Abstract:
:An infant presented with fatal infantile lactic acidosis and cardiomyopathy, and was found to have profoundly decreased activity of respiratory chain complex I in muscle, heart and liver. Exome sequencing revealed compound heterozygous mutations in NDUFB10, which encodes an accessory subunit located within the PD part of complex I. One mutation resulted in a premature stop codon and absent protein, while the second mutation replaced the highly conserved cysteine 107 with a serine residue. Protein expression of NDUFB10 was decreased in muscle and heart, and less so in the liver and fibroblasts, resulting in the perturbed assembly of the holoenzyme at the 830 kDa stage. NDUFB10 was identified together with three other complex I subunits as a substrate of the intermembrane space oxidoreductase CHCHD4 (also known as Mia40). We found that during its mitochondrial import and maturation NDUFB10 transiently interacts with CHCHD4 and acquires disulfide bonds. The mutation of cysteine residue 107 in NDUFB10 impaired oxidation and efficient mitochondrial accumulation of the protein and resulted in degradation of non-imported precursors. Our findings indicate that mutations in NDUFB10 are a novel cause of complex I deficiency associated with a late stage assembly defect and emphasize the role of intermembrane space proteins for the efficient assembly of complex I.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Friederich MW,Erdogan AJ,Coughlin CR 2nd,Elos MT,Jiang H,O'Rourke CP,Lovell MA,Wartchow E,Gowan K,Chatfield KC,Chick WS,Spector EB,Van Hove JLK,Riemer Jdoi
10.1093/hmg/ddw431subject
Has Abstractpub_date
2017-02-15 00:00:00pages
702-716issue
4eissn
0964-6906issn
1460-2083pii
ddw431journal_volume
26pub_type
杂志文章abstract::Prolactinomas are the most frequent type of pituitary tumors, which represent 10-20% of all intracranial neoplasms in humans. Prolactinomas develop in mice lacking the prolactin receptor (PRLR), which is a member of the cytokine receptor superfamily that signals via Janus kinase-2-signal transducer and activator of tr...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy396
更新日期:2019-03-15 00:00:00
abstract::Spinocerebellar ataxia 2 (SCA2) is an autosomal dominant neurodegenerative disorder that results from the expansion of a cryptic CAG repeat within the exon 1 of the SCA2 gene. The CAG repeat in normal individuals varies in length from 14 to 31 repeats and is frequently interrupted by one or more CAA triplets, whereas ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.21.2437
更新日期:2001-10-01 00:00:00
abstract::Systemic sclerosis (SSc) is complex autoimmune disease affecting the connective tissue; influenced by genetic and environmental components. Recently, we performed the first successful genome-wide association study (GWAS) of SSc. Here, we perform a large replication study to better dissect the genetic component of SSc....
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds099
更新日期:2012-06-15 00:00:00
abstract::Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterized by brittle hair and also associated with various systemic symptoms. Approximately half of TTD patients exhibit photosensitivity, resulting from the defect in the nucleotide excision repair. Photosensitive TTD is due to mutations in three ge...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddp390
更新日期:2009-10-15 00:00:00
abstract::Autosomal dominant lateral temporal epilepsy (EPT; OMIM 600512) is a form of epilepsy characterized by partial seizures, usually preceded by auditory signs. The gene for this disorder has been mapped by linkage studies to chromosomal region 10q24. Here we show that mutations in the LGI1 gene segregate with EPT in two ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.9.1119
更新日期:2002-05-01 00:00:00
abstract::The DTNBP1 gene, encoding dysbindin, is now generally considered to be a susceptibility gene for schizophrenia. However, the confidence with which this hypothesis can be held has to be tempered by the poor reproducibility between studies in terms of the exact nature of the associated haplotypes, by the failure so far ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi199
更新日期:2005-07-15 00:00:00
abstract::Epilepsy, deafness, onychodystrophy, osteodystrophy and intellectual disability are associated with a spectrum of mutations of human TBC1D24. The mechanisms underlying TBC1D24-associated disorders and the functions of TBC1D24 are not well understood. Using CRISPR-Cas9 genome editing, we engineered a mouse with a prema...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy445
更新日期:2019-05-01 00:00:00
abstract::Although genetic variations in several genes encoding for synaptic adhesion proteins have been found to be associated with autism spectrum disorders, one of the most consistently replicated genes has been CNTNAP2, encoding for contactin-associated protein-like 2 (CASPR2), a multidomain transmembrane protein of the neu...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds320
更新日期:2012-11-01 00:00:00
abstract::During human spermatogenesis, germ cells undergo dynamic changes in chromatin organization/re-packaging and in transcriptomes. In order to better understand the underlying mechanism(s), scATAC-Seq of 5376 testicular cells from 3 normal men were performed. Data were analyzed in parallel with the scRNA-Seq data of human...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddab006
更新日期:2021-01-12 00:00:00
abstract::Mutations in fibroblast growth factor receptors (FGFRs) cause human birth defect syndromes and are associated with a variety of cancers. Although forced expression of mutant activated FGFRs has been shown to oncogenically transform some immortal cell types, their activity in primary cells remains unclear. Here, we sho...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp195
更新日期:2009-07-15 00:00:00
abstract::Despite advancements in genetic studies, it is difficult to understand and characterize the functional relevance of disease-associated genetic variants, especially in the context of a complex multifactorial disease such as multiple sclerosis (MS). As a large proportion of expression quantitative trait loci (eQTLs) are...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy001
更新日期:2018-03-01 00:00:00
abstract::The genes of the piwi family are defined by conserved PAZ and Piwi domains and play important roles in stem-cell self-renewal, RNA silencing and translational regulation in various organisms. Both, mouse and human Piwil2 genes, members of the piwi gene family, are specifically expressed in testis. We report here enhan...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi430
更新日期:2006-01-15 00:00:00
abstract::Gene amplification plays a critical role in tumor progression. Hence, understanding the factors triggering this process in human cancers is an important concern. Unfortunately, the structures formed at early stages are usually unavailable for study, hampering the identification of the initiating events in tumors. Here...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.23.2887
更新日期:2002-11-01 00:00:00
abstract::Many genetic mutations have been identified as monogenic causes of nephrotic syndrome (NS), but important knowledge gaps exist in the roles of these genes in kidney cell biology and renal diseases. More animal models are needed to assess the functions of these genes in vivo, and to determine how they cause NS in a tim...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw428
更新日期:2017-02-15 00:00:00
abstract::Osteoarthritis (OA), a common skeletal disease, is a leading cause of disability among the elderly populations. OA is characterized by gradual loss of articular cartilage, but the etiology and pathogenesis of OA are largely unknown. Epidemiological and genetic studies have demonstrated that genetic factors play an imp...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi093
更新日期:2005-04-15 00:00:00
abstract::The lifetime accumulation of low-abundance, somatic mtDNA re-arrangements (sublimons) has been proposed as a potential contributor to aging, and also to diseases such as cardiomyopathy or coronary heart disease. Tissue-specific sublimons, varying in abundance by three orders of magnitude between individuals, have rece...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.3.317
更新日期:2002-02-01 00:00:00
abstract::Genetics of Holoprosencephaly (HPE), a congenital malformation of the developing human forebrain, is due to multiple genetic defects. Most genes that have been implicated in HPE belong to the sonic hedgehog signaling pathway. Here we describe a new candidate gene isolated from array comparative genomic hybridization r...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq556
更新日期:2011-03-15 00:00:00
abstract::Mutations in the survival motor neuron (SMN1) gene lead to the neuromuscular disease spinal muscular atrophy (SMA). Although SMA is primarily considered as a motor neuron disease, the importance of muscle defects in its pathogenesis has not been fully examined. We use both primary cell culture and two different SMA mo...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu142
更新日期:2014-08-15 00:00:00
abstract::Expression of misfolded protein in cultured cells frequently leads to the formation of juxtanuclear inclusions that have been termed 'aggresomes'. Aggresome formation is an active cellular response that involves trafficking of the offending protein along microtubules, reorganization of intermediate filaments and recru...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg074
更新日期:2003-04-01 00:00:00
abstract::Newborn screening (NBS) for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) revealed a higher birth prevalence and genotypic variability than previously estimated, including numerous novel missense mutations in the ACADM gene. On average, these mutations are associated with milder biochemical phenotypes raising...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp079
更新日期:2009-05-01 00:00:00
abstract::The breast cancer susceptibility gene BRCA2 encodes a protein of 3418 amino acids which does not exhibit substantial sequence similarity to any other protein in the public databases. A dot matrix comparison of BRCA2 with itself revealed an eight times repeated motif in the segment of the protein encoded by exon 11. As...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.1.53
更新日期:1997-01-01 00:00:00
abstract::Mutations in glucokinase (GCK) cause a spectrum of glycemic disorders. Heterozygous loss-of-function mutations cause mild fasting hyperglycemia irrespective of mutation severity due to compensation from the unaffected allele. Conversely, homozygous loss-of-function mutations cause permanent neonatal diabetes requiring...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu360
更新日期:2014-12-15 00:00:00
abstract::Transposable elements (TEs) are major sources of new exons in higher eukaryotes. Almost half of the human genome is derived from TEs, and many types of TEs have the potential to exonize. In this work, we conducted a large-scale analysis of human exons derived from mammalian-wide interspersed repeats (MIRs), a class of...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp152
更新日期:2009-06-15 00:00:00
abstract::Germline mutations in the RB1 gene confer hereditary predisposition to retinoblastoma. The majority of these mutations occur de novo and differ from one patient to another. Cytogenetics and Southern blotting were shown to detect less than 15% of constitutional rearrangements. In this study we used the polymerase chain...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.7.975
更新日期:1993-07-01 00:00:00
abstract::Autism is a heterogeneous condition that is likely to result from the combined effects of multiple genetic factors interacting with environmental factors. Given its complexity, the study of autism associated with Mendelian single gene disorders or known chromosomal etiologies provides an important perspective. We used...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm116
更新日期:2007-07-15 00:00:00
abstract::Niemann-Pick C1 (NPC1) disease is a rare, neurodegenerative lysosomal cholesterol storage disorder, typified by progressive cognitive and motor function impairment. Affected individuals usually succumb to the disease in adolescence. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) has emerged as a promising intervention that ...
journal_title:Human molecular genetics
pub_type: 临床试验,杂志文章
doi:10.1093/hmg/ddu331
更新日期:2014-11-15 00:00:00
abstract::Homozygosity for Cst6 null alleles causes the phenotype of the ichq mouse, which is a model for human harlequin ichthyosis (OMIM 242500), a genetically heterogeneous group of keratinization disorders. Here we report evidence for the mechanism by which deficiency of the cysteine protease inhibitor cystatin M/E (the Cst...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddh115
更新日期:2004-05-15 00:00:00
abstract::Waardenburg syndrome type 2 (WS2) is an autosomal dominant disorder characterized by a combination of pigmentary and auditory abnormalities. Approximately 20% of WS2 cases are associated with mutations in the gene encoding microphthalmia-associated transcription factor (MITF). MITF plays a critical role in the develop...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/8.8.1431
更新日期:1999-08-01 00:00:00
abstract::Fourteen neurological diseases have been associated with the expansion of trinucleotide repeat regions. These diseases have been categorized into those that give rise to the translation of toxic polyglutamine proteins and those that are untranslated. Thus far, compelling evidence has not surfaced for the inclusion of ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.15.1531
更新日期:2001-07-15 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