The exome sequencing identified the mutation in YARS2 encoding the mitochondrial tyrosyl-tRNA synthetase as a nuclear modifier for the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation.

Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder. Nuclear modifier genes are proposed to modify the phenotypic expression of LHON-associated mitochondrial DNA (mtDNA) mutations. By using an exome sequencing approach, we identified a LHON susceptibility allele (c.572G>T, p.191Gly>Val) in YARS2 gene encoding mitochondrial tyrosyl-tRNA synthetase, which interacts with m.11778G>A mutation to cause visual failure. We performed functional assays by using lymphoblastoid cell lines derived from members of Chinese families (asymptomatic individuals carrying m.11778G>A mutation, or both m.11778G>A and heterozygous p.191Gly>Val mutations and symptomatic subjects harboring m.11778G>A and homozygous p.191Gly>Val mutations) and controls lacking these mutations. The 191Gly>Val mutation reduced the YARS2 protein level in the mutant cells. The aminoacylated efficiency and steady-state level of tRNA(Tyr) were markedly decreased in the cell lines derived from patients both carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The failure in tRNA(Tyr) metabolism impaired mitochondrial translation, especially for polypeptides with high content of tyrosine codon such as ND4, ND5, ND6 and COX2 in cells lines carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The YARS2 p.191Gly>Val mutation worsened the respiratory phenotypes associated with m.11778G>A mutation, especially reducing activities of complexes I and IV. The respiratory deficiency altered the efficiency of mitochondrial ATP synthesis and increased the production of reactive oxygen species. Thus, mutated YARS2 aggravates mitochondrial dysfunctions associated with the m.11778G>A mutation, exceeding the threshold for the expression of blindness phenotype. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA mutation and mutated nuclear-modifier YARS2.

Altered amygdala-related structural covariance and resting-state functional connectivity in end-stage renal disease patients.

Depression and cognitive control deficits were frequently reported in concurrent end-stage renal disease (ESRD) patients. Neuroimaging studies indicated depression could be a risk factor for cognitive control deficits, and amygdala-related circuitry may play a critical role in this abnormal interaction. To investigate the potential relationship between depressive symptoms and cognitive control reduction in ESRD patients, T1-weighted and resting fMRI images were obtained in 29 ESRD patients and 29 healthy controls. Voxel-based morphometry (VBM), structural covariance (SC) analysis based on grey matter volume (GMV), and functional connectivity (FC) analysis were adopted. All subjects performed the Beck Depression Inventory (BDI) assessment and Stroop test. The patients also underwent blood biochemistry tests (urea, creatinine, phosphate, Ca2+, hematocrit, cystatin, hemoglobin). Compared with controls, GMV reductions were found mainly in the anterior cingulate cortex (ACC) and bilateral amygdala, and decreased SC was found between the amygdala and ACC in ESRD patients. This indicated that structural changes in the amygdala may be related to the GMV alterations in the ACC. Additionally, decreased FC between the amygdala and ACC was revealed in ESRD patients. Negative correlation was found between the FC of the amygdala-ACC and reaction delay during the Stroop test, but this correlation disappeared after controlling BDI. Stepwise regression analysis showed that the low level of hemoglobin was contributed to the reduced FC of the amygdala-ACC in ESRD patients. Our results demonstrated the abnormal interaction between depressive mood and cognitive control deficits in ESRD patients.

Functional connection between the stereotyped behavior and the motor front area in children with autism.

OBJECT: Autism spectrum disorders (ASD) is characterized by stereotyped behavior, attention deficit and/or impaired sensory perception to external stimuli. Its neurobiological mechanisms remain unclear. In this study we examined the resting-state functional connectivity of the premotor area and investigated its correlation with behavioral variables to determine whether connectivity alterations can distinguish ASD from healthy controls. METHODS: 39 children with ASD and 42 healthy children with matched age, sex and intelligence were recruited. All the 81 subjects had behavioral index evaluation and underwent resting-state functional magnetic resonance imaging (fMRI) scans. After MRI data preprocessing, the left and right premotor areas were selected as region of interest (ROI) seeds to perform functional connectivity. Groups were compared, and the correlation between functional connectivity and behavioral indicators was analyzed. RESULTS: Compared with healthy controls, ASD children showed significantly increased functional connectivity between the left premotor area and the posterior cingulate gyrus or anterior lobe of wedge, but functional connectivity between the left premotor area and the left insular lobe was decreased (p < 0.05, FDR correction). In addition, the connectivity between the left premotor area and the left insular lobe was negatively correlated with the behavioral scores (p < 0.05). CONCLUSION: Imbalanced premotor functional connectivity may be one possible mechanism of stereotyped behavior in ASD.

[The role of MT-ND1 m.3635G>A mutation in Leber's hereditary optic neuropathy].

OBJECTIVE: To investigate the role of MT-ND1 m.3635G>A mutation in the pathogenesis of Leber's hereditary optic neuropathy (LHON). METHODS: Biochemical characteristics including the activity of complex Ⅰ, ATP production and oxygen consumption rate among lymphoblastoid cell lines derived from 3 carriers, 3 affected matrilineal relatives of the families and 3 controls were compared. RESULTS: Comparison of mitochondrial functions in lymphoblastoid cell lines of the carriers, patients and controls showed a 51.0% decrease in the activity of complex Ⅰ in patients compared with controls (P<0.05). The m.3635G>A mutation has resulted in decreased efficiency of ATP synthesis (P<0.05). Comparison of oxygen consumption rate showed that the basal OCR (P<0.05), ATP-linked OCR (P<0.05) and the maximum OCR (P<0.05) have all reduced to some extent compared with the controls. CONCLUSION: These results showed that m.3635G>A, as a LHON-associated mutation, can lead to mitochondrial dysfunction.

[Identification of mitochondrial DNA ND1 T3866C mutation in three ethnic Han Chinese families affected with Leber's hereditary optic neuropathy].

OBJECTIVE: To report on the clinical, genetic and molecular characteristics of three ethnic Han Chinese families affected with Leber's hereditary optic neuropathy (LHON). METHODS: The three families were all diagnosed with LHON. Ophthalmologic examinations were conducted on the probands . The ND1, ND4 and ND6 genes of the mitochondrial DNA (mtDNA) were amplified with PCR respectively for the screening of three primary mutations G3460A, G11778A and T14484C. The entire mtDNA of the probands were also amplified by PCR. RESULTS: Analysis of mtDNA in the three pedigrees has failed to find the presence of the three LHON associated mutations but presence of a homoplastic ND1 T3866C mutation in all probands and their matrilineal relatives . The probands had different levels of visual impairment. The penetrance in the three families has been calculated as 12.5%, 11.1% and 33.3%, respectively. The T3866C mutation has resulted in replacement of isoleucine at position 187 with theronine. The isoleucine at position 187 is located at one of the transmembrane domains of ND1 polypeptide. CONCLUSION: Above results have suggested that the ND1 T3866C mutation might have been involved in the pathogenesis of LHON in the three Chinese families studied.

[A novel mutation T8821G in mitochondrial DNA may be associated with Leber's hereditary optic neuropathy].

OBJECTIVE: To report on clinical, genetic and molecular characterization of two Chinese families with Leber's hereditary optic neuropathy. METHODS: Ophthalmological examinations have revealed variable severity and age at onset of visual loss among the probands and other matrilineal relatives of both families. The entire mitochondrial genome of the two probands was amplified with PCR in 24 overlapping fragments using sets of oligonucleotide primers. RESULTS: The ophthalmological examinations showed that penetrance was 12.5% and 30.0% respectively in the two families. Sequence analysis of the complete mitochondrial genomes in these pedigrees has identified unreported homoplasmic T8821G mutation in the ATPase 6 gene and distinct sets of polymorphisms belonging to haplogroups M10a. The T8821G mutation has occurred at the extremely conserved nucleotide (conventional position 99) of the ATPase6. Thus, this mutation may alter structural formation of ATPase6, thereby leading to failure in the synthesis of ATP involved in visual impairment. CONCLUSION: Above observations have suggested that the ATPase6 T8821G mutation may be involved in the pathogenesis of optic neuropathy in these families.

Abnormal interaction between cognitive control network and affective network in patients with end-stage renal disease.

End-stage renal disease (ESRD) is a common complicated disorder that is generally associated with an altered central nervous system and cognitive impairment. Neuroimaging studies have recorded aberrant brain circuits in patients with ESRD that were closely associated with abnormal clinical manifestations. However, whether the altered interaction was within and/or between these circuits is largely unclear. We investigated brain topological organization and/or module interaction by employing resting-state functional magnetic resonance imaging (rs-fMRI) and modularity network analysis in 24 patients with ESRD and 20 age- and gender-matched healthy control (HC) subjects. Stroop task was used to evaluate the performance of cognitive control in all subjects. At the global level, ESRD patients exhibited significantly decreased global and local efficiency which were mainly related to abnormal functional connectivity of the amygdala and inferior frontal gyrus (IFG). Stepwise regression analysis was applied to estimate the relationships between network efficiency and blood biochemistry level (urea, creatine, phosphate, Ca2+, hematocrit, cystatin, hemoglobin levels, parathyroid hormone, K+ and Na+), and only the hematocrit level was significantly associated with global efficiency in patients with ESRD. At the modular level, we discovered an aberrant brain interaction between the amygdala- and IFG-related circuits in the ESRD group, and the regional efficiency of the amygdala was observably relative to the performance of cognitive control in patients with ESRD. Our results suggested that ESRD exhibited aberrant brain functional topological organization and module-level interaction between the affective and cognitive control circuits, providing crucial insights into the pathophysiological mechanism of ESRD patients.

Mitochondrial ND1 Variants in 1281 Chinese Subjects With Leber's Hereditary Optic Neuropathy.

PURPOSE: The purpose of this study was to investigate the mutational incidence and spectrum of mitochondrial ND1 gene in subjects with Leber's hereditary optic neuropathy (LHON). METHODS: A cohort of 1281 Han Chinese probands and 478 control subjects underwent sequence analysis of mitochondrial (mt)DNA. Resultant variants were evaluated for evolutionary conservation, allelic frequencies, and structural and functional consequences. Respiratory complex activities were measured using lymphoblastoid cell lines derived from 25 probands carrying the mtDNA mutation and 3 controls. RESULTS: Mutational analysis identified 178 (70 missense and 108 silent) variants in the MT-ND1 gene. The incidences of known m.3460G>A, m.3635G>A, m.3733G>A, m.3866T>C, and m.3394T>C mutations were 1.33%, 0.86%, 0.08%, 0.55%, and 2.97%, respectively. Fifteen novel putative mutations were identified in 27 probands, translated into 2.1% cases of this cohort. The activity of complex I in mutant cell lines carrying one of putative mutations ranged from 66% to 76% of the average values in control cell lines, whereas activities of complexes II, III, and IV in mutant cells were comparable with those in controls. The low penetrances of optic neuropathy were observed in pedigrees carrying novel putative mutation(s). Moreover, mtDNAs in 101 probands carrying the MT-ND1 mutation(s) were widely dispersed among 15 Eastern Asian haplogroups. In particular, the occurrences of haplogroups M, M9, and M10 in patients carrying the ND1 mutations were higher than those in controls. CONCLUSIONS: These data demonstrated that the MT-ND1 gene is a hot spot for mutations associated with LHON. Our findings may provide valuable information for pathophysiology, management, and genetic counseling of LHON.

Children with congenital cystic adenomatoid malformation of the lung CT diagnosis.

In this study, we aim to investigate the imaging appearances of congenital cystic adenomatoid malformation (CCAM) of the lung, and to enhance the understanding of this disease. A total of 11 cases with CCAM of the lung were confirmed by surgery and pathology. Preoperative chest computed tomography (CT) scan was performed in all patients, and high resolution CT scan was performed in lesion areas of 7 cases. Our results showed that there were 3 cases involving left and right lung, 5 cases involving right lung and 3 cases involving left lung. CT scan showed 6 cases with single or multiple air-filled cavities (> 2 cm in diameter) and 5 cases with multiple honeycomb-like cysts (< 1 cm in diameter). The cysts of CCAM contained air in 9 cases and a small amount of liquid in 2 cases. The complications of CCAM included different degree of emphysema in 7 patients, mediastinal hernia in 5 cases and congenital pulmonary sequestration in 1 case. All lesions have certain space-occupying effect. In conclusion, CT manifestation of CCAM of lung has certain characteristics and can provide reliable information for diagnosis of the disease.