Germline Mitochondrial DNA Mutations As a Novel First Event in Childhood Myelodysplastic Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1711-1711
Author(s):  
Andrica de Vries ◽  
Christian M. Zwaan ◽  
H. Berna Beverloo ◽  
Anja Wagner ◽  
Arjan Lankester ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Clonal Evolution ◽  
Type I ◽  
Primary Therapy ◽  
Mtdna Mutation ◽  
Mtdna Mutations ◽  
Mutational Status

Abstract Abstract 1711 Introduction: Mutations in the mitochondrial DNA (mtDNA) have been found in 50–60% of adult MDS patients, with an increasing frequency with rising age and ahigher incidence in more advanced MDS. In general, cells contain different amounts of mitochondria which can simultaneously harbour wildtype and mutated mtDNA. Co-existence of normal and mutant mtDNA is referred to as heteroplasmy, whereas the existence of only mutated mtDNA is called homoplasmy. As yet no information is available on the role of mtDNA mutations in pediatric MDS. We recently identified a family with (germline) mtDNA mutations and childhood MDS. We hypothesized that mtDNA mutations, catalyzed by ATP deficiency, reflect the genetic instability of the stem cells that facilitates that the development of MDS clone initiation and subsequent clonal evolution to acute myeloid leukemia triggered by type I and II events. Methods: Based on our findings in the above mentioned cases we analyzed the role of mtDNA mutations in the index family, in combination with studying oxidative phosphorylation, as well as in an extended cohort of 19 childhood MDS patients, including sporadic primary, therapy-related and familial MDS, using Mito-Chip (Affymetrix) and direct sequencing validation approach. To investigate whether the mutations were germline or somatic, in a subset of patients, germline mtDNA mutation analysis was performed. Results: In 14/19 of the pediatric MDS patients non-recurrent mtDNA mutations were found. Mt-mutational status was not correlated with the different WHO subgroups of childhood MDS. Heteroplasmic mutations were only found as somatic events, whereas. germline mutated cases were solely homoplasmic. Conclusion: We describe the first family in which germline mtDNA mutations trigger the devlopment of MDS, and show for the first time, that also in sporadic MDS cases, germline homoplasmic mutations may genetically predispose for developping childhood proliferative myeloid disease. Disclosures: No relevant conflicts of interest to declare.

Abstract 17097: Non-Synonymous Mitochondrial DNA Variants Are Common in Myocardial Tissue of Heart Failure Patients

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Pappu Ananya ◽  
Michael Binder ◽  
Yang Wanjun ◽  
Rebecca McClellan ◽  
Brittney Murray ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
Left Ventricular ◽  
Individual Risk ◽  
Myocardial Tissue ◽  
Mtdna Mutation ◽  
Mtdna Mutations ◽  
Ventricular Tissue ◽  
Mtdna Variants

Introduction: Mitochondrial heart disease due to pathogenic mitochondrial DNA (mtDNA) mutations can present as hypertrophic or dilated cardiomyopathy, ventricular arrhythmias and conduction disease. It is estimated that the mutation rate of mtDNA is 10 to 20-fold higher than that of nuclear DNA genes due to damage from reactive oxygen species released as byproducts during oxidative phosphorylation. When a new mtDNA mutation arises, it creates an intracellular heteroplasmic mixture of mutant and normal mtDNAs, called heteroplasmy. Heteroplasmy levels can vary in various tissues and examining mtDNA variants in blood may not be representative for the heart. The frequency of pathogenic mtDNA variants in myocardial tissues in unknown. Hypothesis: Human ventricular tissue may contain mtDNA mutations which can lead to alterations in mitochondrial function and increase individual risk for heart failure. Methods: Mitochondrial DNA was isolated from 61 left ventricular myocardial samples obtained from failing human hearts at the time of transplantation. mtDNA was sequenced with 23 primer pairs. In silico prediction of non-conservative missense variants was performed via PolyPhen-2. Heteroplasmy levels of variants predicted to be pathogenic were quantified using allele-specific ARMS-PCR. Results: We identified 21 mtDNA non-synonymous variants predicted to be pathogenic in 17 hearts. Notably, one heart contained four pathogenic mtDNA variants (ATP6: p.M104; ND5: p.P265S; ND4: p.N390S and p.L445F). Heteroplasmy levels exceeded 90% for all four variants in myocardial tissue and were significantly lower in blood. No pathogenic mtDNA variants were identified in 44 hearts. Hearts with mtDNA mutations had higher levels of myocardial GDF-15 (growth differentiation factor-15; 6.2±2.3 vs. 1.3±0.18, p=0.045), an established serum biomarker in various mitochondrial diseases. Conclusions: Non-synonymous mtDNA variants predicted to be pathogenic are common in human left ventricular tissue and may be an important modifier of the heart failure phenotype. Future studies are necessary to correlate myocardial mtDNA mutations with cardiovascular outcomes and to assess whether serum GDF-15 allows identifying patients with myocardial mtDNA mutations.

Noval Mutation in Four Saudi Families with Glanzmann Thrombasthenia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1136-1136
Author(s):  
Tarek Owaidah ◽  
Hala Abalkhail ◽  
Abdulrahman Al Musa ◽  
Hasan Mosmali ◽  
Albanyan Abdulmajeed ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Stop Codon ◽  
Direct Sequencing ◽  
Family Members ◽  
Premature Stop Codon ◽  
Type I ◽  
Bleeding Tendency ◽  
Coding Region ◽  
Glanzmann Thrombasthenia ◽  
Exon 1

Abstract Abstract 1136 Introduction: Glanzmann thrombasthenia (GT) is a rare autosomal recessive inherited bleeding disorder characterized by an impaired platelet aggregation and variable bleeding tendency. Inherited genetic mutations in integrin alpha IIb and beta3 (ITGA2B, ITGB3) result in a heterogeneity of the thrombasthenia phenotypes. It is phenotypically expressed in homozygotes or compound heterozygotes, given that 50% of normal aIIbb3 is sufficient to guarantee unimpaired platelet function that result in asymptomatic carriers. Defects in ITGB3 result in failure of binding of B3 and alpha IIb. These defects had been reported in Arabs (Iraqi Jews). We are reporting some results of Saudi GT genotype project. Materials & Methods: In this study, we analyzed the entire coding region ITGB3 gene using polymerase chain reaction (PCR) and direct sequencing with primers specifically designed to amplify the coding region of exon 1–15 and exon /Intron boundaries in a cohort of 51 GT patients diagnosed and treated in our institute. Results: Out of 51 cases from 20 families had mutational screening of the ITGB3 gene with the aim to detect the causative pathogenic mutations to enable the pre-symptomatic diagnosis in at risk family members. In this study we detect 1 novel germline mutation c.2190delC (p.Ser703fs) in exon 13. The mutation is predicted to result in premature stop codon and protein truncation. The mutation was detected in 6 patients in homozygous stat (3 males and 3 females). Three tested samples from the patients family members detected the mutation in heterozygous state and all of them were asymptomatic with normal PFA and Intact expression of Platelet Glycoprotiens CD41(Gpllb), CD42a(GPIX), CD42b(GPlb), and CD61(Gpllla). All the GT patients with this mutation were type I GT with Prolonged PFA and complete absence of CD41(Gpllb) and CD61(Gpllla) glycoprotein. Conclusion: The result of this study represents the first Molecular analysis of ITGB3 gene in Saudi Arabia and displays the existence of novel pathogenic and possibly a founder effect in Saudi families. Disclosures: No relevant conflicts of interest to declare.

Correlations Between TET2 Mutation and Clinicohematologic Parameters in Myeloproliferative Neoplasms

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1455-1455
Author(s):  
Jung Sook Ha ◽  
Jae Hee Lee ◽  
Sung Gyun Park ◽  
Nam Hee Ryoo ◽  
Dong Suk Jeon ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Direct Sequencing ◽  
Jak2 V617f ◽  
Putative Tumor Suppressor Gene ◽  
Allele Burden ◽  
Frame Shift ◽  
Mutational Status ◽  
Tet2 Mutation ◽  
Disease Specific

Abstract Abstract 1455 Background: Since the acquired somatic mutation, JAK2 V617F, was discovered as a first molecular marker of myeloproliferative neoplasms (MPN), and it has been detected variably in each MPN subtypes. However, JAK2 V617F does not found in all of MPN cases and not necessarily specific to a particular clinicpathologic entity. Recently, mutation of the putative tumor suppressor gene, Ten-Eleven-Translocation-2(TET2), has been identified in MPN patients. However, the frequency of TET2 mutation or its relationship with JAK2 V617F mutation or pathologic function in MPN has not been concluded, yet. The aim of our study was to evaluate the frequency of TET2 in MPN patients, and whether there is any correlation of TET2 mutation with JAK2V617F mutation or the clinicohematologic parameters. Materials and Methods: Total 99 adult MPN patients (18 PV, 62 ET, 11 PMF and 8 MPN unclassified) whose bone marrow cells had been stored from 2007 to 2010 at point of first diagnosis were included in this study. Hematological diagnoses and subtyping were reconfirmed according to the 2008 WHO classification and clinicohematologic datas were collected from patient records. Direct sequencing for TET2(exon3–11) and JAK2 (exons 12 and 14) were performed using an ABI 3730XL DNA analyzer. The JAK2V617F allele burdens were determined by pyrosequencing for samples available and MPL was analyzed by allele-specific PCR. Results: The overall TET2 mutational frequency was 12.1%, and disease-specific mutational frequencies were 22.2% in PV, 9.7% in ET and 18.2% in PMF. The found mutations included 11 mutations, 7 frame-shift (p.Lys95AsnfsX18, p.Gln967AsnfsX40, p.Lys1022GlufsX4, p.Asp1314MetfsX49, p.Gln1534AlafsX43, p.Tyr1618LeufsX4, p.Leu1609GlufsX45), 1 nonsense (p.Gly1735X), 1 missense (Q599R) and 2 splicing mutations (c.3409+1G>T, c.4044+2insT). Those mutations most frequently involved exon 3(four mutations) and exon 11(four mutaions), and rarely intron 3, intron 8 and exon 7. None of the mutations were associated with a karyotypically apparent 4q24 rearrangement. All patients were also screened for JAK2 V617F, and the overall JAK2 V617F positive rate was 68%(94.4% in PV, 69.4% in ET, 45.5% in PMF and 37.5% in MPN, unclassified). All TET2 mutations occurred in JAK2 V617F positive cases. JAK2 exon12 mutation was not found in all patients. MPL W515L was found in one ET patient who also carried JAK2V617F, but not TET2 mutation. Information on JAK2 V617F allele burden was available in 78 patients. Considering all 99 patients, the patient age, hematologic indexes (leukocyte count, neutrophil fraction, lymphocyte fraction, monocyte fraction, Hb, Hct and platelet count), the frequency of organomegaly, marrow fibrosis or thrombotic/hemorrhagic complications were not different according to carrying TET2 mutation. However, TET2 mutation was more frequently found in JAK2 V617F carriers than non-carriers (P=0.008), but JAK2 V617F allele burden did not correlated with the presence of mutant TET2. When analysis was performed for each PV, ET, and PMF (no TET2 mutation in MPN-unclassifiable patients), correlation between TET2 and JAK2 V617F mutational status was not found in each subtypes (P=0.078 in PV, P=0.099 in ET and P=0.182 in PMF). However, the JAK2 V617F allele burden was significantly higher in PMF harboring TET2 mutation than PMF patients did not (88.0 ± 4.3% vs 19.1 ± 28.7%, P=0.034). In statistical analysis for the correlations of clinicohematologic parameters with TET2 mutation in each PV, ET and PMF patients, only a few statistically significant results were identified. The presence of TET2 mutation was correlated with high Hct in PMF (47.4 ± 5.4 vs 25.5 ± 6.2, P=0.037), and TET2 positive ET patients showed relatively higher frequency of organomegaly compared to ET patients without TET2 mutation (50% vs 19.6%, P=0.018). Conclusions: The overall and disease-specific frequencies of TET2 mutation in our study are similar with previous studies, and frame-shift mutation is the most frequent mutation type. There is no specific relationship between JAK2 V617F and TET2 mutation occurrence, but TET2 mutant PMF has higher JAK2 V617F allele burden than non-mutant. TET2 mutation is also associated with a higher Hct in PMF and higher frequency of organomegaly in ET. Larger scale studies involving more MPN patients are needed. Disclosures: No relevant conflicts of interest to declare.

Hodgkin Lymphoma Variant of Richter Transformation: Morphology, EBV Status, Clonality and Survival Analysis a Retrospective Study of 77 Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2637-2637 ◽  
Author(s):  
Wenbin Xao ◽  
Wayne Chen ◽  
Lynn Sorbara ◽  
Theresa Davies-Hill ◽  
Stefania Pittaluga ◽  
...  
Keyword(s):  
Overall Survival ◽  
Hodgkin Lymphoma ◽  
Conflicts Of Interest ◽  
Advanced Age ◽  
Type I ◽  
Type Ii ◽  
Clonal Relationship ◽  
Kaplan Meier ◽  
Mutational Status ◽  
Morphological Patterns

Abstract The classical Hodgkin lymphoma variant of Richter transformation (CHL-RT) occurs rarely in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). Two morphological patterns have been described: type I with Hodgkin/Reed-Sternberg (HRS) cells scattered in a CLL background, and type II with typical CHL morphology. HRS cells are frequently positive for EBV and can be clonally related or unrelated to CLL. The clinical significance of the different morphological patterns is unclear. What factors dictate the cellular derivation of the HRS cells remains elusive. We retrospectively reviewed 77 cases of CHL-RT submitted to our consultation service. Clinicopathological characteristics were summarized, EBV status was examined, and clonality was analyzed after microdissection of HRS-cells and CLL cells. Patients with the type I pattern (N=26) had a significantly shorter time to progression from CLL to CHL-RT than those with type II pattern (N=51, 15 vs. 49 months, p<0.0001, see Figure 1A). Consistent with these data, 27% of patients with the type I pattern had a prior CLL history as compared to 73% with the type II pattern. 12% (6/51) of type II cases had extranodal involvement (sites other than bone marrow) while none of type I cases did. Three patients with sequential biopsies progressed from type I to II and 2 had an aggressive clinical course. HRS cells were positive for EBV in 71% (55/77) of patients. Clonality analysis was performed in 33 cases: HRS cells were clonally related to the underlying CLL in 14 cases and unrelated in 19 cases. Among all the features examined, ZAP-70 expression of the CLL cells, but not EBV status or morphological pattern, was strongly correlated with clonal relationship: all 14 clonally related cases were negative for ZAP-70 while 74% (14/19) of the clonally unrelated cases were positive for ZAP-70. Overall median survival after the diagnosis of CHL-RT was 44 months. Advanced age was an adverse risk factor for survival (p<0.05, see Figure 1B). In conclusion, we provide evidence that type I morphology is more likely an early stage of CHL-RT and can progress to type II. The majority of CHL-RT cases are EBV positive. Clonal relationship in RT is determined by ZAP-70 and thus likely IGHV mutational status. Advanced age is associated with inferior survival. Figure 1. A, Time to progress from CLL to CHL-RT. B, Kaplan-Meier analysis of overall survival. Figure 1. A, Time to progress from CLL to CHL-RT. B, Kaplan-Meier analysis of overall survival. Disclosures No relevant conflicts of interest to declare.

scholarly journals Associations of Mitochondrial DNA 3777-4679 region mutations with maternally inherited essential hypertensive subjects in China.

2020 ◽  
Author(s):  
Ye Zhu ◽  
Jia You ◽  
Chao Xu ◽  
Xiang Gu
Keyword(s):  
Mitochondrial Dna ◽  
Essential Hypertension ◽  
Fasting Blood Glucose ◽  
Chinese Patients ◽  
Abdominal Circumference ◽  
Control Group ◽  
Mtdna Mutation ◽  
Mutation Site ◽  
Genetic Characteristics ◽  
Mtdna Mutations

Abstract Background: Nuclear genome or family mitochondrial screening system has become the hot focus of studies into essential hypertension. The role of mitochondrial DNA (mtDNA) in sporadic Chinese patients with hypertension has not been fully understood. The study was to evaluate the associations of mtDNA mutations with maternally inherited essential hypertensive subjects in China.Methods: From June 2009 to June 2016, a total of 800 gender-matched Chinese patients with maternally inherited essential hypertension (MIEH) and control group were 1:1 enrolled in this case-control study. Genomic DNA was extracted from each person's peripheral blood cells. The main mtDNA locations for MIEH were screened with oligodeoxynucleotides 3777-4679bp, analyzed and compared with the updated consensus Cambridge Sequence. Pathogenic mtDNA mutations were identified from the mitochondrial map.Results: MIEH subjects presented significantly higher values than those of control group in abdominal circumference(AC), waist circumference(WC), body mass index(BMI), fasting blood glucose(FBG), triglyceride(TG), low-density lipoprotein cholesterol (LDL) and renal function (P<0.05). MIEH subjects carried more amino acid changes and coding sequence variants (P<0.01) than control group. The allele frequencies of the eight single nucleotide polymorphisms(SNPs) were significantly different between the two groups, including m.3970 C>T, m.4048G>A, m.4071C>T, m.4086C>T, m. 4164A>G and m.4248T>C in ND1 gene, and m.4386T>C and m.4394C>T in tRNAGln gene(P<0.001). Fifty-five homoplasmic or heteroplasmic mutations were detected in 5 genes: ND1, tRNAIle, tRNAMet, tRNAGln and ND2 gene. The ND1 gene was the main mutation site, where the most mtDNA mutation was m.3970 C>T.Conclusions: The mtDNA mutations were involved in the process of MIEH. We identified mitochondrial genetic characteristics in MIEH patients in China. The present research serves as a solid foundation for further detailed research on the association between MIEH and mitochondrial dysfunction, and their causal relationship in Chinese and other populations with a similar lifestyle.

scholarly journals M6PR-Specific Targeting of Lysosomal Heparanase Regulates Platelet Hemostatic Function in Mice

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1059-1059
Author(s):  
Nathan Eaton ◽  
Caleb Drew ◽  
Theresa A. Dlugi ◽  
Karin M. Hoffmeister ◽  
Hervé Falet
Keyword(s):  
Platelet Function ◽  
Conflicts Of Interest ◽  
Blood Platelets ◽  
Critical Role ◽  
Fluorescent Microscopy ◽  
Type I ◽  
Dense Granules ◽  
Specific Targeting

Besides α-granules and dense granules, which play critical roles in and beyond hemostasis, circulating blood platelets and their precursor cells megakaryocytes contain lysosomes, the contents of which are also secreted during platelet activation. In their delivery to the lysosome, acid hydrolases bearing phosphomannosyl residues are trafficked from the trans-Golgi network to the acidic late-endosomal compartment via the mannose 6-phosphate receptor (M6PR) pathway. To determine the role of M6PR-specific targeting of lysosomal enzymes in platelet function, platelet parameters were investigated in M6pr-/- mice lacking the 46-kDa M6PR, the physiological role of which is unclear. M6pr-/- mice had normal platelet count but displayed an increased number of distinct proplatelet-like cells compared to control mice, as determined by immunofluorescent microscopy. Moreover, transmission electron microscopy revealed the presence of abnormal membrane tubulations, elongated and electron-dense granules, and large vacuole-like structures within resting M6pr-/- platelets. M6pr-/- platelets expressed normally major glycoproteins on their surface and von Willebrand factor and fibrinogen in their α-granules. M6pr-/- mice were hyper-thrombotic, as assessed by tail bleeding time, and M6pr-/- platelets adhered to type I collagen with a significantly greater propensity than control platelets under arterial shear in in vitro flow experiments. Heparanase, an endo-β-glucuronidase that cleaves extracellular matrix heparan sulfate proteoglycans, is the most abundant lysosomal enzyme in platelets. Thus, its contribution to the phenotype of M6pr-/- mice was investigated further. Heparanase expression was decreased in the bone marrow megakaryocytes and blood platelets of M6pr-/- mice and increased in M6pr-/- plasma, as evidenced by immunoblot and fluorescent microscopy analysis, consistent with its mistargeting in the absence of M6PR. Interestingly, pharmacological inhibition of heparanase with OGT 2115 normalized the adhesion of M6pr-/- platelets to collagen in vitro, indicating that increased plasma heparanase contributes to the thrombotic phenotype of M6pr-/- mice. Taken together, the data suggest that the M6PR-specific targeting of lysosomal heparanase plays a critical role in platelet function, thereby regulating hemostasis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Detection of Mitochondrial DNA Mutations by Temporal Temperature Gradient Gel Electrophoresis

1999 ◽  
Vol 45 (8) ◽  
pp. 1162-1167 ◽  
Author(s):  
Tian-Jian Chen ◽  
Richard G Boles ◽  
Lee-Jun C Wong
Keyword(s):  
Mitochondrial Dna ◽  
Temperature Gradient ◽  
Gel Electrophoresis ◽  
Direct Sequencing ◽  
Polymorphism Analysis ◽  
Mtdna Mutations ◽  
Sequence Variations ◽  
Pcr Products ◽  
Gradient Gel Electrophoresis ◽  
Temperature Gradient Gel Electrophoresis

Abstract Background: A unique requirement for the molecular diagnosis of mitochondrial DNA (mtDNA) disorders is the ability to detect heteroplasmic mtDNA mutations and to distinguish them from homoplasmic sequence variations before further testing (e.g., sequencing) is performed. We evaluated the potential utility of temporal temperature gradient gel electrophoresis (TTGE) for these purposes in patients with suspected mtDNA mutations. Methods: DNA samples were selected from patients with known mtDNA mutations and patients suspected of mtDNA disorders without detectable mutations by routine analysis. Six regions of mtDNA were PCR amplified and analyzed by TTGE. Electrophoresis was carried out at 145 V with a constant temperature increment of 1.2 °C/h. Mutations were identified by direct sequencing of the PCR products and confirmed by PCR/allele-specific oligonucleotide or PCR/restriction fragment length polymorphism analysis. Results: In the experiments using patient samples containing various amounts of mutant mtDNA, TTGE detected as little as 4% mutant heteroplasmy and identified heteroplasmy in the presence of a homoplasmic polymorphism. In 109 specimens with 15 different known mutations, TTGE detected the presence of all mutations and distinguished heteroplasmic mutations from homoplasmic polymorphisms. When 11% of the mtDNA genome was analyzed by TTGE in 104 patients with clinically suspected mitochondrial disorders, 7 cases of heteroplasmy (≈7%) were detected. Conclusions: TTGE distinguishes heteroplasmic mutation from homoplasmic polymorphisms and appears to be a sensitive tool for detection of sequence variations and heteroplasmy in patients suspected of having mtDNA disorders.

scholarly journals Associations of mitochondrial DNA 3777–4679 region mutations with maternally inherited essential hypertensive subjects in China

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Ye Zhu ◽  
Jia You ◽  
Chao Xu ◽  
Xiang Gu
Keyword(s):  
Mitochondrial Dna ◽  
Essential Hypertension ◽  
Fasting Blood Glucose ◽  
Chinese Patients ◽  
Abdominal Circumference ◽  
Control Group ◽  
Mtdna Mutation ◽  
Mutation Site ◽  
Genetic Characteristics ◽  
Mtdna Mutations

Abstract Background Nuclear genome or family mitochondrial screening system has become the hot focus of studies into essential hypertension. The role of mitochondrial DNA (mtDNA) in sporadic Chinese patients with hypertension has not been fully understood. The study was to evaluate the associations of mtDNA mutations with maternally inherited essential hypertensive subjects in China. Methods From June 2009 to June 2016, a total of 800 gender-matched Chinese patients with maternally inherited essential hypertension (MIEH) and control group were 1:1 enrolled in this case-control study. Genomic DNA was extracted from each person’s peripheral blood cells. The main mtDNA locations for MIEH were screened with oligodeoxynucleotides 3777-4679 bp, analyzed and compared with the updated consensus Cambridge Sequence. Pathogenic mtDNA mutations were identified from the mitochondrial map. Results MIEH subjects presented significantly higher values than those of control group in abdominal circumference (AC), waist circumference (WC), body mass index (BMI), fasting blood glucose (FBG), triglyceride (TG), low-density lipoprotein cholesterol (LDL) and renal function (P < 0.05). MIEH subjects carried more amino acid changes and coding sequence variants (P < 0.01) than control group. The allele frequencies of the eight single nucleotide polymorphisms (SNPs) were significantly different between the two groups, including m.3970 C > T, m.4048G > A, m.4071C > T, m.4086C > T, m. 4164A > G and m.4248 T > C in ND1 gene, and m.4386 T > C and m.4394C > T in tRNAGln gene(P < 0.001). Fifty-five homoplasmic or heteroplasmic mutations were detected in 5 genes: ND1, tRNAIle, tRNAMet, tRNAGln and ND2 gene. The ND1 gene was the main mutation site, where the most mtDNA mutation was m.3970 C > T. Conclusions The mtDNA mutations were involved in the process of MIEH. We identified mitochondrial genetic characteristics in MIEH patients in China. The present research serves as a solid foundation for further detailed research on the association between MIEH and mitochondrial dysfunction, and their causal relationship in Chinese and other populations with a similar lifestyle.

Genomic Aberrations Dramatically Improve The Strong Prognostic Impact Of IGHV Mutational Status In Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1370-1370
Author(s):  
Giovanni Del Poeta ◽  
Dario Ragusa ◽  
Francesco Buccisano ◽  
Michele Dal Bo ◽  
Luca Maurillo ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Sanger Sequencing ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Univariate Analysis ◽  
Intermediate Stage ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Mutational Status ◽  
Genomic Aberrations

Abstract CLL is a heterogeneous disease with patients (pts) experiencing rapid disease progression and others living for years without requiring treatment. Recently, next generation sequencing has revealed new molecular alterations, targeting the NOTCH1 and BIRC3 genes which occur in about 10% CLL at diagnosis and correlate with poor outcome. Given the possibility of targeting NOTCH1 and BIRC3 with drugs currently under development, the primary endpoints of our research were: 1) to determine overall survival (OS) upon IGHV, NOTCH1, TP53 and BIRC3 in univariate analysis; 2) to correlate these genomic aberrations with other biological or clinical prognostic factors, and finally 3) to confirm NOTCH1, BIRC3 and TP53 as independent prognostic factors. We investigated 475 pts with a median age of 65 years (range 33-89), whose 160 had low Rai stage, 301 intermediate stage and 14 high stage. NOTCH1 mutations (mut) were studied by ARMS PCR for c.7544-7545delCT and by Sanger sequencing of NOTCH1 exon 34. Mutations of TP53 were analysed by DNA direct sequencing, while BIRC3 disruption (disr) was studied by Sanger sequencing for mutations and by interphase FISH for deletions. All these alterations were studied at diagnosis or before any chemotherapeutic approach. NOTCH1mut and TP53mut pts were 52 (10.9%) and 36/475 (7.6%), respectively. Thirty four patients were BIRC3mut (7.2%) and 26 BIRC3 deleted (5.5%) for a total of 46 cases (9.7%) BIRC3disr. NOTCH1, TP53 and BIRC3 alterations were mutually exclusive. There were significant correlations between NOTCH1 (P<0.00001), TP53 (P=0.004), BIRC3 status (P=0.00004) and IGHV mutations. Concerning FISH cytogenetics (460 patients), a significant correlation (P<0.0001) was found between NOTCH1mut and trisomy 12 (20/62; 32%). TP53mut were strictly associated with del17p (15/25; 60%; P<0.0001), while BIRC3disr was found mainly within 11q22-q23 deletions subset (22/46;49%; P<0.0001). With regard to clinical outcome, 30 (83%) of 36 TP53mut pts (P=0.00009), 47 (90%) of 52 NOTCH1mut (P<0.00001) and 40 (87%) of 46 BIRC3disr pts had received chemotherapy at the time of analysis. Twenty nine NOTCH1mut (56%), 15 TP53mut (42%) and 18 BIRC3disr (39%) pts underwent at least two lines of treatment (P<0.0001). Noteworthy, shorter OS was observed in IGHV unmutated (UM) patients (12% vs 80% at 18 years, P<0.00001), in NOTCH1mut pts (12% vs 71% at 16 years, P<0.00001), in TP53mut pts (9% vs 76% at 14 years, P<0.00001) and in BIRC3disr pts (29% vs 65% at 16 years, P=0.00001). To further explore the prognostic impact of NOTCH1mut, TP53mut and BIRC3disr, we investigated them within the UM (153 pts) IGHV subset, notoriously at worst prognosis. As a matter of fact, NOTCH1mut (16% vs 45% at 14 years, P=0.012), TP53mut (0% vs 43% at 13 years, P=0.002) and BIRC3disr (0% vs 57% at 11 years, P=0.011) pts showed significant shorter OS [Figure]. Within the mutated IGHV subgroup we obtained similar results. In multivariate analysis of OS, TP53mut (HR 5.2, P<0.00001), age >60 years (HR 3.8, P=0.00002), IGHV UM status (HR 0.30, P=0.0001), intermediate/high Rai stages (HR 2.8, P=0.0002), NOTCH1mut (HR 2.6, P=0.001), and BIRC3disr (HR 2.5, P=0.005) were confirmed to be independent adverse prognostic factors. Noteworthy, here, we demonstrated that genomic aberrations are able to improve the historical prognostic ability of the IgHV mutational status. In conclusion, genomic aberrations, particularly TP53mut, NOTCH1mut and BIRC3disr should be considered as novel important prognostic parameters in CLL and therefore they have to be necessarily considered in updated scoring prognostic systems. Disclosures: No relevant conflicts of interest to declare.

Mitochondrial DNA Mutation, Diseases, and Nutrient-Regulated Mitophagy

2019 ◽  
Vol 39 (1) ◽  
pp. 201-226 ◽  
Author(s):  
Xuan Yang ◽  
Ruoyu Zhang ◽  
Kiichi Nakahira ◽  
Zhenglong Gu
Keyword(s):  
Mitochondrial Dna ◽  
Molecular Mechanisms ◽  
Genetic Manipulation ◽  
Wide Spectrum ◽  
Human Diseases ◽  
Nutrient Deficiencies ◽  
Mtdna Mutation ◽  
Mitochondrial Dna Mutation ◽  
Mtdna Mutations ◽  
Mitochondrial Homeostasis

A wide spectrum of human diseases, including cancer, neurodegenerative diseases, and metabolic disorders, have been shown to be associated with mitochondrial dysfunction through multiple molecular mechanisms. Mitochondria are particularly susceptible to nutrient deficiencies, and nutritional intervention is an essential way to maintain mitochondrial homeostasis. Recent advances in genetic manipulation and next-generation sequencing reveal the crucial roles of mitochondrial DNA (mtDNA) in various pathophysiological conditions. Mitophagy, a term coined to describe autophagy that targets dysfunctional mitochondria, has emerged as an important cellular process to maintain mitochondrial homeostasis and has been shown to be regulated by various nutrients and nutritional stresses. Given the high prevalence of mtDNA mutations in humans and their impact on mitochondrial function, it is important to investigate the mechanisms that regulate mtDNA mutation. Here, we discuss mitochondrial genetics and mtDNA mutations and their implications for human diseases. We also examine the role of mitophagy as a therapeutic target, highlighting how nutrients may eliminate mtDNA mutations through mitophagy.

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