scholarly journals Mutations in MT-ATP6 are a frequent cause of adult-onset spinocerebellar ataxia

2021 ◽  
Author(s):  
Dagmar Nolte ◽  
Jun-Suk Kang ◽  
Amrei Hofmann ◽  
Eva Schwaab ◽  
Heidrun H. Krämer ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Mitochondrial Gene ◽  
Transmembrane Helix ◽  
Point Mutations ◽  
Gene Mutations ◽  
Nuclear Gene ◽  
Adult Onset ◽  
High Prevalence ◽  
Repeat Expansions ◽  
Sporadic Cases

AbstractAdult-onset ataxias are a genetically and clinically heterogeneous group of movement disorders. In addition to nuclear gene mutations, sequence changes have also been described in the mitochondrial genome. Here, we present findings of mutation analysis of the mitochondrial gene MT-ATP6. We analyzed 94 patients with adult-onset spinocerebellar ataxia (SCA), including 34 sporadic cases. In all patients, common sequence changes found in SCAs such as repeat expansions and point mutations had been excluded previously. We found pathogenic MT-ATP variants in five of these patients (5.32%), two of whom were sporadic. Four of the five mutations have not previously been described in ataxias. All but one of these mutations affect transmembrane helices of subunit-α of ATP synthase. Two mutations (p.G16S, and p.P18S) disrupt transmembrane helix 1 (TMH1), one mutation (p.G167D) affects TMH5, and another one (p.L217P) TMH6. The fifth mutation (p.T96A) describes an amino acid change in close proximity to transmembrane helix 3 (TMH3). The level of heteroplasmy was either complete or very high ranging from 87 to 99%. The high prevalence of pathogenic MT-ATP6 variants suggests that analysis of this gene should be included in the routine workup of both hereditary and sporadic ataxias.

scholarly journals Spinocerebellar ataxias (SCAs) caused by common mutations

Neurogenetics ◽  
2021 ◽  
Author(s):  
Ulrich Müller
Keyword(s):  
Mitochondrial Gene ◽  
Point Mutations ◽  
Signs And Symptoms ◽  
Common Disease ◽  
Disease Genes ◽  
Spinocerebellar Ataxias ◽  
Locus Heterogeneity ◽  
Disease Mechanisms ◽  
Extrapyramidal Signs ◽  
Repeat Expansions

AbstractThe term SCA refers to a phenotypically and genetically heterogeneous group of autosomal dominant spinocerebellar ataxias. Phenotypically they present as gait ataxia frequently in combination with dysarthria and oculomotor problems. Additional signs and symptoms are common and can include various pyramidal and extrapyramidal signs and intellectual impairment. Genetic causes of SCAs are either repeat expansions within disease genes or common mutations (point mutations, deletions, insertions etc.). Frequently the two types of mutations cause indistinguishable phenotypes (locus heterogeneity). This article focuses on SCAs caused by common mutations. It describes phenotype and genotype of the presently 27 types known and discusses the molecular pathogenesis in those 21 types where the disease gene has been identified. Apart from the dominant types, the article also summarizes findings in a variant caused by mutations in a mitochondrial gene. Possible common disease mechanisms are considered based on findings in the various SCAs described.

Coaction of Electrostatic and Hydrophobic Interactions: Dynamic Constraints on Disordered TrkA Juxtamembrane Domain

2019 ◽  
Author(s):  
Zichen Wang ◽  
Huaxun Fan ◽  
Xiao Hu ◽  
John Khamo ◽  
Jiajie Diao ◽  
...  
Keyword(s):  
Single Molecule ◽  
Protein Function ◽  
Hydrophobic Interactions ◽  
Transmembrane Helix ◽  
Point Mutations ◽  
Salt Bridge ◽  
Receptor Activation ◽  
Membrane Dynamics ◽  
Juxtamembrane Domain ◽  
Joint Work

<p>The receptor tyrosine kinase family transmits signals into cell via a single transmembrane helix and a flexible juxtamembrane domain (JMD). Membrane dynamics makes it challenging to study the structural mechanism of receptor activation experimentally. In this study, we employ all-atom molecular dynamics with Highly Mobile Membrane-Mimetic to capture membrane interactions with the JMD of tropomyosin receptor kinase A (TrkA). We find that PIP<sub>2 </sub>lipids engage in lasting binding to multiple basic residues and compete with salt bridge within the peptide. We discover three residues insertion into the membrane, and perturb it through computationally designed point mutations. Single-molecule experiments indicate the contribution from hydrophobic insertion is comparable to electrostatic binding, and in-cell experiments show that enhanced TrkA-JMD insertion promotes receptor ubiquitination. Our joint work points to a scenario where basic and hydrophobic residues on disordered domains interact with lipid headgroups and tails, respectively, to restrain flexibility and potentially modulate protein function.</p>

scholarly journals Cosegregation of Single Genes Associated with Fertility Restoration and Transcript Processing of Sorghum Mitochondrial orf107 and urf209

Genetics ◽  
1998 ◽  
Vol 150 (1) ◽  
pp. 383-391 ◽  
Author(s):  
Hoang V Tang ◽  
Ruying Chang ◽  
Daryl R Pring
Keyword(s):  
Fertility Restoration ◽  
Mitochondrial Gene ◽  
Pollen Viability ◽  
Single Gene ◽  
Dominant Gene ◽  
Nuclear Gene ◽  
Male Sterile ◽  
Reading Frame ◽  
Transcript Processing ◽  
Backcross Populations

Abstract Defective nuclear-cytoplasmic interactions leading to aberrant microgametogenesis in sorghum carrying the IS1112C male-sterile cytoplasm occur very late in pollen maturation. Amelioration of this condition, the restoration of pollen viability, involves a novel two-gene gametophytic system, wherein genes designated Rf3 and Rf4 are required for viability of individual gametes. Rf3 is tightly linked to, or represents, a single gene that regulates a transcript processing activity that cleaves transcriptsof orf107, a chimeric mitochondrial open reading frame specific to IS1112C. The mitochondrial gene urf 209 is also subject to nucleus-specific enhanced transcript processing, 5′ to the gene, conferred by a single dominant gene designated Mmt1. Examinations of transcript patterns in F2 and two backcross populations indicated cosegregation of the augmented orf107 and urf209 processing activities in IS1112C. Several sorghum lines that do not restore fertility or confer orf107 transcript processing do exhibit urf209 transcript processing, indicating that the activities are distinguishable. We conclude that the nuclear gene(s) conferring enhanced orf107 and urf209 processing activities are tightly linked in IS1112C. Alternatively, the similarity in apparent regulatory action of the genes may indicate allelic differences wherein the IS1112C Rf3 allele may differ from alleles of maintainer lines by the capability to regulate both orf107 and urf209 processing activities.

scholarly journals Molecular Basis of In Vivo Resistance to Sulfadoxine-Pyrimethamine in African Adult Patients Infected withPlasmodium falciparum Malaria Parasites

1998 ◽  
Vol 42 (7) ◽  
pp. 1811-1814 ◽  
Author(s):  
Leonardo K. Basco ◽  
Rachida Tahar ◽  
Pascal Ringwald
Keyword(s):  
Dihydrofolate Reductase ◽  
Point Mutations ◽  
Gene Mutations ◽  
Adult Patients ◽  
Wild Type ◽  
Dihydropteroate Synthase ◽  
Reductase Gene ◽  
Parasite Populations

ABSTRACT In vitro sulfadoxine and pyrimethamine resistance has been associated with point mutations in the dihydropteroate synthase and dihydrofolate reductase domains, respectively, but the in vivo relevance of these point mutations has not been well established. To analyze the correlation between genotype and phenotype, 10 Cameroonian adult patients were treated with sulfadoxine-pyrimethamine and followed up for 28 days. After losses to follow-up (n = 1) or elimination of DNA samples due to mixed parasite populations with pyrimethamine-sensitive and pyrimethamine-resistant profiles (n = 3), parasite genomic DNA from day 0 blood samples of six patients were analyzed by DNA sequencing. Three patients who were cured had isolates characterized by a wild-type or mutant dihydrofolate reductase gene (with one or two mutations) and a wild-type dihydropteroate synthase gene. Three other patients who failed to respond to sulfadoxine-pyrimethamine treatment carried isolates with triple dihydrofolate reductase gene mutations and either a wild-type or a mutant dihydropteroate synthase gene. Three dihydrofolate reductase gene codons (51, 59, and 108) may be reliable genetic markers that can accurately predict the clinical outcome of sulfadoxine-pyrimethamine treatment in Africa.

scholarly journals Low Prevalence of Pneumocystis pneumonia (PCP) but High Prevalence of Pneumocystis dihydropteroate synthase (dhps) Gene Mutations in HIV-Infected Persons in Uganda

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e49991 ◽  
Author(s):  
Steve M. Taylor ◽  
Steven R. Meshnick ◽  
William Worodria ◽  
Alfred Andama ◽  
Adithya Cattamanchi ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Pneumocystis Pneumonia ◽  
Dihydropteroate Synthase ◽  
High Prevalence ◽  
Dhps Gene ◽  
Low Prevalence

scholarly journals Point Mutations in Transmembrane Helices 2 and 3 of ExbB and TolQ Affect Their Activities in Escherichia coli K-12

2004 ◽  
Vol 186 (13) ◽  
pp. 4402-4406 ◽  
Author(s):  
Volkmar Braun ◽  
Christina Herrmann
Keyword(s):  
Escherichia Coli ◽  
Amino Acid ◽  
Transmembrane Helix ◽  
Point Mutations ◽  
Transmembrane Helices ◽  
The Third ◽  
Form Part ◽  
K 12

ABSTRACT Replacement of glutamate 176, the only charged amino acid in the third transmembrane helix of ExbB, with alanine (E176A) abolished ExbB activity in all determined ExbB-dependent functions of Escherichia coli. Combination of the mutations T148A in the second transmembrane helix and T181A in the third transmembrane helix, proposed to form part of a proton pathway through ExbB, also resulted in inactive ExbB. E176 and T148 are strictly conserved in ExbB and TolQ proteins, and T181 is almost strictly conserved in ExbB, TolQ, and MotA.

Leber's Hereditary Optic Neuropathy as a Cause of Severe Visual Loss in Childhood

PEDIATRICS ◽  
1993 ◽  
Vol 91 (5) ◽  
pp. 988-989
Author(s):  
C. M. MOORMAN ◽  
J. S. ELSTON ◽  
P. MATTHEWS
Keyword(s):  
Optic Neuropathy ◽  
Visual Loss ◽  
Age Of Onset ◽  
Transmitted Disease ◽  
Point Mutations ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Leber's Hereditary Optic Neuropathy ◽  
Severe Visual Loss ◽  
Sporadic Cases ◽  
Hereditary Optic Neuropathy

Leber's hereditary optic neuropathy (LHON) is a rare, maternally transmitted disease that most commonly causes acute or subacute visual loss in young men, typically between the ages of 17 and 24 years (although perhaps 14% of affected individuals are women), which may be associated with systemic disorders, eg, cardiac dysrhythmias and neurologic problems.1 Onset is usually asymmetric, but intervals between involvement of the two eyes are usually less than a few months. A definitive diagnosis rested on a family history, age of onset, and the characteristic circumpapillary microangiopathy of the optic disc in the acute phase. However, recent demonstration of point mutations of mitochondrial DNA in affected individuals means that confirmation of the diagnosis can now be obtained in atypical or sporadic cases.2

In vivo analysis of sequences necessary for CBP1-dependent accumulation of cytochrome b transcripts in yeast mitochondria

1993 ◽  
Vol 13 (7) ◽  
pp. 4203-4213
Author(s):  
T M Mittelmeier ◽  
C L Dieckmann
Keyword(s):  
Cytochrome B ◽  
Mitochondrial Gene ◽  
Microprojectile Bombardment ◽  
Nuclear Gene ◽  
State Level ◽  
Transcription Unit ◽  
Endonucleolytic Cleavage ◽  
In Vivo Analysis ◽  
Nucleotide Region

In Saccharomyces cerevisiae, cytochrome b, an essential component of the respiratory chain, is encoded by the mitochondrial gene cob. The cob transcription unit includes the tRNA(Glu) gene from positions -1170 to -1099 relative to the cob ATG at +1. The initial tRNA(Glu)-cob transcript undergoes several processing events, including removal of tRNA(Glu) and production of the mature 5' end of cob mRNA at nucleotide -954. The nuclear gene product CBP1 is specifically required for the accumulation of cob mRNA. In cbp1 mutant strains, cob transcripts are not detectable by Northern (RNA) blot analysis, but the steady-state level of tRNA(Glu) is similar to that of wild type. The results of a previous study led to the conclusion that a 400-nucleotide region just downstream of tRNA(Glu) is sufficient for CBP1 function. In the present study, the microprojectile bombardment method of mitochondrial transformation was used to introduce deletions within this region of cob. The analysis of cob transcripts in strains carrying the mitochondrial deletion genomes indicates that a 63-nucleotide sequence that encompasses the cleavage site at -954 is sufficient both for CBP1 function and for correct positioning of the cleavage. Furthermore, the data indicate that CBP1 prevents the degradation of unprocessed cob transcripts produced by endonucleolytic cleavage at the 3' end of tRNA(Glu).

scholarly journals Gene Sequence Analysis of Mitochondrial COI in Genus Saperda (Coleoptera: Cerambycidae: Lamiinae)

2021 ◽  
Author(s):  
Wei XU ◽  
Qinhua Gan ◽  
Jian Pu ◽  
Yingwen Pan ◽  
Bo Cai ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Detection Rate ◽  
Gene Sequence ◽  
Mitochondrial Gene ◽  
Dna Barcode ◽  
Nuclear Gene ◽  
Rapid Identification ◽  
Mitochondrial Coi ◽  
Gene Sequence Analysis ◽  
Total Dna

In this study, the total DNA of nine species of Saperda (Lopezcolonia) octopunctata (Scopoli, 1772), Saperda (Lopezcolonia) scalaris (Linnaeus, 1758), Saperda interrupta Gebler, Saperda Alberti (Plavilstshikov), Saperda (Saperda) similis Laicharting, 1784, Saperda (Compsidia) populnea (Linnaeus, 1758), Saperda (Saperda) carcharias (Linnaeus, 1758), Saperda (Lopezcolonia) perforata Pallas, 1773 and Saperda ohbayashi were extracted. Two partial sequences of mitochondrial gene and one partial sequence of nuclear gene were amplified. Comparing the COI sequence with the DNA barcode data in GenBank can effectively identify the related species of Saperda. It will be applied to the rapid identification of some species of Saperda in imported wood at ports, and improve the detection rate of plant quarantine.

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