified in case 13. Oligonucleotide array comparative genomic hybridization identified a ∼3.86 Mb deletion at chromosome 17q24 in case 73. Epigenotype-phenotype analysis revealed that group 1 had more reduced birth length and weight, more preserved birth occipitofrontal circumference (OFC), more frequent body asymmetry and brachydactyly, and less frequent speech delay than group 2. The degree of placental hypoplasia was similar between the two groups. In group 1, the methylation index for the H19-DMR was positively correlated with birth length and weight, present height and weight, and placental weight, but with neither birth nor present OFC.Conclusions/SignificanceThe results are grossly consistent with the previously reported data, although the frequency of epimutations is lower in the Japanese SRS patients than in the Western European SRS patients. Furthermore, the results provide useful information regarding placental hypoplasia in SRS, clinical phenotypes of the hypomethylated ARHI-DMR, and underlying causative factors for idiopathic SRS.

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“…Recently Dörr et al (2001) identified the karyopherin a2 (KNA2) gene in 17q23-q24; however, they excluded this positional candidate gene as relevant to the etiology of SRS. Furthermore, the identification of a SRS patient with a hemizygous deletion of the CSH1 gene in 17q24-q25 (Eggermann et al, 1998) raises the question of the frequency and the significance of this genomic alteration in the disease.…”

Section: Discussionmentioning

confidence: 98%

Characterization of Genomic Variants inCSH1andGH2, Two Candidate Genes for Silver-Russell Syndrome in 17q24-q25

et al. 2003

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Silver-Russell syndrome (SRS) is a syndrome of severe pre- and postnatal growth retardation and typical dysmorphic features. Rare chromosomal aberrations have been reported in SRS; among these are two balanced translocations involving 17q24-q25. Recently, we described a patient with a paternally inherited heterozygous deletion of the chorionic somatomammotropin hormone 1 (CSH1) gene. The CSH1 gene is member of the growth hormone (GH) gene cluster on 17q, which consists of two growth hormone genes and three CSH genes. Genomic alterations in the GH cluster are well known, causing different phenotypes depending on the size of the deletion and the genes involved. By screening 63 SRS cases with marker D17S254, we have detected 2 further patients with a heterozygous deletion in the GH cluster. Quantitative analysis using restriction assays confirmed these findings. Additionally, in a cohort of 17 patients with isolated intrauterine and postnatal growth retardation, we detected a further patient to be carrier of a CSH1 deletion. Screening of 141 unrelated controls revealed hemizygosity in one person for which data on growth were not available. We additionally analyzed our cohort of SRS patients for mutations in CSH1 and its 3' neighbour GH2. However, analyses failed to reveal any pathogenic mutation. While the central role of GH1 in human growth is well established, the physiological roles of CSH1 and other components of the cluster are unclear. The increased prevalence of hemizygosity of CSH1 in our population in comparison to controls indicates a role for CSH1 haploinsufficiency in the etiology of growth retardation. Investigation of CSH1 deletions in further SRS and growth retarded patients will enable us to establish under which circumstances haploinsufficiency of CSH1 is likely to result in clinical changes.

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Genomic structure of karyopherin ?2 ( KPNA2 ) within a low-copy repeat on chromosome 17q23-q24 and mutation analysis in patients with Russell-Silver syndrome

Cited by 16 publications

References 36 publications

Overexpression of Karyopherin 2 in Human Ovarian Malignant Germ Cell Tumor Correlates with Poor Prognosis

Overexpression of Karyopherin 2 in Human Ovarian Malignant Germ Cell Tumor Correlates with Poor Prognosis

Molecular and Clinical Studies in 138 Japanese Patients with Silver-Russell Syndrome

Characterization of Genomic Variants inCSH1andGH2, Two Candidate Genes for Silver-Russell Syndrome in 17q24-q25

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