Abstract:
:Dominant mutations in the mitochondrial paralogs coiled-helix-coiled-helix (CHCHD) domain 2 (C2) and CHCHD10 (C10) were recently identified as causing Parkinson's disease and amyotrophic lateral sclerosis/frontotemporal dementia/myopathy, respectively. The mechanism by which they disrupt mitochondrial cristae, however, has been uncertain. Using the first C2/C10 double knockout (DKO) mice, we report that C10 pathogenesis and the normal function of C2/C10 are intimately linked. Similar to patients with C10 mutations, we found that C2/C10 DKO mice have disrupted mitochondrial cristae, because of cleavage of the mitochondrial-shaping protein long form of OPA1 (L-OPA1) by the stress-induced peptidase OMA1. OMA1 was found to be activated similarly in affected tissues of mutant C10 knock-in (KI) mice, demonstrating that L-OPA1 cleavage is a novel mechanism for cristae abnormalities because of both C10 mutation and C2/C10 loss. Using OMA1 activation as a functional assay, we found that C2 and C10 are partially functionally redundant, and some but not all disease-causing mutations have retained activity. Finally, C2/C10 DKO mice partially phenocopied mutant C10 KI mice with the development of cardiomyopathy and activation of the integrated mitochondrial integrated stress response in affected tissues, tying mutant C10 pathogenesis to C2/C10 function.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Liu YT,Huang X,Nguyen D,Shammas MK,Wu BP,Dombi E,Springer DA,Poulton J,Sekine S,Narendra DPdoi
10.1093/hmg/ddaa077subject
Has Abstractpub_date
2020-06-03 00:00:00pages
1547-1567issue
9eissn
0964-6906issn
1460-2083pii
5825277journal_volume
29pub_type
杂志文章abstract::Renal-coloboma syndrome, also known as papillorenal syndrome, is an autosomal dominant human disorder in which optic disc coloboma is associated with kidney abnormalities. Mutations in the paired domain transcription factor PAX2 have been found to be the underlying cause of this disease. Disease severity varies betwee...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq457
更新日期:2011-01-15 00:00:00
abstract::Huntingtin-associated protein 1 (Hap1) is the first huntingtin interacting protein identified in a yeast two-hybrid screen. Although Hap1 expression has been demonstrated in neuronal and non-neuronal tissues, its molecular role is poorly understood. Recently, it has been shown that targeted disruption of Hap1 in mice ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddh328
更新日期:2004-12-15 00:00:00
abstract::A single-base substitution in the coding region of the androgen receptor (AR) gene caused complete androgen insensitivity in a patient with 46,XY karyotype. The mutation was a T-to-G transition in exon 6 and changed the codon 807 from ATG (methionine) to AGG (arginine) in the hormone-binding domain of the protein. The...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.11.1809
更新日期:1993-11-01 00:00:00
abstract::Family history of endometrial cancer increases the risk of developing the disease, but it is still largely unknown which germ-line genetic factors are involved in the aetiology of endometrial cancer. In a Swedish population-based case-control study including 705 cases and 1565 controls, we examined common variation in...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl451
更新日期:2007-01-15 00:00:00
abstract::This study provides first insights into the biosynthesis, structure, biochemistry and complex processing of the proteins encoded by hNOT/ALG3, the human counterpart of the Drosophila Neighbour of TID (NOT) and the yeast asparagine linked glycosylation 3 gene (ALG3), which encodes a mannosyltransferase. Unambiguous evi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy315
更新日期:2018-12-15 00:00:00
abstract::Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA,...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv286
更新日期:2015-10-15 00:00:00
abstract::The MELAS syndrome is a mitochondrial encephalomyopathy associated with a point mutation at nucleotide 3243 of mitochondrial DNA (mtDNA). The same mutation has also been found in patients with maternally inherited diabetes mellitus. The mutation occurs within a sequence needed for termination of mitochondrial transcri...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.5.525
更新日期:1993-05-01 00:00:00
abstract::Synapsin I (SynI) is a synaptic vesicle (SV) phosphoprotein playing multiple roles in synaptic transmission and plasticity by differentially affecting crucial steps of SV trafficking in excitatory and inhibitory synapses. SynI knockout (KO) mice are epileptic, and nonsense and missense mutations in the human SYN1 gene...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt071
更新日期:2013-06-01 00:00:00
abstract::Fragile X syndrome (FXS), a common inherited form of intellectual disability with learning deficits, results from a loss of fragile X mental retardation protein (FMRP). Despite extensive research, treatment options for FXS remain limited. Since FMRP is known to play an important role in adult hippocampal neurogenesis ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr501
更新日期:2012-02-01 00:00:00
abstract::The molecular genetic basis that leads to Lewy Body (LB) pathology in 15-20% of Alzheimer disease cases (LBV/AD) was largely unknown. Alpha-synuclein (SNCA) and Leucine-rich repeat kinase2 (LRRK2) have been implicated in the pathogenesis of Parkinson's disease (PD), the prototype of LB spectrum disorders. We tested th...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu196
更新日期:2014-09-15 00:00:00
abstract::Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by mutations in either of two genes, TSC1 or TSC2, resulting in the constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1). mTOR inhibitors are now considered the treatment of choice for TSC disease. A major path...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx214
更新日期:2017-09-01 00:00:00
abstract::Progressive forms of multiple sclerosis lead to chronic disability, substantial decline in quality of life and reduced longevity. It is often suggested that they occur independently of inflammation. Here we investigated the disease progression in mouse models carrying PLP1 point mutations previously found in patients ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw296
更新日期:2016-11-01 00:00:00
abstract::Emerging evidence implicates epigenetic mechanisms in the pathogenesis of rheumatoid arthritis (RA). In this study, we have investigated the role of histone deacetylase (HDAC) enzymes in RA synovial fibroblasts (RASFs), a key cellular mediator of cartilage and bone destruction and determined effects of HDAC1 inhibitio...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv258
更新日期:2015-10-01 00:00:00
abstract::Choroideremia (CHM) is an X-linked progressive eye disorder which results from defects in the human Rab escort protein-1 (REP-1) gene. A gene targeting approach was used to disrupt the mouse chm/rep-1 gene. Chimeric males transmitted the mutated gene to their carrier daughters but, surprisingly, these heterozygous fem...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.6.851
更新日期:1997-06-01 00:00:00
abstract::Nephropathic cystinosis, a lysosomal storage disease caused by mutations in the CTNS gene encoding the lysosomal cystine transporter cystinosin, is characterized by generalized proximal tubule (PT) dysfunction that progresses, if untreated, to end-stage renal disease. The pathogenesis of defective PT cellular transpor...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt617
更新日期:2014-05-01 00:00:00
abstract::The intraflagellar transport (IFT) machinery containing the IFT-A and IFT-B complexes mediates ciliary protein trafficking. Mutations in the genes encoding the six subunits of the IFT-A complex (IFT43, IFT121, IFT122, IFT139, IFT140, and IFT144) are known to cause skeletal ciliopathies, including cranioectodermal dysp...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx421
更新日期:2018-02-01 00:00:00
abstract::Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date...
journal_title:Human molecular genetics
pub_type: 杂志文章,meta分析
doi:10.1093/hmg/ddr270
更新日期:2011-09-15 00:00:00
abstract::The cone photoreceptor cyclic nucleotide-gated (CNG) channel is essential for central and color vision and visual acuity. Mutations in the channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophy. We investigated the gene expression profiles in mouse retina with CNG channel deficiency usin...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt245
更新日期:2013-10-01 00:00:00
abstract::Mutations in DNAJC13 gene have been linked to familial form of Parkinson's disease (PD) with Lewy pathology. DNAJC13 is an endosome-related protein and believed to regulate endosomal membrane trafficking. However, the mechanistic link between DNAJC13 mutation and α-synuclein (αSYN) pathology toward neurodegeneration r...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy003
更新日期:2018-03-01 00:00:00
abstract::Neural tube defects (NTDs) are birth defects that can be disabling or lethal and are second in their prevalence after cardiac defects among major human congenital malformations. Spina bifida is a NTD where the spinal cord is dysplastic, and the overlying spinal column is absent. At present, the molecular mechanisms un...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm333
更新日期:2008-02-15 00:00:00
abstract::Apoptosis is a morphologically distinct form of cell death involved in many physiological and pathological processes. The regulation of Fas/Apo-1 involved in membrane-mediated apoptosis has also been known to play crucial roles in many systems. More and more naturally occurring antisense RNAs are now known to regulate...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi156
更新日期:2005-06-01 00:00:00
abstract::Transcobalamin II (TC II) deficiency is a rare autosomal recessive disease leading to cobalamin (Cbl; Vitamin B12) deficiency characterized by failure to thrive, megaloblastic anemia, impaired immunodefence and neurological manifestations. By means of Southern blotting and sequence analysis of TC II cDNA amplified fro...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.10.1835
更新日期:1994-10-01 00:00:00
abstract::The rapid increase in the prevalence of type 2 diabetes (T2D) represents a major challenge for health care delivery worldwide. Identification of genes influencing individual susceptibility to disease offers a route to better understanding of the molecular mechanisms underlying pathogenesis, a necessary prerequisite fo...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddh057
更新日期:2004-04-01 00:00:00
abstract::Missense mutations in the gene, MAP3K1, are a common cause of 46,XY gonadal dysgenesis, accounting for 15-20% of cases [Ostrer, 2014, Disorders of sex development (DSDs): an update. J. Clin. Endocrinol. Metab., 99, 1503-1509]. Functional studies demonstrated that all of these mutations cause a protein gain-of-function...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz002
更新日期:2019-05-15 00:00:00
abstract::Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant disease caused by mutations in the gene encoding protein kinase C gamma (PKC gamma). We report an SCA14 family with a novel deletion of a termination-codon-containing region, resulting in a missense change and a C-terminal 13-amino-acid extension with inc...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp298
更新日期:2009-10-01 00:00:00
abstract::The members of the huntingtin-interacting protein-1 (HIP1) family, HIP1 and HIP1-related (HIP1r), are multi-domain proteins that interact with inositol lipids, clathrin and actin. HIP1 is over-expressed in a variety of cancers and both HIP1 and HIP1r prolong the half-life of multiple growth factor receptors. To better...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm076
更新日期:2007-06-01 00:00:00
abstract::Immunoglobulin E (IgE) concentration in serum is elevated in atopic diseases such as asthma. A large genomic region on chromosome 5 has previously been implicated in the control of IgE levels and bronchial hyperreactivity and may, therefore, harbor genes predisposing to asthma. In an effort to confirm this linkage and...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.12.2069
更新日期:1997-11-01 00:00:00
abstract::CUL4A and CUL4B are closely related cullin family members and can each assemble a Cullin-RING E3 ligase complex (CRL) and participate in a variety of biological processes. While the CRLs formed by the two cullin members may have common targets, the two appeared to have very different consequences when mutated or disru...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu503
更新日期:2015-02-01 00:00:00
abstract::Retinitis pigmentosa (RP), the most common form of inherited retinal degeneration, is clinically and genetically heterogeneous and can appear as syndromic or non-syndromic. Mucopolysaccharidosis type IIIC (MPS IIIC) is a lethal disorder, caused by mutations in the heparan-alpha-glucosaminide N-acetyltransferase (HGSNA...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv118
更新日期:2015-07-01 00:00:00
abstract::Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in TSC1 or TSC2 resulting in hyperactivity of the mammalian target of rapamycin and disabling brain lesions. These lesions contain misplaced neurons enriched in hypoxia-inducible factor 1a (HIF1a). However, the relationship between TSC1/2 and H...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt018
更新日期:2013-05-01 00:00:00