TY  - JOUR
AB  - Mitochondrial diseases are characterized by impaired energy production due to mitochondrial dysfunction. Despite advances in sequencing technologies, many cases remain genetically undiagnosed. We report two cases of mitochondrial disease harboring identical de novo variant in the non-coding RNA gene RNU4-2, previously associated with neurodevelopmental disorders. Re-analysis of whole genome sequencing data from 357 patients ascertained as possibly having mitochondrial disease (see Methods: Supplementary Data S1) identified two cases with a pathogenic RNU4-2 variant (GRCh38: chr.12:120291839: T > TA; NR_003137.2: n.64_65insT). Both patients exhibited decreased oxygen consumption rates and clinical features including developmental delay, microcephaly, short stature. This study provides the first evidence linking RNU4-2 variant to mitochondrial disease, expanding the phenotypic spectrum associated with this gene. Our findings highlight the importance of re-analyzing genomic data and considering non-coding RNA gene variants in mitochondrial disease diagnostics, potentially improving the diagnosis of previously unsolved cases.
AU  - Nakamura, K.*
AU  - Kishita, Y.*
AU  - Imai-Okazaki, A.*
AU  - Omata, T.*
AU  - Nodera, M.*
AU  - Yatsuka, Y.*
AU  - Sugiura, A.*
AU  - Matsumoto, N.*
AU  - Prokisch, H.
AU  - Matsumoto, H.*
AU  - Ohtake, A.*
AU  - Murayama, K.*
AU  - Okazaki, Y.*
C1  - 75221
C2  - 57863
CY  - Campus, 4 Crinan St, London, N1 9xw, England
TI  - Identification of a pathogenic RNU4-2 variant in patients with mitochondrial disease: Broadening the spectrum of non-coding RNA gene variants in mitochondrial dysfunction.
JO  - J. Hum. Genet.
PB  - Springernature
PY  - 2025
SN  - 1434-5161
ER  - 

TY  - JOUR
AB  - The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.
AU  - Crawford, A.A.*
AU  - Bankier, S.*
AU  - Altmaier, E.
AU  - Barnes, C.L.K.*
AU  - Clark, D.W.*
AU  - Ermel, R.*
AU  - Friedrich, N.*
AU  - van der Harst, P.*
AU  - Joshi, P.K.*
AU  - Karhunen, V.*
AU  - Lahti, J.*
AU  - Mahajan, A.*
AU  - Mangino, M.*
AU  - Nethander, M.*
AU  - Neumann, A.*
AU  - Pietzner, M.*
AU  - Sukhavasi, K.*
AU  - Wang, C.A.*
AU  - Bakker, S.J.L.*
AU  - Bjorkegren, J.L.M.*
AU  - Campbell, H.*
AU  - Eriksson, J.*
AU  - Gieger, C.
AU  - Hayward, C.*
AU  - Jarvelin, M.R.*
AU  - McLachlan, S.*
AU  - Morris, A.P.*
AU  - Ohlsson, C.*
AU  - Pennell, C.E.*
AU  - Price, J.*
AU  - Rudan, I.*
AU  - Ruusalepp, A.*
AU  - Spector, T.*
AU  - Tiemeier, H.*
AU  - Völzke, H.*
AU  - Wilson, J.F.*
AU  - Michoel, T.*
AU  - Timpson, N.J.*
AU  - Smith, G.D.*
AU  - Walker, B.R.*
C1  - 61082
C2  - 50040
CY  - Campus, 4 Crinan St, London, N1 9xw, England
SP  - 625–636
TI  - Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease.
JO  - J. Hum. Genet.
VL  - 66
PB  - Springernature
PY  - 2021
SN  - 1434-5161
ER  -