scholarly journals Mutated CCDC51 Coding for a Mitochondrial Protein, MITOK Is a Candidate Gene Defect for Autosomal Recessive Rod-Cone Dystrophy

2021 ◽  
Vol 22 (15) ◽  
pp. 7875
Author(s):  
Christina Zeitz ◽  
Cécile Méjécase ◽  
Christelle Michiels ◽  
Christel Condroyer ◽  
Juliette Wohlschlegel ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Mitochondrial Protein ◽  
Coiled Coil ◽  
Cone Dystrophy ◽  
Gene Defect ◽  
Rare Mutation ◽  
Coiled Coil Domain ◽  
Retinal Disorders ◽  
First Time ◽  
Inherited Retinal Disorders

The purpose of this work was to identify the gene defect underlying a relatively mild rod-cone dystrophy (RCD), lacking disease-causing variants in known genes implicated in inherited retinal disorders (IRD), and provide transcriptomic and immunolocalization data to highlight the best candidate. The DNA of the female patient originating from a consanguineous family revealed no large duplication or deletion, but several large homozygous regions. In one of these, a homozygous frameshift variant, c.244_246delins17 p.(Trp82Valfs*4); predicted to lead to a nonfunctional protein, was identified in CCDC51. CCDC51 encodes the mitochondrial coiled-coil domain containing 51 protein, also called MITOK. MITOK ablation causes mitochondrial dysfunction. Here we show for the first time that CCDC51/MITOK localizes in the retina and more specifically in the inner segments of the photoreceptors, well known to contain mitochondria. Mitochondrial proteins have previously been implicated in IRD, although usually in association with syndromic disease, unlike our present case. Together, our findings add another ultra-rare mutation implicated in non-syndromic IRD, whose pathogenic mechanism in the retina needs to be further elucidated.

scholarly journals Targeted Next Generation Sequencing Identifies Novel Mutations inRP1as a Relatively Common Cause of Autosomal Recessive Rod-Cone Dystrophy

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Said El Shamieh ◽  
Elise Boulanger-Scemama ◽  
Marie-Elise Lancelot ◽  
Aline Antonio ◽  
Vanessa Démontant ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Autosomal Recessive ◽  
Cone Dystrophy ◽  
Next Generation ◽  
Prevalence Studies ◽  
Targeted Next Generation Sequencing ◽  
Retinal Disorders ◽  
Inherited Retinal Disorders ◽  
Generation Sequencing ◽  
Index Cases

We report ophthalmic and genetic findings in families with autosomal recessive rod-cone dystrophy (arRCD) andRP1mutations. Detailed ophthalmic examination was performed in 242 sporadic and arRCD subjects. Genomic DNA was investigated using our customized next generation sequencing panel targeting up to 123 genes implicated in inherited retinal disorders. Stringent filtering coupled with Sanger sequencing and followed by cosegregation analysis was performed to confirm biallelism and the implication of the most likely disease causing variants. Sequencing identified 9RP1mutations in 7 index cases. Eight of the mutations were novel, and all cosegregated with severe arRCD phenotype, found associated with additional macular changes. Among the identified mutations, 4 belong to a region, previously associated with arRCD, and 5 others in a region previously associated with adRCD. Our prevalence studies showed thatRP1mutations account for up to 2.5% of arRCD. These results point out for the necessity of sequencingRP1when genetically investigating sporadic and arRCD. It further highlights the interest of unbiased sequencing technique, which allows investigating the implication of the same gene in different modes of inheritance. Finally, it reports that different regions ofRP1can also lead to arRCD.

scholarly journals Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

2011 ◽  
Vol 208 (8) ◽  
pp. 1635-1648 ◽  
Author(s):  
Luyan Liu ◽  
Satoshi Okada ◽  
Xiao-Fei Kong ◽  
Alexandra Y. Kreins ◽  
Sophie Cypowyj ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Coiled Coil ◽  
Cellular Responses ◽  
Chronic Mucocutaneous Candidiasis ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Mucocutaneous Candidiasis ◽  
Coiled Coil Domain ◽  
Whole Exome ◽  
Ifn Γ

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.

scholarly journals Coiled Coil Domain-containing Protein 56 (CCDC56) Is a Novel Mitochondrial Protein Essential for CytochromecOxidase Function

2012 ◽  
Vol 287 (29) ◽  
pp. 24174-24185 ◽  
Author(s):  
Susana Peralta ◽  
Paula Clemente ◽  
Álvaro Sánchez-Martínez ◽  
Manuel Calleja ◽  
Rosana Hernández-Sierra ◽  
...  
Keyword(s):  
Mitochondrial Protein ◽  
Coiled Coil ◽  
Coiled Coil Domain

scholarly journals A stutter in the coiled coil domain of E.coli co-chaperone GrpE connects structure with function

2020 ◽  
Author(s):  
Tulsi Upadhyay ◽  
Vaibhav V Karekar ◽  
Ishu Saraogi
Keyword(s):  
Heat Stress ◽  
Coiled Coil ◽  
Bacterial Survival ◽  
Nucleotide Exchange ◽  
E Coli ◽  
Coiled Coil Domain ◽  
Nucleotide Exchange Factor ◽  
First Time

AbstractIn bacteria, the co-chaperone GrpE acts as a nucleotide exchange factor and plays an important role in controlling the chaperone cycle of DnaK. The functional form of GrpE is an asymmetric dimer, consisting of a long non-ideal coiled-coil. During heat stress, this region partially unfolds and prevents DnaK nucleotide exchange, ultimately ceasing the chaperone cycle. In this study, we elucidate the role of thermal unfolding of the coiled-coil domain of E. coli GrpE in regulating its co-chaperonic activity. The presence of a stutter disrupts the regular heptad arrangement typically found in an ideal coiled coil resulting in structural distortion. Introduction of hydrophobic residues at the stutter altered the structural stability of the coiled-coil. Using an in vitro FRET assay, we show for the first time that the enhanced stability of GrpE resulted in an increased affinity for DnaK. However, the mutants were defective in in vitro functional assays, and were unable to support bacterial growth at heat shock temperature in a grpE-deleted E. coli strain. This work provides valuable insights into the functional role of a stutter in the GrpE coiled-coil, and its role in regulating the DnaK-chaperone cycle for bacterial survival during heat stress. More generally, our findings illustrate how a sequence specific stutter in a coiled-coil domain regulates the structure function trade-off in proteins.

scholarly journals Identification of a frame shift mutation in the CCDC151 gene in a Han-Chinese family with Kartagener syndrome

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Sheng Deng ◽  
Shan Wu ◽  
Hong Xia ◽  
Wei Xiong ◽  
Xiong Deng ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Coiled Coil ◽  
Han Chinese ◽  
Chinese Family ◽  
Kartagener Syndrome ◽  
Coiled Coil Domain ◽  
Frame Shift ◽  
Frame Shift Mutation ◽  
Recessive Form ◽  
Ciliary Dyskinesia

Abstract Kartagener syndrome (KS), a subtype of primary ciliary dyskinesia (PCD), is characterized by bronchiectasis, chronic sinusitis, male infertility and situs inversus. KS is a genetically heterogeneous disease that is inherited in an autosomal recessive form; however, X-linked inheritance has also been reported. As of this writing [late 2020], at least 34 loci, most of which have known genes, have been reported in the literature as associating with KS. In the present study, we identified a frame shift mutation, c.167delG (p.G56Dfs*26), in the coiled-coil domain containing 151 gene (CCDC151) responsible for KS in a Han-Chinese family. To our knowledge, this is the first report of a CCDC151 c.167delG mutation in the KS patient. These findings may expand the CCDC151 mutation spectrum of KS, and contribute to future genetic counseling and gene-targeted therapy for this disease.

scholarly journals The third coiled coil domain of Atg11 is required for shaping mitophagy initiation sites

2020 ◽  
Author(s):  
Hannah K. Margolis ◽  
Sarah Katzenell ◽  
Kelsie A. Leary ◽  
Michael J. Ragusa
Keyword(s):  
Mitochondrial Protein ◽  
Coiled Coil ◽  
Membrane Vesicles ◽  
Scaffolding Protein ◽  
Hydrophobic Residues ◽  
Dimer Interface ◽  
Selective Autophagy ◽  
The Third ◽  
Coiled Coil Domain ◽  
Dimerization Interface

AbstractSelective autophagy is the capture of specific cytosolic contents in double membrane vesicles that subsequently fuse with the vacuole or lysosome, thereby delivering cargo for degradation. Selective autophagy receptors (SARs) mark the cargo for degradation and, in yeast, recruit Atg11, the scaffolding protein for selective autophagy initiation. The mitochondrial protein Atg32 is the yeast SAR that mediates mitophagy, the selective autophagic capture of mitochondria. Atg11- Atg32 interactions concentrate Atg32 into puncta that are thought to represent sites of mitophagy initiation. However, it is unclear how Atg11 concentrates Atg32 to generate mitophagy initiation sites. We show here that the coiled coil 3 (CC3) domain of Atg11 is required for concentrating Atg32 into puncta. We determined the structure of the majority of the CC3, demonstrating that the CC3 forms a parallel homodimer whose dimer interface is formed by a small number of hydrophobic residues. We further show that the CC3 dimerization interface is required for shaping Atg32 into functional mitophagy initiation sites and for delivery of mitochondria to the vacuole. Our findings suggest that Atg11 self-interactions help concentrate SARs as a necessary precondition for cargo capture.

TMCC3 localizes at the three-way junctions for the proper tubular network of the endoplasmic reticulum

2019 ◽  
Vol 476 (21) ◽  
pp. 3241-3260
Author(s):  
Sindhu Wisesa ◽  
Yasunori Yamamoto ◽  
Toshiaki Sakisaka
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Membrane Protein ◽  
Mammalian Cells ◽  
Coiled Coil ◽  
Transmembrane Domains ◽  
Domain Family ◽  
Coiled Coil Domain ◽  
U2os Cells ◽  
Er Membrane

The tubular network of the endoplasmic reticulum (ER) is formed by connecting ER tubules through three-way junctions. Two classes of the conserved ER membrane proteins, atlastins and lunapark, have been shown to reside at the three-way junctions so far and be involved in the generation and stabilization of the three-way junctions. In this study, we report TMCC3 (transmembrane and coiled-coil domain family 3), a member of the TEX28 family, as another ER membrane protein that resides at the three-way junctions in mammalian cells. When the TEX28 family members were transfected into U2OS cells, TMCC3 specifically localized at the three-way junctions in the peripheral ER. TMCC3 bound to atlastins through the C-terminal transmembrane domains. A TMCC3 mutant lacking the N-terminal coiled-coil domain abolished localization to the three-way junctions, suggesting that TMCC3 localized independently of binding to atlastins. TMCC3 knockdown caused a decrease in the number of three-way junctions and expansion of ER sheets, leading to a reduction of the tubular ER network in U2OS cells. The TMCC3 knockdown phenotype was partially rescued by the overexpression of atlastin-2, suggesting that TMCC3 knockdown would decrease the activity of atlastins. These results indicate that TMCC3 localizes at the three-way junctions for the proper tubular ER network.

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