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... MitoTool (www.mitotool.org) [30]. We classified each sample based on the haplogroup motifs that were identified according to the PhyloTree (http://www.phylotree.org; mtDNA tree Build 9, 20 Jun 2010) =-=[31]-=-. For samples which could not be unambiguously determined by the mtDNA control region sequence variants, PCR- restriction fragment length polymorphism (RFLP) analysis for specific coding region varian...

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...nalyzer (Applied Biosystems). Each sample was sequenced for an approximate 1.4 kb fragment (mtDNA regions 16033–16569 and 1–850; numbering according to the revised Cambridge reference sequence (rCRS) =-=[28]-=-) which cover the mtDNA control region, the MT-TF gene and part of the MT-RNR1 gene. We determined the entire mtDNA sequences for four LHON patients (Fig. S1) belonging to haplogroup M7b192 using the ...

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...ts (n= 304) with the reported LHON patients (n= 175; [15]). Combining these two different datasets provide more statistical power than the strategy of analyzing both data sets separately (Methods S1) =-=[32]-=-. Pearson’s chi-square test with a one degree of freedom was used to assess the significance of the differences observed in haplogroup frequencies between cases and controls. The Fisher Exact test (tw...

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...variants of haplogroup D4 might be responsible for the potentially functional effect. Indeed, variant m.5178C.A had been reported to be associated with a variety of human disorders [39] and longevity =-=[40]-=-, despite the fact that there was controversy regarding its role in longevity [41], and the functional assay did not support the notion that this variant could alter mitochondrial matrix pH and intrac...

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...d the hydrophobicity of m.13928G.C did not prove itself to be the possible pathogenic mutation, although recent studies showed that ancient variation may influence mtDNA replication and transcription =-=[43]-=- or contribute to cellular physiological changes in the presence of the primary mutations [44]. The deletion of adenine at position 249 is a characteristic variant of haplogroup F and other Asian hapl...

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...here was controversy regarding its role in longevity [41], and the functional assay did not support the notion that this variant could alter mitochondrial matrix pH and intracellular calcium dynamics =-=[42]-=-. The exact role of haplogroup D4 in LHON needs further study. Haplogroup F was very rare in the LHON patients (for 304 new patients, 3/304 = 0.99%; for pooled 479 patients, 6/ 479 = 1.25%), compared ...

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..., although recent studies showed that ancient variation may influence mtDNA replication and transcription [43] or contribute to cellular physiological changes in the presence of the primary mutations =-=[44]-=-. The deletion of adenine at position 249 is a characteristic variant of haplogroup F and other Asian haplogroups CZ, M31a1 and M36d1 [31]. Variant m.249delA was located in the mtTF1 binding site (MTT...

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...of the haplogroup association, namely, haplogroup J is present at an increased frequency in LHON families with m.11778G.A and m.14484T.C, and subdivisions of this haplogroup show increased penetrance =-=[5]-=-. Dissecting haplogroups in European LHON families have shown that the increased frequency of J was indeed due to an increased frequency of two specific nested sub-clades of J (one deriving from J1 an...

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...ication and statistical analysis The sequences were compared with the rCRS [28] and the variants in each mtDNA sequence were recorded and were further checked by using the MitoTool (www.mitotool.org) =-=[30]-=-. We classified each sample based on the haplogroup motifs that were identified according to the PhyloTree (http://www.phylotree.org; mtDNA tree Build 9, 20 Jun 2010) [31]. For samples which could not...

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...pean populations [19,20]. Similarly, we found that the MT-ND1 and MT-ND5 genes are mutational hotspots in Chinese suspected LHON patients with a family history but lacking the three primary mutations =-=[21]-=-. Whether there is an effect of mtDNA background on suspected LHON has not been tested so far. In order to further verify the mtDNA haplogroup effect on LHON and to discern the potential effect of mtD...

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...on described in our previous study [27]. Novelty and potential pathogenicity for those non-synonymous private variants in these lineages were analyzed using the same method reported by Bandelt et al. =-=[29]-=-. mtDNA haplogroup classification and statistical analysis The sequences were compared with the rCRS [28] and the variants in each mtDNA sequence were recorded and were further checked by using the Mi...

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...eported in our previous study [15] and 304 patients newly sequenced) and 843 suspected LHON patients without the three primary mutations, with the aim of primarily addressing the following questions: =-=(1)-=- does mtDNA haplogroup background contribute to the suspected LHON? (2) will the enlarged LHON patients with m.11778G.A discern the internal consistency of the haplogroup association of LHON penetranc...

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...11 | e27750 Discussion In recent years, many studies reported that mtDNA background affects the expression of human disorders [33–37], although some positive findings could respond to false positives =-=[38]-=-. Among these studies, LHON is probably the most extensively studied disease that has been reported to be modulated by mtDNA haplogroups [5,12–15]. In this study, we analyzed 479 unrelated LHON sample...

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...the non-synonymous variants of haplogroup D4 might be responsible for the potentially functional effect. Indeed, variant m.5178C.A had been reported to be associated with a variety of human disorders =-=[39]-=- and longevity [40], despite the fact that there was controversy regarding its role in longevity [41], and the functional assay did not support the notion that this variant could alter mitochondrial m...

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...m.11778G.A [5,12– 14]. Our previous study of Chinese families with m.11778G.A showed that haplogroup M7b192 could increase the risk of vision loss but haplogroup M8a might produce a protective effect =-=[15]-=-. However, frequencies of haplogroups M7b192 and M8a are not significantly altered in LHON pedigrees compared to the normal controls despite their apparent background effect on the penetrance [15]. Th...

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...ession of LHON clinical features (e.g. painless, acute or sub-acute vision deterioration without apparent reasons). LHON patients with primary mutation m.14484T.C or m.3460G.A were reported elsewhere =-=[22,23]-=- and were not discussed in this study. 175 LHON patients with m.11778G.A had a family history and were described in our previous study [15]; these patients were reanalyzed with the new samples in this...

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...nt of haplogroup F and other Asian haplogroups CZ, M31a1 and M36d1 [31]. Variant m.249delA was located in the mtTF1 binding site (MTTFX or TFAM) which binds with mtTF and controls mtDNA transcription =-=[45]-=-. Some single base changes within this region have been identified to alter protein binding efficiency [43]. Whether m.249delA could affect the efficiency of mtDNA transcription remains unclear. Popul...

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...European LHON families have shown that the increased frequency of J was indeed due to an increased frequency of two specific nested sub-clades of J (one deriving from J1 and another deriving from J2) =-=[5,14]-=-. Insufficient sampling (limited statistical power), and/or potential population stratification may account for the lack of internal consistency in our observation [15]. Besides the LHON patients with...

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...ession of LHON clinical features (e.g. painless, acute or sub-acute vision deterioration without apparent reasons). LHON patients with primary mutation m.14484T.C or m.3460G.A were reported elsewhere =-=[22,23]-=- and were not discussed in this study. 175 LHON patients with m.11778G.A had a family history and were described in our previous study [15]; these patients were reanalyzed with the new samples in this...

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... and complete genome The PCR-single strand conformation polymorphism (PCRSSCP) and allele specific PCR (AS-PCR) methods were jointly used to detect the three primary mutations as previously described =-=[25]-=-. The presence of the three primary mutations in the patients was independently screened in Kunming using method described by Bi et al. [26]. The mtDNA control region sequence of each patient was ampl...

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...94uC for 30 sec, 52uC for 30 sec, 72uC for 2 min; and one extension cycle at 72uC for 10 min. The PCR products were purified and sequenced by sequencing primers, which were used in our previous study =-=[27]-=-, on a 3730 DNA analyzer (Applied Biosystems). Each sample was sequenced for an approximate 1.4 kb fragment (mtDNA regions 16033–16569 and 1–850; numbering according to the revised Cambridge reference...

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...d 843 suspected LHON patients without the three primary mutations, with the aim of primarily addressing the following questions: (1) does mtDNA haplogroup background contribute to the suspected LHON? =-=(2)-=- will the enlarged LHON patients with m.11778G.A discern the internal consistency of the haplogroup association of LHON penetrance? Dissecting the matrilineal components of the enlarged sample size of...

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...while M7b is a risk factor. Citation: Zhang A-M, Jia X, Bi R, Salas A, Li S, et al. (2011) Mitochondrial DNA Haplogroup Background Affects LHON, but Not Suspected LHON, in Chinese Patients. PLoS ONE 6=-=(11)-=-: e27750. doi:10.1371/journal.pone.0027750 Editor: Alfred Lewin, University of Florida, United States of America Received July 5, 2011; Accepted October 24, 2011; Published November 15, 2011 Copyright...

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...erogeneous patients with suspected LHON has not been well examined. Rare pathogenic mutations, e.g. m.3635G.A, might account for the disease expression in a very small portion of these patients (Ref. =-=[17,18]-=- and references therein). The MT-ND1 and MT-ND6 genes were found to be mutational hotspots for LHON patients without the three primary mutations in European populations [19,20]. Similarly, we found th...

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... detect the three primary mutations as previously described [25]. The presence of the three primary mutations in the patients was independently screened in Kunming using method described by Bi et al. =-=[26]-=-. The mtDNA control region sequence of each patient was amplified by using primer pair (L15594: 59-CGCCTACACAATTCTCCGATC-39 and H901: 59-ACTTGGGTTAATCGTGTGACC-39) and the following PCR condition: one ...

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...ons (274/1689 = 16.22%) and in the suspected LHON patients (143/843 = 16.96%). This result again confirmed the observation in our previous study [15] and a recent study in LHON patients from Thailand =-=[10]-=-, in which an extremely low frequency of haplogroup F (including its subhaplogroups) was observed in LHON patients with m.11778G.A. Although the confounding effect of population stratification cannot ...

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...erogeneous patients with suspected LHON has not been well examined. Rare pathogenic mutations, e.g. m.3635G.A, might account for the disease expression in a very small portion of these patients (Ref. =-=[17,18]-=- and references therein). The MT-ND1 and MT-ND6 genes were found to be mutational hotspots for LHON patients without the three primary mutations in European populations [19,20]. Similarly, we found th...

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...of these patients (Ref. [17,18] and references therein). The MT-ND1 and MT-ND6 genes were found to be mutational hotspots for LHON patients without the three primary mutations in European populations =-=[19,20]-=-. Similarly, we found that the MT-ND1 and MT-ND5 genes are mutational hotspots in Chinese suspected LHON patients with a family history but lacking the three primary mutations [21]. Whether there is a...

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...of these patients (Ref. [17,18] and references therein). The MT-ND1 and MT-ND6 genes were found to be mutational hotspots for LHON patients without the three primary mutations in European populations =-=[19,20]-=-. Similarly, we found that the MT-ND1 and MT-ND5 genes are mutational hotspots in Chinese suspected LHON patients with a family history but lacking the three primary mutations [21]. Whether there is a...

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...ents were reanalyzed with the new samples in this study. LHON patients with both m.11778G.A and m.593T.C (n = 14) and suspected LHON patients with m.593T.C (n = 12) were discussed in a separate paper =-=[24]-=-. Patients without the three primary mutations of LHON were simply regarded as patients with suspected LHON, despite that this grouping included a very small proportion of LHON patients that were caus...

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...ct. Indeed, variant m.5178C.A had been reported to be associated with a variety of human disorders [39] and longevity [40], despite the fact that there was controversy regarding its role in longevity =-=[41]-=-, and the functional assay did not support the notion that this variant could alter mitochondrial matrix pH and intracellular calcium dynamics [42]. The exact role of haplogroup D4 in LHON needs furth...