Mitochondrial DNA Haplogroups Do Not Play a Role in the Variable Phenotypic Presentation of the A3243G Mutation

Torroni, Antonio; Campos, Yolanda; Rengo, Chiara; Sellitto, Daniele; Achilli, Alessandro; Magri, Chiara; Semino, Ornella; García, Ana Isabel Morales; Jara, P.; Arenas, Joaquı́n; Scozzari, Rosaria

doi:10.1086/373936

Cited by 51 publications

(44 citation statements)

References 36 publications

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“…46 Our data suggest a possible distortion towards haplogroup cluster HV among patients with early-onset but postlingual hearing impairment, at least compared with population controls or patients with ARHI, although of borderline statistical significance. Previous associations with longevity 31 suggest that tightly age-matched controls might be needed to judge the issue definitively.…”

Section: Mitochondrial Haplogroup Affiliations and Hearing Impairmentmentioning

confidence: 49%

Mitochondrial DNA mutations in patients with postlingual, nonsyndromic hearing impairment

et al. 2004

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Mitochondrial mutations have previously been reported anecdotally in families with maternally inherited, nonsyndromic hearing impairment. To ascertain the contribution of mitochondrial mutations to postlingual but early-onset, nonsyndromic hearing impairment, we screened patients collected from within two different populations (southern Italy and UK) for previously reported mtDNA mutations associated with hearing disorders. Primer extension (SNP analysis) was used to screen for specific mutations, revealing cases of heteroplasmy and its extent. The most frequently implicated tRNA genes, Leu(UUR) and Ser(UCN), were also sequenced in all Italian patients. All tRNA genes were sequenced in those UK patients showing the clearest likelihood of maternal inheritance. Causative mtDNA mutations were found in approximately 5% of patients in both populations, representing almost 10% of cases that were clearly familial. Age of onset, where known, was generally before adulthood, and hearing loss was typically progressive. Haplogroup analysis revealed a possible excess of haplogroup cluster HV in the patients, compared with population controls, but of borderline statistical significance. In contrast, we did not find any of the previously reported mtDNA mutations, nor a significant deviation from haplogroup cluster frequencies typical of the control population, in patients with late adult-onset hearing loss (age-related hearing impairment) from the UK or Finland.

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Section: Mitochondrial Haplogroup Affiliations and Hearing Impairmentmentioning

confidence: 49%

Mitochondrial DNA mutations in patients with postlingual, nonsyndromic hearing impairment

et al. 2004

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“…14 We therefore sequenced the complete mtDNA of 27 patients, searching for susceptibility mtDNA mutations. Among this group, 22 individuals were familiar cases belonging to pedigrees with either mother-to-child transmission in more than one generation or with all-affected siblings in the sibship (Supplementary Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Analysis of complete mitochondrial genomes of patients with schizophrenia and bipolar disorder

et al. 2011

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The present study aims at investigating the association between common and rare variants of mitochondrial DNA (mtDNA), and increased risk of schizophrenia (SZ) and bipolar disorder (BPD) in a cohort of patients originating from the same Italian population. The distribution of the major European mtDNA haplogroups was determined in 89 patients and their frequencies did not significantly differ from those observed in the Italian population. Moreover, 27 patients with high probability of having inherited the disease from the maternal side were selected for whole mitochondrial genome sequencing to investigate the possible presence of causative point mutations. Overall, 213 known variants and 2 novel changes were identified, but none of them was predicted to have functional effects. Hence, none of the sequence changes we found in our sample could explain the maternal component of SZ and BPD predisposition. Keywords: bipolar disorder; mtDNA variants; schizophrenia INTRODUCTION Schizophrenia (SZ) and bipolar disorder (BPD) are among the top ten causes of disability worldwide. 1 Despite extensive genetic and pharmacological studies, the etiology and pathophysiology of these mental disorders are still unknown, and the nuclear susceptibility loci identified so far can explain only a small fraction of the genetic component of these diseases. 2 The growing body of observations published in the last decade points to the involvement of mitochondria in the pathophysiology of psychiatric disorders, including SZ and BPD. 3 Several genetic studies reported association between these diseases and common mitochondrial DNA (mtDNA) polymorphisms defining ethnic-specific mitochondrial haplogroups. [4][5] Other analyses found new rare variants with a putative functional effect 6 and a global excess of synonymous substitutions in the dorsolateral prefrontal cortex of SZ patients. 7 Despite the great interest of these findings, the role of mtDNA in the pathogenesis of SZ/BDP remains unclear.The present study aims at investigating the association between common and rare variants of mtDNA and the increased risk of SZ/ BPD in a sample of patients originating from the same Italian population.

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“…The fact that the m.7510T>C mutation arose on different mitochondrial subgroups provides further evidence for the pathogenecity of this mutation. Evolutionary studies showed that deleterious mitochondrial mutations are influenced very strongly by selection and are eliminated rapidly, so their appearance should be the result of very recent mutational events and transmitted through very few generations; thus, founder events are not likely to be found (Torroni et al 2003). The finding that all four so far described families carry the m.7510T>C mutation on different European mtDNA haplogroup backgrounds indicates that European haplogroups do not increase or reduce the risk of expressing the disease phenotype.…”

Section: Discussionmentioning

confidence: 97%

Non-syndromic Hearing Impairment in a Hungarian Family with the m.7510T>C Mutation of Mitochondrial tRNASer(UCN) and Review of Published Cases

et al. 2012

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The m.7510T>C mitochondrial DNA (mtDNA) mutation is a tRNA Ser(UCN) alteration leading to matrilineal isolated hearing impairment. The current paper reviews the available reports on the m.7510T>C mtDNA mutation, with special attention to phenotypic variations and haplogroup background. A Hungarian family, the fourth family reported in the literature, is presented, in which analysis of three generations with bilateral isolated hearing loss revealed the m.7510T>C tRNA Ser(UCN) mutation in homoplasmic form in the affected members. Haplogroup analysis verified an unnamed subgroup of mitochondrial haplogroup H. Previously reported Spanish and North American Caucasian families belong to different subgroups of haplogroup H. Analyzing our biobank of Hungarian patients with sensorineural hearing loss, we did not detect this mutation in any other patient, nor was it found in Caucasian haplogroup H control samples. Comparing the cases reported so far, there is interfamilial variablity in the age of onset, accompanying symptoms, and haplogroup background. Our case adds further genetic evidence for the pathogenicity of the m.7510T>C mutation and underlines the need to include full mtDNA sequencing in the screening for unexplained hearing loss.

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Mitochondrial DNA Haplogroups Do Not Play a Role in the Variable Phenotypic Presentation of the A3243G Mutation

Cited by 51 publications

References 36 publications

Mitochondrial DNA mutations in patients with postlingual, nonsyndromic hearing impairment

Mitochondrial DNA mutations in patients with postlingual, nonsyndromic hearing impairment

Analysis of complete mitochondrial genomes of patients with schizophrenia and bipolar disorder

Non-syndromic Hearing Impairment in a Hungarian Family with the m.7510T>C Mutation of Mitochondrial tRNASer(UCN) and Review of Published Cases

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