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Relapsing polychondritis is a rare multisystem disease involving cartilaginous and proteoglycan-rich structures. The diagnosis of this disease is mainly suggested by the presence of flares of inflammation of the cartilage, particularly in the ears, nose or respiratory tract, and more rarely, in the presence of other manifestations. The spectrum of clinical presentations may vary from intermittent episodes of painful and often disfiguring auricular and nasal chondritis to an occasional organ or even life-threatening manifestations such as lower airway collapse. There is a lack of awareness about this disease is mainly due to its rarity. In 2020, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, a novel autoinflammatory syndrome, was described. VEXAS syndrome is attributed to somatic mutations in methionine-41 of UBA1, the major E1 enzyme that initiates ubiquitylation. This new disease entity connects seemingly unrelated conditions: systemic inflammatory syndromes (relapsing chondritis, Sweet's syndrome, and neutrophilic dermatosis) and hematologic disorders (myelodysplastic syndrome or multiple myeloma). Therefore, this article reviews the current literature on both disease entities.
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Doenças Ósseas , Policondrite Recidivante , Humanos , Policondrite Recidivante/diagnóstico , Policondrite Recidivante/tratamento farmacológico , Policondrite Recidivante/genética , Inflamação/complicações , Doenças Ósseas/complicaçõesRESUMO
Abstract Relapsing polychondritis is a rare multisystem disease involving cartilaginous and proteoglycan-rich structures. The diagnosis of this disease is mainly suggested by the presence of flares of inflammation of the cartilage, particularly in the ears, nose or respiratory tract, and more rarely, in the presence of other manifestations. The spectrum of clinical presentations may vary from intermittent episodes of painful and often disfiguring auricular and nasal chondritis to an occasional organ or even life-threatening manifestations such as lower airway collapse. There is a lack of awareness about this disease is mainly due to its rarity. In 2020, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, a novel autoinflammatory syndrome, was described. VEXAS syndrome is attributed to somatic mutations in methionine-41 of UBA1, the major E1 enzyme that initiates ubiquitylation. This new disease entity connects seemingly unrelated conditions: systemic inflammatory syndromes (relapsing chondritis, Sweet's syndrome, and neutrophilic dermatosis) and hematologic disorders (myelodysplastic syndrome or multiple myeloma). Therefore, this article reviews the current literature on both disease entities.
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OBJECTIVE: The authors searched for genetic and transcriptional signatures associated with tumor progression and recurrence in their cohort of patients with meningiomas, combining the analysis of targeted exome, NF2-LOH, transcriptome, and protein expressions. METHODS: The authors included 91 patients who underwent resection of intracranial meningioma at their institution between June 2000 and November 2007. The search of somatic mutations was performed by Next Generation Sequencing through a customized panel and multiplex ligation-dependent probe amplification for NF2 loss of heterozygosity. The transcriptomic profile was analyzed by QuantSeq 3' mRNA-Seq. The differentially expressed genes of interest were validated at the protein level analysis by immunohistochemistry. RESULTS: The transcriptomic analysis identified an upregulated set of genes related to metabolism and cell cycle and downregulated genes related to immune response and extracellular matrix remodeling in grade 2 (atypical) meningiomas, with a significant difference in recurrent compared with nonrecurrent cases. EZH2 nuclear positivity associated with grade 2, particularly with recurrent tumors and EZH2 gene expression level, correlated positively with the expression of genes related to cell cycle and negatively to genes related to immune response and regulation of cell motility. CONCLUSIONS: The authors identified modules of dysregulated genes in grade 2 meningiomas related to the activation of oxidative metabolism, cell division, cell motility due to extracellular remodeling, and immune evasion that were predictive of survival and exhibited significant correlations with EZH2 expression.
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Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/cirurgia , Neoplasias Meníngeas/cirurgia , Recidiva Local de Neoplasia/patologia , Ciclo Celular , Divisão Celular , Proteína Potenciadora do Homólogo 2 de Zeste/genéticaRESUMO
Cancer progression relies on cellular transition states accompanied by changes in the functionality of adhesion molecules. The gene for adhesion G protein-coupled receptor latrophilin-3 (aGPCR Lphn3 or ADGRL3) is targeted by tumor-specific somatic mutations predominantly affecting the conserved GAIN domain where most aGPCRs are cleaved. However, it is unclear how these GAIN domain-altering mutations impact Lphn3 function. Here, we studied Lphn3 cancer-related mutations as a proxy for revealing unknown GAIN domain functions. We found that while intra-GAIN cleavage efficiency was unaltered, most mutations produced a ligand-specific impairment of Lphn3 intercellular adhesion profile paralleled by an increase in cell-matrix actin-dependent contact structures for cells expressing the select S810L mutation. Aberrant remodeling of the intermediate filament vimentin, which was found to coincide with Lphn3-induced modification of nuclear morphology, had less impact on the nuclei of S810L expressing cells. Notoriously, receptor signaling through G13 protein was deficient for all variants bearing non-homologous amino acid substitutions, including the S810L variant. Analysis of cell migration paradigms revealed a non-cell-autonomous impairment in collective cell migration indistinctly of Lphn3 or its cancer-related variants expression, while cell-autonomous motility was potentiated in the presence of Lphn3, but this effect was abolished in S810L GAIN mutant-expressing cells. These data identify the GAIN domain as an important regulator of Lphn3-dependent cell motility, thus furthering our understanding of cellular and molecular events linking Lphn3 genetic somatic mutations to cancer-relevant pathogenesis mechanisms.
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Movimento Celular , Neoplasias , Receptores Acoplados a Proteínas G , Transdução de Sinais , Substituição de Aminoácidos , Linhagem Celular , Humanos , Mutação , Neoplasias/genética , Domínios Proteicos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de PeptídeosRESUMO
Introducción: Los síndromes mielodisplásicos constituyen un grupo heterogéneo de alteraciones de la célula progenitora hematopoyética. Estos se caracterizan por presentar una médula ósea hipercelular, una hematopoyesis inefectiva, displasia y citopenia periférica y la posibilidad de evolución a leucemia mieloide aguda. Objetivo: Describir las alteraciones citogenéticas y moleculares más frecuentes de los síndromes mielodisplásicos. Métodos: Se realizó una revisión de la literatura en los idiomas inglés y español, a través del sitio web PubMed y el motor de búsqueda Google académico, de artículos publicados en los últimos cinco años. Se realizó análisis y resumen de la bibliografía. Análisis y síntesis de la información: En los síndromes mielodisplásicos están presentes alteraciones citogenéticas frecuentes como la deleción de los cromosomas 5q, 7q y 20q, la monosomía del cromosoma 7, la trisomía del cromosoma 8 y la presencia de cariotipos complejos, que, unido a mutaciones somáticas en diferentes genes, intervienen en la patogénesis de la enfermedad y su conocimiento permite la estratificación pronóstica de los pacientes. Conclusiones: El diagnóstico a través de los estudios citogenéticos convencionales, la hibridación in situ por fluorescencia y la secuenciación génica permite una mayor comprensión de la biología de la enfermedad, la estratificación del riesgo y la toma de decisiones terapéuticas(AU)
Introduction: Myelodysplastic syndromes constitute a heterogeneous group of alterations of the hematopoietic progenitor cell, characterized by hypercellular bone marrow, ineffective hematopoietic, dysplasia and peripheral cytopenia; and the possibility of progressing to acute myeloid leukemia. Objective: To describe the most frequent cytogenetic and molecular alterations of myelodysplastic syndromes. Methods: A review of the literature in English and in Spanish was carried out, in the PubMed website and using the search engine Google, for articles published in the last five years. We performed analysis and summary of the reviewed bibliography. Analysis and synthesis of information: In myelodysplastic syndromes, frequent cytogenetic alterations are present such as deletion of chromosomes 5q, 7q and 20q, as well as the monosomy of chromosome 7, trisomy of chromosome 8 and the presence of complex karyotypes, which together with somatic mutations in different genes intervene in the pathogenesis of the disease and allow prognostic stratification of patients. Conclusions: Diagnosis through conventional cytogenetic studies, fluorescence in situ hybridization and gene sequencing allow a better understanding of the biology of the disease, risk stratification and therapeutic decision making(AU)
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Humanos , Medula Óssea , Cromossomos Humanos Par 7 , Cromossomos Humanos Par 8 , Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Hibridização In Situ , Citogenética , Tomada de DecisõesRESUMO
Introducción: La leucemia linfoide crónica es un trastorno linfoproliferativo caracterizado por la acumulación de linfocitos pequeños de aspecto maduro en sangre periférica, médula ósea y tejidos linfoides con un período de vida prolongado. Presenta una gran variabilidad clínica y genética. Objetivo: Describir los aspectos citogenéticos y moleculares de la leucemia linfoide crónica. Métodos: Se realizó revisión de la literatura en inglés y español, a través del sitio web PubMed y el motor de búsqueda Google académico, de artículos publicados en los últimos 5 años. Se hizo un análisis y resumen de la bibliografía revisada. Desarrollo: En la leucemia linfoide crónica están presentes alteraciones citogenéticas frecuentes como la deleción de los cromosomas 13q, 11q y 17p, así como la trisomía 12, que unido al conocimiento del estado mutacional del gen de la región variable de la cadena pesada de la inmunoglobulina, y otras mutaciones somáticas en diferentes genes, así como a variables clínicas y de laboratorio permiten la estratificación pronóstica de los pacientes. Conclusiones: El diagnóstico a través de los estudios citogenéticos convencionales estimulados con mitógenos, la hibridación in situ por fluorescencia y la secuenciación génica permite una mayor comprensión de la biología de la enfermedad, así como tomar decisiones terapéuticas más personalizadas(AU)
Introduction: Chronic B lymphoid leukemia is a lymphoproliferative disorder characterized by the accumulation of small, mature-looking lymphocytes in peripheral blood, bone marrow and lymphoid tissues with a long life span. It has great clinical and genetic variability. Objective: To describe the cytogenetic and molecular aspects of the disease. Methods: A review of the literature in English and in Spanish was carried out, in the PubMed website and using the search engine of Google Scholar, for articles published in the last five years. We performed analysis and summary of the reviewed bibliography. Development: In chronic lymphoid leukemia, frequent cytogenetic alterations are present such as deletion of chromosomes 13q, 11q and 17p, as well as trisomy 12, which together with the knowledge of the mutational status of the gene for the variable region of the immunoglobulin heavy chain and other somatic mutations in different genes, as well as clinical and laboratory variables allows prognostic stratification of patients. Conclusions: Diagnosis through conventional mitogen-stimulated cytogenetic studies, fluorescence in situ hybridization and gene sequencing allow a better understanding of the biology of the disease, as well as making more personalized therapeutic decisions(AU)
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Humanos , Masculino , Feminino , Biologia , Terapia Genética , Leucemia Linfoide/genética , Hibridização In Situ , Citogenética , Transtornos Linfoproliferativos , MutaçãoRESUMO
The advances in technology has shifted healthcare from a "one size fits all" model to focus on personalized therapy. Understanding the relationship of genome variations and its effect on drug response has led to individualized drug selection, maximizing drug efficacy and improving toxicity profile. The developments in pharmacogenomics has led to the discovery of predictive and prognostic biomarkers, and has transformed cancer research leading to the creation of pharmacogenomics databases. While challenges associated with the implementation of pharmacogenomics based medicine exist, integrating data amongst collaborative networks will be crucial for researchers to identify all the functional elements of the human genome sequence. Future advances in the area of pharmacogenomics research will eventually lead to the identification of the right therapeutic drug for the right patient.
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Neoplasias , Farmacogenética , Medicina de Precisão , Genoma Humano , Humanos , Farmacogenética/tendências , Medicina de Precisão/tendências , Projetos de PesquisaRESUMO
BACKGROUND: Mitochondrial and oxidative stress has been related to obesity and breast cancer being this cancer more frequent and more aggressive in postmenopausal women with obesity. OBJECTIVE: The objective of this study was to investigate whether Mexican-Mestizo postmenopausal women with breast cancer and obesity present different somatic mutations in the mitochondrial DNA (mtDNA) when compared to women with normal body mass index (BMI). SUBJECTS AND METHODS: We included six Mexican-Mestizo postmenopausal women bearing breast cancer and who underwent mastectomy or breast-conserving surgery. BMI was determined in each case. Patients' genomic DNA was isolated from blood leukocytes and tumor tissue samples. Whole mtDNA sequence was determined by MitoChip v2.0 mitochondrial resequencing array, and data were analyzed using the GeneChip Sequence Analysis Software. Tumor mtDNA sequence was compared with matched leukocyte mtDNA sequence. RESULTS: Three women had a normal BMI and three presented obesity. Overall, we found 64 genetic variants: 53.1% were somatic mutations and 46.9% were polymorphisms; 44.1% were in the non-coding region and 55.9% were in genes that encode for mitochondrial proteins. Among the somatic mutations, 67.7% were in patients with normal BMI and 32.3% in patients with obesity. CONCLUSIONS: We did not find a higher frequency of mitochondrial somatic mutations in postmenopausal women with breast cancer and obesity compared to those with normal BMI. However, results could be due to the small number of women studied.
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Neoplasias da Mama/patologia , Genoma Mitocondrial , Obesidade/epidemiologia , Pós-Menopausa , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , DNA Mitocondrial/genética , Feminino , Humanos , Mastectomia/métodos , Mastectomia Segmentar/métodos , México , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo GenéticoRESUMO
Abstract Background Mitochondrial and oxidative stress has been related to obesity and breast cancer being this cancer more frequent and more aggressive in postmenopausal women with obesity. Objective The objective of this study was to investigate whether Mexican-Mestizo postmenopausal women with breast cancer and obesity present different somatic mutations in the mitochondrial DNA (mtDNA) when compared to women with normal body mass index (BMI). Subjects and Methods We included six Mexican-Mestizo postmenopausal women bearing breast cancer and who underwent mastectomy or breast-conserving surgery. BMI was determined in each case. Patients genomic DNA was isolated from blood leukocytes and tumor tissue samples. Whole mtDNA sequence was determined by MitoChip v2.0 mitochondrial resequencing array, and data were analyzed using the GeneChip Sequence Analysis Software. Tumor mtDNA sequence was compared with matched leukocyte mtDNA sequence. Results Three women had a normal BMI and three presented obesity. Overall, we found 64 genetic variants: 53.1% were somatic mutations and 46.9% were polymorphisms; 44.1% were in the non-coding region and 55.9% were in genes that encode for mitochondrial proteins. Among the somatic mutations, 67.7% were in patients with normal BMI and 32.3% in patients with obesity. Conclusions We did not find a higher frequency of mitochondrial somatic mutations in postmenopausal women with breast cancer and obesity compared to those with normal BMI. However, results could be due to the small number of women studied.
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Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Pós-Menopausa , Genoma Mitocondrial , Obesidade/epidemiologia , Polimorfismo Genético , Neoplasias da Mama/cirurgia , Neoplasias da Mama/genética , DNA Mitocondrial/genética , Mastectomia Segmentar/métodos , Índice de Massa Corporal , Análise de Sequência com Séries de Oligonucleotídeos , Mastectomia/métodos , MéxicoRESUMO
Malignant tumors originate from somatic mutations and other genomic and epigenomic alterations, which lead to loss of control of the cellular circuitry. These alterations present patterns of co-occurrence and mutual exclusivity that can influence prognosis and modify response to drugs, highlighting the need for multitargeted therapies. Studies in this area have generally focused in particular malignancies and considered whole genes instead of specific mutations, ignoring the fact that different alterations in the same gene can have widely different effects. Here, we present a comprehensive analysis of co-dependencies of individual somatic mutations in the whole spectrum of human tumors. Combining multitesting with conditional and expected mutational probabilities, we have discovered rules governing the codependencies of driver and nondriver mutations. We also uncovered pairs and networks of comutations and exclusions, some of them restricted to certain cancer types and others widespread. These pairs and networks are not only of basic but also of clinical interest, and can be of help in the selection of multitargeted antitumor therapies. In this respect, recurrent driver comutations suggest combinations of drugs that might be effective in the clinical setting, while recurrent exclusions indicate combinations unlikely to be useful.
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Biomarcadores Tumorais , Biologia Computacional , Neoplasias/etiologia , Neoplasias/terapia , Mapeamento Cromossômico , Biologia Computacional/métodos , Suscetibilidade a Doenças , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Terapia de Alvo Molecular , Mutação , Locos de Características QuantitativasRESUMO
Due to the fact that mitochondrial defects and oxidative stress have been related with obesity and breast cancer is more aggressive in women with obesity, we investigated if postmenopausal Mexican-Mestizo women with breast cancer presented somatic mutations in the sequence of the ATP6 and/or ND3 genes. Twenty one postmenopausal Mexican-Mestizo women with breast cancer who underwent mastectomy or breast conserving surgery were studied. Height and weight were used to calculate body mass index. DNA from tumor tissue samples and blood leukocytes was amplified by polymerase chain reaction and sequenced the ATP6 and ND3 mitochondrial genes. Ages ranged from 46 to 82. According to World Health Organization criteria among the 21 women, 7 had a normal BMI, 7 were overweight and 7 had obesity. In regard to the molecular study, after sequencing the coding region of ATP6 and ND3 genes of the DNA obtained from both leukocytes and tumor tissue, we did not find somatic mutations. All of the changes that we found in both genes were polymorphisms: in ATP6, we identified in ten patients 3 non-synonymous nucleotide changes and in ND3 we observed that six patients presented polymorphisms, three of them were synonymous and two non-synonymous. To our knowledge, this constitutes the first report where the complete sequence of the ATP6 and ND3 genes has been analyzed in postmenopausal Mexican-Mestizo women with breast cancer and diverse BMI. Our results differ with those reported in Caucasian and Asian populations, possibly due to ethnic differences.
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Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Complexo I de Transporte de Elétrons/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Neoplasias da Mama/complicações , Carcinoma Ductal de Mama/complicações , Análise Mutacional de DNA , Feminino , Genes Mitocondriais/genética , Humanos , México , Pessoa de Meia-Idade , Obesidade/complicações , Sobrepeso/complicações , Pós-MenopausaRESUMO
Tumor suppressor genes (TSGs) are commonly inactivated by somatic mutation and/or promoter methylation; yet, recent high-throughput genomic studies have not identified key TSGs inactivated by both mechanisms. We pursued an integrated molecular analysis based on methylation binding domain sequencing (MBD-seq), 450K Methylation arrays, whole exome sequencing, and whole genome gene expression arrays in primary head and neck squamous cell carcinoma (HNSCC) tumors and matched uvulopalatopharyngoplasty tissue samples (UPPPs). We uncovered 186 downregulated genes harboring cancer specific promoter methylation including PAX1 and PAX5 and we identified 10 key tumor suppressor genes (GABRB3, HOXC12, PARP15, SLCO4C1, CDKN2A, PAX1, PIK3AP1, HOXC6, PLCB1, and ZIC4) inactivated by both promoter methylation and/or somatic mutation. Among the novel tumor suppressor genes discovered with dual mechanisms of inactivation, we found a high frequency of genomic and epigenomic alterations in the PAX gene family of transcription factors, which selectively impact canonical NOTCH and TP53 pathways to determine cell fate, cell survival, and genome maintenance. Our results highlight the importance of assessing TSGs at the genomic and epigenomic level to identify key pathways in HNSCC, deregulated by simultaneous promoter methylation and somatic mutations.
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Carcinoma de Células Escamosas/genética , Metilação de DNA , Inativação Gênica , Genes Supressores de Tumor , Neoplasias de Cabeça e Pescoço/genética , Regiões Promotoras Genéticas , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Ilhas de CpG , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Masculino , Mutação , Fator de Transcrição PAX5/genética , Fator de Transcrição PAX5/metabolismo , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Tumorigenesis can be seen as an evolutionary process, in which the transformation of a normal cell into a tumor cell involves a number of limiting genetic and epigenetic events, occurring in a series of discrete stages. However, not all mutations in a cell are directly involved in cancer development and it is likely that most of them (passenger mutations) do not contribute in any way to tumorigenesis. Moreover, the process of tumor evolution is punctuated by selection of advantageous (driver) mutations and clonal expansions. Regarding these driver mutations, it is uncertain how many limiting events are required and/or sufficient to promote a tumorigenic process or what are the values associated with the adaptive advantage of different driver mutations. In spite of the availability of high-quality cancer data, several assumptions about the mechanistic process of cancer initiation and development remain largely untested, both mathematically and statistically. Here we review the development of recent mathematical/computational models and discuss their impact in the field of tumor biology.
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The accumulation of somatic mutations in mtDNA is correlated with aging. In this work, we sought to identify somatic mutations in the HVS-1 region (D-loop) of mtDNA that might be associated with aging. For this, we compared 31 grandmothers (mean age: 63 ± 2.3 years) and their 62 grandchildren (mean age: 15 ± 4.1 years), the offspring of their daughters. Direct DNA sequencing showed that mutations absent in the grandchildren were detected in a presumably homoplasmic state in three grandmothers and in a heteroplasmic state in an additional 13 grandmothers; no mutations were detected in the remaining 15 grandmothers. However, cloning followed by DNA sequencing in 12 grandmothers confirmed homoplasia in only one of the three mutations previously considered to be homoplasmic and did not confirm heteroplasmy in three out of nine grandmothers found to be heteroplasmic by direct sequencing. Thus, of 12 grandmothers in whom mtDNA was analyzed by cloning, eight were heteroplasmic for mutations not detected in their grandchildren. In this study, the use of genetically related subjects allowed us to demonstrate the occurrence of age-related (> 60 years old) mutations (homoplasia and heteroplasmy). It is possible that both of these situations (homoplasia and heteroplasmy) were a long-term consequence of mitochondrial oxidative phosphorylation that can lead to the accumulation of mtDNA mutations throughout life.
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The accumulation of somatic mutations in mtDNA is correlated with aging. In this work, we sought to identify somatic mutations in the HVS-1 region (D-loop) of mtDNA that might be associated with aging. For this, we compared 31 grandmothers (mean age: 63 ± 2.3 years) and their 62 grandchildren (mean age: 15 ± 4.1 years), the offspring of their daughters. Direct DNA sequencing showed that mutations absent in the grandchildren were detected in a presumably homoplasmic state in three grandmothers and in a heteroplasmic state in an additional 13 grandmothers; no mutations were detected in the remaining 15 grandmothers. However, cloning followed by DNA sequencing in 12 grandmothers confirmed homoplasia in only one of the three mutations previously considered to be homoplasmic and did not confirm heteroplasmy in three out of nine grandmothers found to be heteroplasmic by direct sequencing. Thus, of 12 grandmothers in whom mtDNA was analyzed by cloning, eight were heteroplasmic for mutations not detected in their grandchildren. In this study, the use of genetically related subjects allowed us to demonstrate the occurrence of age-related (> 60 years old) mutations (homoplasia and heteroplasmy). It is possible that both of these situations (homoplasia and heteroplasmy) were a long-term consequence of mitochondrial oxidative phosphorylation that can lead to the accumulation of mtDNA mutations throughout life.