BackgroundNeuronal intranuclear inclusion disease (NIID) is a heterogenous neurodegenerative disorder named after its pathological features. It has long been considered a disease of genetic origin. Recently, the GGC repeated expansion in the 5′-untranslated region (5′UTR) of the NOTCH2NLC gene has been found in adult-onset NIID in Japanese individuals. This study was aimed to investigate the causative mutations of NIID in Chinese patients.MethodsFifteen patients with NIID were identified from five academic neurological centres. Biopsied skin samples were analysed by histological staining, immunostaining and electron microscopic observation. Whole-genome sequencing (WGS) and long-read sequencing (LRS) were initially performed in three patients with NIID. Repeat-primed PCR was conducted to confirm the genetic variations in the three patients and the other 12 cases.ResultsOur patients included 14 adult-onset patients and 1 juvenile-onset patient characterised by degeneration of multiple nervous systems. All patients were identified with intranuclear inclusions in the nuclei of fibroblasts, fat cells and ductal epithelial cells of sweat glands. The WGS failed to find any likely pathogenic variations for NIID. The LRS successfully identified that three patients with adult-onset NIID showed abnormalities of GGC expansion in 5′UTR of the NOTCH2NLC gene. The GGC repeated expansion was further confirmed by repeat-primed PCR in seven familial cases and eight sporadic cases.ConclusionOur findings provided evidence that confirmed the GGC repeated expansion in the 5′UTR of the NOTCH2NLC gene is associated with the pathogenesis of NIID. Additionally, the GGC expansion was not only responsible for adult-onset patients, but also responsible for juvenile-onset patients.
DNA methylation (DNAm) clocks are important biomarkers of cellular aging and are associated with a variety of age-related chronic diseases and all-cause mortality. Examining the relationship between education and lifestyle risk factors for age-related diseases and multiple DNAm clocks can increase the understanding of how risk factors contribute to aging at the cellular level. This study explored the association between education or lifestyle risk factors for age-related diseases and the acceleration of four DNAm clocks, including intrinsic (IEAA) and extrinsic epigenetic age acceleration (EEAA), PhenoAge acceleration (PhenoAA), and GrimAge acceleration (GrimAA) in the African American participants of the Genetic Epidemiology Network of Arteriopathy. We performed both cross-sectional and longitudinal analyses. In cross-sectional analyses, gender, education, BMI, smoking, and alcohol consumption were all independently associated with GrimAA, whereas only some of them were associated with other clocks. The effect of smoking and education on GrimAA varied by gender. Longitudinal analyses suggest that age and BMI continued to increase GrimAA, and that age and current smoking continued to increase PhenoAA after controlling DNAm clocks at baseline. In conclusion, education and common lifestyle risk factors were associated with multiple DNAm clocks. However, the association with each risk factor varied by clock, which suggests that different clocks may capture adverse effects from different environmental stimuli.
The MoxR family of AAA+ ATPases is widespread throughout bacteria and archaea but remains poorly characterized. We recently found that the Escherichia coli MoxR protein, RavA (Regulatory ATPase variant A), tightly interacts with the inducible lysine decarboxylase, LdcI/CadA, to form a unique cage-like structure. Here, we present the X-ray structure of RavA and show that the αβα and all-α subdomains in the RavA AAA+ module are arranged as in magnesium chelatases rather than as in classical AAA+ proteins. RavA structure also contains a discontinuous triple-helical domain as well as a β-barrel-like domain forming a unique fold, which we termed the LARA domain. The LARA domain was found to mediate the interaction between RavA and LdcI. The RavA structure provides insights into how five RavA hexamers interact with two LdcI decamers to form the RavA-LdcI cage-like structure.acid stress | alarmone P roteins of the AAA+ superfamily (ATPases Associated with diverse cellular Activities) are highly ubiquitous and found in all kingdoms of life. These proteins are characterized by the structural conservation of a central ATPase domain of about 250 amino acids called the AAA+ module (1, 2). AAA+ ATPases employ the energy derived from ATP hydrolysis to remodel proteins, DNA, or RNA. Typically, the AAA+ domain can be divided into two structural subdomains, an N-terminal P-loop NTPase αβα subdomain that is connected to a smaller C-terminal all-α subdomain. The αβα subdomain adopts a Rossman fold and contains several motifs involved in ATP binding and hydrolysis, including Walker A, Walker B, and Sensor 1 signature sequences (3-6). The all-α subdomain, which contains the Sensor 2 motif (7), is much less conserved across AAA+ proteins.AAA+ proteins form oligomers, usually hexameric rings, in the presence of nucleotides (8). The ATP-binding pocket is located at the interface between two neighboring subunits. A highly conserved arginine from one subunit, called an "arginine finger," contacts the γ-phosphate of bound ATP of the neighboring subunit (9). AAA+ proteins typically go through a cycle of ATP binding, hydrolysis, and release of products. This reaction cycle results in a series of conformational changes and mechanical movements that allow these proteins to exert their activity either directly or through domains attached to the AAA+ domain (3, 10).The RavA protein (Regulatory ATPase Variant A) belongs to the MoxR AAA+ family (11). Limited experimental data suggest a function of MoxR AAA+ proteins as chaperones in the assembly of multimeric complexes and a possible role in small molecule cofactor insertion/removal (11). However, how these proteins act is not clear. In Escherichia coli, the ravA gene is in an operon with another gene of unknown function, which we termed viaA, and the operon is under the control of σ S promoter, suggesting a function of RavA and ViaA under stress conditions (12). This is further substantiated by our discovery that RavA physically interacts with the inducible lysine decarboxylase enzyme, LdcI/CadA...
Objective-To determine susceptibility genes for high myopia in Singaporean Chinese.Design-A meta-analysis of two genome wide association (GWA) datasets in Chinese and a follow-up replication cohort in Japanese.Participants and Controls-Two independent datasets of Singaporean Chinese individuals aged 10-12 years (SCORM --Singapore Cohort Study of the Risk factors for Myopia: cases=65, controls=238) and aged > 21 years (SP2 --Singapore Prospective Study Program: cases=222, controls=435) for GWA studies, and a Japanese dataset aged >20 years (cases=959, controls=2128) for replication.Methods-Genomic DNA samples from SCORM and SP2 were genotyped using various Illumina Beadarray platforms (> HumanHap 500). Single-locus association tests were conducted for each dataset with meta-analysis using pooled z-scores. The top-ranked genetic markers were examined for replication in Japanese dataset. Fisher's P was calculated for the combined analysis of all three cohorts.Main outcome measures-High myopia, defined by spherical equivalent (SE) ≤ −6.00 diopters (D); controls defined by SE between −0.50D and +1.00D. SNPs (rs12716080 and rs6885224) in the gene CTNND2 on chromosome 5p15 ranked top in the meta-analysis of our Chinese datasets (meta-P = 1.14×10 −5 and meta-P = 1.51×10 −5 , respectively) with strong supporting evidence in each individual dataset analysis (Max P = 1.85.x10 −4 in SCORM: Max P = 8.8×10 −3 in SP2). Evidence of replication was observed in Japanese dataset for rs6885224 (P = 0.035, meta-P of three datasets: 7.84×10 −6 ). Results-TwoConclusion-This study identified strong association of CTNND2 for high myopia in Asian datasets. The CTNND2 gene maps to a known high myopia linkage region on chromosome 5p15. Keywords myopia; genome wide association; CTNND2; single nucleotide polymorphism; genetics Myopia is a common eye disorder and a major public health concern in urban East Asian populations, affecting nearly 40% of Chinese persons aged 40 to 79 years1 -3 . High myopia, defined by spherical equivalent (SE) ≤ −5.00 diopter (D) or SE ≤ −6.00 D for at least one eye, is associated with significant ocular morbidity, including retinal detachment and myopic macular degeneration 4; 5.The genetic etiologic basis of myopia and high myopia is supported by data from familial aggregation, segregation, and twin studies [5][6][7][8][9][10][11][12] . The relative risk of myopia in siblings of a person with myopia (λ s ) has been estimated to be strongest in high myopia (SE ≤ −6.00 D; λ s = 5 -20), and moderate for lower degrees of myopia (SE: −1.00 to −3.00D; λ s =1.5-3)5 ;12 . To date, more than 15 chromosomal regions (or genetic loci, designated as MYP loci) have been mapped for myopia-related phenotypes by genome wide linkage scans, and many candidate genes have been reported by association and sequencing studies 13 . However, no gene implicated in myopia has been consistently replicated.Genome wide association (GWA) studies have become an important and unbiased approach to aid in the search for causal sequence va...
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