ライフサイエンスコーパス: LHON

1 LHON has no treatment, so identifying environmental trig

2 LHON optic nerves showed an orderly loss of axons, start

3 LHON tissues were further evaluated by determining regio

4 ffected and 206 unaffected carriers from 125 LHON pedigrees known to harbour one of the three primary

5 imate that this lineage--including the 14484 LHON mutation--arose 900-1,800 years ago.

6 a haplogroup J mtDNA that carried the 14484 LHON mutation.

7 By studying 3,613 subjects from 159 LHON-affected pedigrees, we show that the risk of visual

8 tions in OPA1 we also screened a panel of 28 LHON patients who tested negatively for the three major

9 n exome sequencing approach, we identified a LHON susceptibility allele (c.572G>T, p.191Gly>Val) in Y

10 n these findings, asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to sm

11 DNA sequences conservatively indicate that a LHON mutation has arisen at least 42 times in the Dutch

12 mtDNA developed from a heteroplasmic A3460G LHON subject, confirming the association between the A34

13 However, in A3460G LHON fusion cybrids containing a different nuclear backg

14 es were significantly increased in the acute LHON stage.

15 ikely to be pathogenic, that it can cause an LHON/MELAS overlap syndrome, and that it may be a more f

16 Control and LHON tissues were evaluated by measuring axonal dimensio

17 -zero-dependent, cybridization-dependent and LHON-dependent categories in these cells.

18 n any LHON patients, indicating that DOA and LHON are genetically distinct.

19 ry aim was to define MRI features of LMS and LHON, and to assess the proportions of individuals displ

20 No mutations were identified in any LHON patients, indicating that DOA and LHON are genetica

21 steosarcoma cybrids and lymphoblasts bearing LHON mutations.

22 Both the 11778G-->A and 14484T-->C LHON mutations are preferentially found on a specific mt

23 creased levels of blood NSE may characterize LHON carriers as a biomarker of ongoing RGC stress.

24 stmortem from four molecularly characterized LHON patients with varying degrees of neurodegenerative

25 the choroid is the common outcome in chronic LHON and in DOA.

26 choroidal thickness was decreased in chronic LHON and in DOA.

27 m those pedigrees that did not carry classic LHON mutations suggested candidate pathogenic mutations

28 ined, 56 of which carried one of the classic LHON mutations at nucleotide (nt) 3460, 11778, or 14484.

29 patient lymphoblasts bearing the most common LHON mutation (11778) and the most severe LHON mutation

30 activity, somewhat spared in the most common LHON mutation (G11778A), although adenosine triphosphate

31 rial cybrids harboring the three most common LHON mutations: 3460A, 11778A, and 14484C.

32 N who do not harbour one of the three common LHON mutations.

33 pedigree of m.11778G>A/ND4 mitochondrial DNA LHON mutation.

34 d provides support for a polygenic model for LHON expression in some cases.

35 Thus, male carriers are at higher risk for LHON-related neuronal stress.

36 ions 3460, 11778, and 14484 are specific for LHON and account for 90% of worldwide cases and are thus

37 indicating that this gene is a hot spot for LHON mutations.

38 ERbeta may become a therapeutic strategy for LHON specifically aimed at avoiding or delaying the onse

39 Allotopic gene therapy for LHON at low and medium doses seems to be safe and does n

40 bitors could have some therapeutic value for LHON.

41 less rho(o) cells with enucleated cells from LHON patients carrying both m.11778G > A and m.14502T >

42 nt of visual acuity in patients with G11778A LHON is not common and is partial and limited when it oc

43 tural history study of patients with G11778A LHON to plan a gene therapy clinical trial that will use

44 cipants included 44 individuals with G11778A LHON, recruited between September 2008 and March 2012, w

45 he eyes of 5 blind participants with G11778A LHON.

46 , and from previous studies of heteroplasmic LHON families, we conclude that there is no evidence for

47 ells and their axons, the hallmarks of human LHON.

48 monstrated the involvement of the choroid in LHON pathology.

49 ure of identifying the date of conversion in LHON.

50 cating that increased Fas-dependent death in LHON cybrids was induced by the LHON pathogenic mutation

51 ant for the pathophysiology of cell death in LHON, and potential therapy.

52 the expression of the biochemical defect in LHON patients with the A3460G mutation.

53 ones ameliorate mitochondrial dysfunction in LHON through the estrogen receptors (ERs).

54 vere irreversible loss of visual function in LHON support clinical testing with mutated G11778A mitoc

55 Serum NSE levels are higher in LHON carriers compared with affected and off-pedigree in

56 pathy, and sorbitol levels were increased in LHON cybrids.

57 seeks to predict the order of axonal loss in LHON optic nerves using the Nerve Fiber Layer Stress Ind

58 se reductase transcript was overexpressed in LHON cybrids and lymphoblasts.

59 complete penetrance and male predominance in LHON remains unclear.

60 lex I genes, ND5 mutations are quite rare in LHON.

61 ing the levels of reactive oxygen species in LHON cells.

62 revealed that the PMB is most susceptible in LHON, supporting clinical findings seen early in the cou

63 hat estrogen-like molecules may be useful in LHON prophylactic therapy.

64 s and thus are found in multiple independent LHON families.

65 a low likelihood that an optic neuropathy is LHON.

66 ntiation protocol yielded significantly less LHON cells than controls, by 30%, indicating either a de

67 ts who tested negatively for the three major LHON mutations.

68 arts, cybrids carrying the homoplasmic mouse LHON mutation demonstrated reduced respiration, reduced

69 defect in association with the A3460G mtDNA LHON mutation in cultured fibroblasts compared with age-

70 70% of Leber Hereditary Optic Neuropathies (LHON).

71 stic of Leber's hereditary optic neuropathy (LHON) 2 years before the first stroke-like episode.

72 Leber's hereditary optic neuropathy (LHON) and a multiple sclerosis (MS)-like illness appear

73 such as Leber's hereditary optic neuropathy (LHON) and Autosomal dominant optic atrophy (ADOA) are ca

74 cause of Leber hereditary optic neuropathy (LHON) and/or pediatric-onset dystonia in three unrelated

75 atment of Leber hereditary optic neuropathy (LHON) caused by a mutation in the nicotinamide adenine d

76 Leber's hereditary optic neuropathy (LHON) causes central vision loss from bilateral optic ne

77 lies with Leber hereditary optic neuropathy (LHON) closely fits a model in which a pathogenic mtDNA m

78 whether Leber's hereditary optic neuropathy (LHON) could be caused by mutations in OPA1 we also scree

79 esis of Leber's hereditary optic neuropathy (LHON) has yet to be characterized.

80 causing Leber's hereditary optic neuropathy (LHON) have demonstrated that some continent-specific mtD

81 sible for Leber hereditary optic neuropathy (LHON) into the mouse germ line using fluorescence imagin

82 Leber's hereditary optic neuropathy (LHON) is a common cause of bilateral optic nerve disease

83 Leber hereditary optic neuropathy (LHON) is a disorder characterized by severe and rapidly

84 Leber's hereditary optic neuropathy (LHON) is a form of blindness caused by mitochondrial DNA

85 Leber hereditary optic neuropathy (LHON) is a genetic disorder primarily due to mutations o

86 Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease charact

87 Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease affecting retinal gangl

88 Leber hereditary optic neuropathy (LHON) is a type of blindness caused by mtDNA mutations.

89 Leber hereditary optic neuropathy (LHON) is due primarily to one of three common point muta

90 f G11778A Leber hereditary optic neuropathy (LHON) is important to determine the optimal end points t

91 Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disease.

92 Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder.

93 Leber's hereditary optic neuropathy (LHON) is thought to be the most common disease resulting

94 Leber's hereditary optic neuropathy (LHON) is typically characterized by vascular alterations

95 e primary Leber hereditary optic neuropathy (LHON) mutation at nucleotide 3460 of the mitochondrial g

96 from five Leber hereditary optic neuropathy (LHON) pedigrees.

97 model of Leber hereditary optic neuropathy (LHON) was produced by introducing the human optic atroph

98 rees with Leber hereditary optic neuropathy (LHON) were determined, 56 of which carried one of the cl

99 Leber's hereditary optic neuropathy (LHON), a mitochondrial disease, has clinical manifestati

100 causes Leber's Hereditary Optic Neuropathy (LHON), a specific degeneration of the optic nerve, resul

101 enesis of Leber hereditary optic neuropathy (LHON), caused by mutated complex I subunit genes.

102 tion in Leber's hereditary optic neuropathy (LHON).

103 ophy in Leber's hereditary optic neuropathy (LHON).

104 ons and Leber's hereditary optic neuropathy (LHON).

105 ents with Leber hereditary optic neuropathy (LHON).

106 tory of Leber's hereditary optic neuropathy (LHON).

107 S), and Leber's hereditary optic neuropathy (LHON).

108 ly with Leber's hereditary optic neuropathy (LHON).

109 ons for Leber's hereditary optic neuropathy (LHON: G11778A; T14484C; and G3460A) were not present in

110 inical and genetic characterization of a new LHON mtDNA mutation.

111 Nine LHON-specific transcriptional alterations were shared am

112 This association of LHON and MS (LMS) raises an important question about whe

113 ND4 homologue responsible for most cases of LHON.

114 oping white matter lesions in the context of LHON.

115 ical analyses to compare the distribution of LHON patients on the Caucasian phylogenetic tree.

116 posed to modify the phenotypic expression of LHON-associated mitochondrial DNA (mtDNA) mutations.

117 Peculiar features of LHON are incomplete penetrance and gender bias, with a m

118 viduals who develop the clinical features of LHON but who do not harbour one of these primary LHON mu

119 he optic neuropathy to the histopathology of LHON is powerful evidence supporting ROS as a key factor

120 The natural history of LHON is not a subacute process, as previously believed,

121 ROS have a role in the optic nerve injury of LHON, then increasing mitochondrial levels of ROS should

122 The majority of LHON patients harbour one of three point mutations of th

123 g ROS as a key factor in the pathogenesis of LHON.

124 ded new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA m

125 ded new insights into the pathophysiology of LHON that were manifested by interaction between primary

126 further insight into the pathophysiology of LHON.

127 explain the marked incomplete penetrance of LHON, but previous small studies have failed to confirm

128 generation of RGCs during the acute phase of LHON have not been very effective.

129 in asymptomatic, acute and chronic stages of LHON.

130 culates on a pathogenic role for a subset of LHON secondary mutations and their interaction with prim

131 e prone to manifest the clinical symptoms of LHON than others.

132 we tested the effects of ERbeta targeting on LHON mitochondrial defective metabolism by treating LHON

133 pproximately 75% of worldwide 14484-positive LHON patients occur in association with haplogroup J.

134 ion, segregation, or transmission of primary LHON mutations to white blood cells and platelets.

135 dulated the phenotypic expression of primary LHON-associated m.11778G > A mutation.

136 modify the phenotypic expression of primary LHON-associated mitochondrial DNA (mtDNA) mutations.

137 phorylation defects among all of the primary LHON mtDNA mutations, thus permitting insight into the u

138 ype and phylogenetic analysis of the primary LHON mutations in North American Caucasian patients and

139 e penetrance and expressivity of the primary LHON-associated G11778A mutation in this Chinese family.

140 but who do not harbour one of these primary LHON mutations.

141 e cases and are thus designated as "primary" LHON mutations.

142 and Italian families with genetically proven LHON has excluded the presence of such a VLSL over 169 c

143 The remaining LHON mutations are rare.

144 Fifteen other "secondary" LHON mtDNA mutations have been identified, but their pat

145 ata indicate that the most common and severe LHON pathogenic mutations 11778 and 3460 predispose cell

146 on LHON mutation (11778) and the most severe LHON mutation (3460).

147 We observed that LHON cybrids were sensitized to Fas-dependent death.

148 The LHON-specific increase in transcript level was confirmed

149 ochondrial superoxide which is caused by the LHON mutations, possibly mediated through neuron-specifi

150 ent death in LHON cybrids was induced by the LHON pathogenic mutations.

151 y the cybridization process, and finally the LHON mutations.

152 gnificant increases in ROS production in the LHON-NT2 neurons versus controls, which is abolished by

153 e in choroidal thickness is a feature of the LHON acute stage, which follows the thickening of RNFL.

154 euron-specific degenerative phenotype of the LHON genotype, we have created cybrids using a neuronal

155 e, safety of the test article, rescue of the LHON mouse model, and the severe irreversible loss of vi

156 ive potential or increased cell death of the LHON-NT2 cells.

157 Pooling the LHON pedigree analyses yields a control-region divergenc

158 the reduced NT2 yield; and suggest that the LHON degenerative phenotype may be the result of an incr

159 We infer that the LHON genotype requires a differentiated neuronal environ

160 e have investigated the possibility that the LHON mutation confers a pro-apoptotic stimulus and have

161 In this study, we demonstrated that the LHON susceptibility allele (m.14502T > C, p.

162 used a similar approach were pooled with the LHON pedigree studies, totaling >2,600 transmission even

163 Three LHON mtDNA mutations at nucleotide positions 3460, 11778

164 Thus, LHON pathophysiology may result from oxidative stress.

165 tochondrial defective metabolism by treating LHON cybrid cells carrying the m.11778G>A mutation with

166 We describe two LHON pedigrees that harbour the same novel point mutatio

167 or lifelong disease prevention in unaffected LHON mutation carriers.

168 The undifferentiated LHON-NT2 mutant cells were not significantly different f

169 Of these, all patients with LMS and 25% with LHON were found to have an MRI appearance typical of MS.

170 The mutation associated with LHON, G391S, had little effect on these functions.

171 tDNA) mutations are strongly associated with LHON, only three account for roughly 90% of cases and th

172 d families with dystonia in association with LHON and mtDNA complex I gene mutations.

173 RIs of 30 patients with MS, 31 patients with LHON and 11 patients with LMS was conducted by three ind

174 Female patients with LHON had a significantly greater risk of having white ma

175 l patients with LMS and 26% of patients with LHON had white matter lesions.

176 onverted to affected status, 6 patients with LHON were identified.

177 ene should be sequenced in all patients with LHON who do not harbour one of the three common LHON mut

178 We enrolled 49 patients with LHON, 19 with Dominant Optic Atrophy (DOA) and 22 health

179 nerves examined at autopsy of patients with LHON.

180 clinical development of MS in patients with LHON.

181 from 74 members of a Brazilian pedigree with LHON carrying the homoplasmic 11778/ND4 mitochondrial DN

182 nder sequence for these Dutch pedigrees with LHON matches the control-region sequence that Macmillan

183 tch and French Canadian 14484 pedigrees with LHON share a common ancestor, that the single origin of

184 ntified in seven of the Dutch pedigrees with LHON, including six of those described by van Senus.

185 nder mtDNA of French Canadian pedigrees with LHON.

186 DNA sequences of two Canadian pedigrees with LHON.