scholarly journals Determining Clinical Correleation of CALR Type 1 and CALR Type 2 Gene Mutations In Chronic Myeloproliferative Disease Cases

2020 ◽  
Vol Volume: 2 Issue: 2 (Volume: 2 Issue: 2) ◽  
pp. 84-89
Author(s):  
Duygu Aygunes Jafari-
Keyword(s):  
Gene Mutations ◽  
Myeloproliferative Disease ◽  
Chronic Myeloproliferative Disease

scholarly journals Mutations in CALR Are Associated with Del(13q) and Are Mutually Exclusive of Monosomy 7 in BCR-ABL1-Negative MPN

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1870-1870
Author(s):  
Sabine Jeromin ◽  
Claudia Haferlach ◽  
Manja Meggendorfer ◽  
Wolfgang Kern ◽  
Torsten Haferlach ◽  
...  
Keyword(s):  
Chromosomal Aberrations ◽  
Gene Mutations ◽  
Melting Curve Analysis ◽  
Employment Equity ◽  
Monosomy 7 ◽  
Blastic Phase ◽  
Equity Ownership ◽  
Calr Mutations

Abstract Introduction: Mutations (mut) in the Calreticulin gene (CALR) were recently described in BCR-ABL1-negative myeloproliferative neoplasms (MPN). They occur frequently in essential thrombocythemia (ET; 15-30%) and primary myelofibrosis (PMF; 25-35%), but not in cases with polycythemia vera (PV). Other well-known mutations in ET and PMF are JAK2V617F (50-60%) and MPLW515 (5-10%). These three mutations are nearly mutually exclusive of each other. Furthermore, also chromosomal aberrations are frequently detected in PMF (40%), whereas they are rare in ET (3%). However, no association of CALRmut with any cytogenetic aberration has been reported yet. Aims: Investigate CALRmut and JAK2V617F in cytogenetic subgroups of BCR-ABL1-negative MPN. Patients: We studied 220 patients with cytomorphological confirmed BCR-ABL1-negative MPN excluding PV and with following chromosomal aberrations: del(20q) (n=64), trisomy 8 (+8; n=57), +1q (n=30), del(5q) (n=25), del(13q) (n=23), monosomy 7/del(7q) (-7/del(7q); n=21). Of these 220 cases, 25 and 12 patients were in accelerated and blastic phase, respectively. The cohort comprised 85 females (38.6%) and 135 males (61.4%). Median hemoglobin (Hb) level was 12.3 g/dl (range: 6.0 - 17.8 g/dl, n=167), platelet count 277,500x109/L (range: 16,000 –1,877,000x109/L; n=170) and white blood cell (WBC) count 16,000 x109/L (range: 1,600 -305,000 x109/L, n=181). Methods: Chromosome banding analysis was performed using standard G-banding. Screening for CALRmut was done by fragment analysis and subsequent Sanger sequencing of positive cases. JAK2V617F and MPLW515 were analyzed by melting curve analysis. MPLW515 was only analyzed in CALR/JAK2V617F-negative patients. Results: All 220 patients were screened for CALRmut and JAK2V617F. The frequency of CALRmut was 16.8% (37/220) and of JAK2V617F 58.2% (128/220). Mutations in these two genes were mutually exclusive (p<0.001). MPLW515 occurred in 3/55 (5.5%) of CALR/JAK2V617F-negative cases. CALR mutations presented as type 1 (p.Leu367Thrfs*46) in 56.8% (21/37) and as type 2 (p.Lys385Asnfs*47) in 27.0% (10/37) according to the nomenclature of Klampfl et al. (NEJM, 2013). The remaining 6 cases represented different mutation types all resulting in the same C-terminus of the mutated CALR protein. Analysis of gene mutations and cytogenetic aberrations showed that CALRmut associated significantly with del(13q) (with vs. without: 10/23, 43.5% vs. 27/197, 13.7%, p=0.001), whereas they were rare in +8 patients (2/57, 3.5% vs. 35/163, 21.5%, p=0.001; Figure 1). Additionally, no CALRmut was detected in patients with -7/del(7q) (0/21, 0% vs. 37/199, 18.6%, p=0.029). For JAK2V617F an association with del(20q) was detected (44/64, 68.8% vs. 84/156, 53.8%, p=0.050). Exclusion of MPN in accelerated or blastic phase from analyses resulted in the same associations between distinct cytogenetic abnormalities and CALRmut. Only the negative correlation to chromosome 7 aberrations lost its significance, probably due to low case numbers (0/9, 0% vs. 28/174, 16.1%, n.s.). For JAK2V617F the association with del(20q) was still present, even though the statistical significance was lost (37/55, 67.3% vs. 77/132, 58.3%, n.s.). Furthermore, we analyzed the distribution between type 1 and type 2 CALR mutations (n=31) in cytogenetic subgroups. Type 1 mutations were more frequent in cases with del(13q) (9/9, 100.0% vs. 12/22, 54.5%, p=0.030), whereas the frequency of type 2 mutations was higher in del(20q) (6/10, 60.0% vs. 4/21, 19.0%, p=0.040). Analysis of clinical data showed that CALRmut vs. wild-type patients had lower Hb levels (mean: 10.9 vs. 12.1 g/dl, p=0.019) and JAK2V617F cases had lower WBC counts vs. JAK2V617F-negative patients (19,308 vs. 30,786 x109/L, p=0.041). Additionally, Hb levels were higher in JAK2V617F patients compared to cases with CALRmut (12.2 vs. 10.9 g/dl, p=0.017). Conclusions: The highest CALR mutation frequency was observed in del(13q) cases (43.5%) and nearly all of them were type 1 mutations (90.0%). In contrast, CALRmut were rare in the cytogenetic subgroups with +8 and -7/del(7q). The highest JAK2V617F frequency was detected in patients with del(20q) (68.8%). Thus, in PMF and ET specific patterns are detectable based on cytogenetic and molecular data. Figure 1: Distribution of gene mutations in cytogenetic subgroups. The percentage of each mutation is depicted in the columns. Figure 1:. Distribution of gene mutations in cytogenetic subgroups. The percentage of each mutation is depicted in the columns. Disclosures Jeromin: MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

scholarly journals Genetic Aspects of Diabetes Mellitus

2001 ◽  
Vol 44 (1) ◽  
pp. 3-6 ◽  
Author(s):  
Eliška Marklová
Keyword(s):  
Diabetes Mellitus ◽  
Gene Mutations ◽  
Specific Gene ◽  
Diabetic Patients ◽  
Complex Interactions ◽  
Hla Dq ◽  
Genetic And Environmental Factors ◽  
Type 1 Dm

Practically all types of diabetes mellitus (DM) result from complex interactions of genetic and environmental factors. Multifactorial and polygenic Type 1 DM is strongly influenced by genes controlling the immune system, mainly HLA-DQ and DR. In addition to this, many other predisposition loci, interacting with each other, have some influence on susceptibility to DM. Heterogeneous Type 2 DM, accounting for about 85 % of all diabetic patients, is supposed to be induced by multiple genes defects involved in insulin action and/or insulin secretion. Other genetically influenced traits like obesity and hyperlipidemia are strongly associated with the Type 2. The group called Other specific types of DM include monogenic forms MODY 1-5 and many various subtypes of the disease, where the specific gene mutations have been identified. Both genetic and intrauterine environmental influences are likely to contribute to the abnormalities defined as Gestational DM.

scholarly journals Novel insights into genetics and clinics of the HNF1A-MODY

2019 ◽  
Vol 53 (2) ◽  
pp. 110-134 ◽  
Author(s):  
Terezia Valkovicova ◽  
Martina Skopkova ◽  
Juraj Stanik ◽  
Daniela Gasperikova
Keyword(s):  
Dna Analysis ◽  
Gene Mutations ◽  
Hereditary Disease ◽  
Actual Problem ◽  
Functional Studies ◽  
Uncertain Significance ◽  
New Gene ◽  
Phenotype Heterogeneity

AbstractMODY (Maturity Onset Diabetes of the Young) is a type of diabetes resulting from a pathogenic effect of gene mutations. Up to date, 13 MODY genes are known. Gene HNF1A is one of the most common causes of MODY diabetes (HNF1A-MODY; MODY3). This gene is polymorphic and more than 1200 pathogenic and non-pathogenic HNF1A variants were described in its UTRs, exons and introns. For HNF1A-MODY, not just gene but also phenotype heterogeneity is typical. Although there are some clinical instructions, HNF1A-MODY patients often do not meet every diagnostic criteria or they are still misdiagnosed as type 1 and type 2 diabetics. There is a constant effort to find suitable biomarkers to help with in distinguishing of MODY3 from Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). DNA sequencing is still necessary for unambiguous confirmation of clinical suspicion of MODY. NGS (Next Generation Sequencing) methods brought discoveries of multiple new gene variants and new instructions for their pathogenicity classification were required. The most actual problem is classification of variants with uncertain significance (VUS) which is a stumbling-block for clinical interpretation. Since MODY is a hereditary disease, DNA analysis of family members is helpful or even crucial. This review is updated summary about HNF1A-MODY genetics, pathophysiology, clinics functional studies and variant classification.

Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD)

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 112-121 ◽  
Author(s):  
Anne Goodeve ◽  
Jeroen Eikenboom ◽  
Giancarlo Castaman ◽  
Francesco Rodeghiero ◽  
Augusto B. Federici ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Von Willebrand Disease ◽  
Clinical Markers ◽  
High Prevalence ◽  
True Type ◽  
History Of ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Type 1 von Willebrand disease (VWD) is characterized by a personal and family history of bleeding coincident with reduced levels of normal plasma von Willebrand factor (VWF). The molecular basis of the disorder is poorly understood. The aims of this study were to determine phenotype and genotype and their relationship in patients historically diagnosed with type 1 VWD. Families were recruited in 9 European countries based on previous type 1 VWD diagnosis. Bleeding symptoms were recorded, plasma phenotype analyzed, and VWF mutation analysis performed in all index cases (ICs). Phenotypic and molecular analysis stratified patients into those with or without phenotypes suggestive of qualitative VWF defects (abnormal multimers) and with or without mutations. A total of 105 of 150 ICs (70%) had mutations identified. A subgroup with abnormal multimers (38% of ICs, 57 of 150) showed a high prevalence of VWF gene mutations (95% of ICs, 54 of 57), whereas in those with qualitatively normal VWF, fewer mutations were identified (55% of ICs, 51 of 93). About one third of the type 1 VWD cases recruited could be reconsidered as type 2. The remaining group could be considered “true” type 1 VWD, although mutations were found in only 55%.

Gene Alterations and Expression of Hematopoietic Transcription Factors in Pediatric Acute Megakaryoblastic Leukemia (AMKL): A Comparison of Down Syndrome (DS)-Associated AMKL with Non-DS-AMKL.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2261-2261
Author(s):  
Asahito Hama ◽  
Hiroshi Yagasaki ◽  
Hideki Muramatsu ◽  
Nobuhiro Nishio ◽  
Akihiro Abe ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Mutations ◽  
Glycophorin A ◽  
Rt Pcr ◽  
Transcript Levels ◽  
Megakaryoblastic Leukemia ◽  
Blast Cells ◽  
Type 3

Abstract Morphological and cytogenetic studies have demonstrated there is a diverse heterogeneity for acute megakaryoblastic leukemia (AMKL). In children, there are 2 major AMKL subgroups, with the disease developing in patients with and without Down syndrome (DS-AMKL and non-DS-AMKL, respectively). Somatic mutations of the GATA1 gene are found in children with DS-AMKL. Recently, activating mutations of the JAK3 gene have been found in both DS-AMKL and non-DS-AMKL patients. Furthermore, JAK2V617F plays a critical role in the pathogenesis of myeloproliferative disorders that are found in adults with non-DS-AMKL. To examine the biological characteristics of the DS-AMKL and non-DS-AMKL blast cells, we compared the morphology, immunophenotypes, gene alterations (GATA1, JAK2, JAK3) and the expression of the hematopoietic transcription factors in blast cells derived from 29 DS-AMKL and 21 non-DS-AMKL children. AMKL was defined by the presence of blast cells that expressed at least one platelet-associated antigen (CD36, CD41, CD42, or CD61). Written informed consent for banking and molecular analysis of the blast cells was obtained from the parents of each of the patients. Blast cell morphology was categorized as follows: type 1, completely undifferentiated blasts; type 2, intermediately differentiated blasts with cytoplasmic blebs; type 3, blasts with dysmegakaryocytopoiesis; and type 4, blasts with deep blue cytoplasm. The respective distributions of the morphology of the blasts in DS-AMKL and non-DS-AMKL patients were as follows: type 1 (41%, 39%), type 2 (4%, 39%), type 3 (11%, 22%), and type 4 (44%, 0%). Type 4 blasts were only seen in DS-AMKL. Atypical expression of lymphoid-associated antigen CD7 was detected in 90% and 53% of the immunophenotyped-patients with DS-AMKL and non-DS-AMKL, respectively (p = 0.003). Glycophorin A was only detected on the blasts of 34% of the patients with DS-AMKL (p = 0.012). Interestingly, 78% of the type 4 blasts were positive for glycophorin A. The GATA1, JAK2 and JAK3 mutations were analyzed in bone marrow or peripheral blood samples. High-molecular weight DNA was extracted from the samples using standard methods. We amplified the genomic DNA corresponding to exon2 of GATA1, exon14 of JAK2, and all 23 exons of the JAK3 gene, respectively, with the amplified products sequenced directly on a DNA sequencer (310; Applied Biosystems, Foster City, CA) using a BigDye terminator cycle sequencing kit (Applied Biosystems). The frequencies of the gene mutations in DS-AMKL and non-DS-AMKL were distributed as follows: GATA1 (100%, 8%), JAK2V617F (6%, 0%) and JAK3 (12%, 8%). To define the differentiation stage based on the molecular level, we quantified the expression of the transcription factors related to the megakaryo-erythroid cell lineages. The expression of the transcription factors (GATA1, GATA2, FOG-1, NF-E2, SCL, PU.1, C/EBPa, c-mpl, Epo-R, CD41b, bglobin) was analyzed by real time RT-PCR in blasts that were sorted by flow cytometry. Total RNA was extracted from the purified blasts. Synthesis of cDNA was performed using a Thermoscript RT-PCR system (Invitrogen, San Diego, CA) according to the manufacturer’s instructions. Real-time RT-PCR was performed using an ABI Prism 7000 Sequence Detection System (Applied Biosystems, Branchburg, NJ). Normalized gene expression levels are given as the ratio between the mean value for the target gene and that for the GAPDH gene in each sample. Median bglobin transcript levels in DS-AMKL blasts were significantly higher than those seen for the non-DS-AMKL blasts (p = 0.006). Particularly, median bglobin and GATA1 transcript levels in the type 4 blasts, which were only found in DS-AMKL, were significantly higher than those found in the blasts of other types (p = 0.033 and p = 0.021, respectively). Median GATA1, NF-E2 and Epo-R transcript levels in type 3 blasts, which differentiated into mature megakaryocytes, were significantly lower than those found in the blasts of other types (p = 0.030, p = 0.036, and p = 0.028, respectively). In conclusion, blasts of DS-AMKL differentiated not only into the megakaryocyte but also the erythroid lineage because of the overexpression of glycophorin A and bglobin under the GATA1 gene mutations. Considering the totally different gene alteration patterns and the levels of transcription factors that were observed, DS-AMKL needs to be classified into a category that differs from non-DS-AMKL.

Type 2 Diabetes Overtakes Type 1 in Hispanic Girls

2008 ◽  
Vol 38 (15) ◽  
pp. 18
Author(s):  
SHERRY BOSCHERT
Keyword(s):  
Type 2 Diabetes
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