Topic
ADCK3
About: ADCK3 is a research topic. Over the lifetime, 18 publications have been published within this topic receiving 1209 citations. The topic is also known as: ARCA2 & CABC1.
Papers
TL;DR: A SNP-based genome-wide scan in a large consanguineous family revealed a locus for autosomal-recessive ataxia at chromosome 1q41, and a phylogenetic analysis shows that ADCK3 belongs to the family of atypical kinases, which includes phosphoinositide and choline kinase, suggesting that ADCk3 plays an indirect regulatory role in ubiquinone biosynthesis possibly as part of a feedback loop that regulates ATP production.
Abstract: Muscle coenzyme Q10 (CoQ10 or ubiquinone) deficiency has been identified in more than 20 patients with presumed autosomal-recessive ataxia. However, mutations in genes required for CoQ10 biosynthetic pathway have been identified only in patients with infantile-onset multisystemic diseases or isolated nephropathy. Our SNP-based genome-wide scan in a large consanguineous family revealed a locus for autosomal-recessive ataxia at chromosome 1q41. The causative mutation is a homozygous splice-site mutation in the aarF-domain-containing kinase 3 gene (ADCK3). Five additional mutations in ADCK3 were found in three patients with sporadic ataxia, including one known to have CoQ10 deficiency in muscle. All of the patients have childhood-onset cerebellar ataxia with slow progression, and three of six have mildly elevated lactate levels. ADCK3 is a mitochondrial protein homologous to the yeast COQ8 and the bacterial UbiB proteins, which are required for CoQ biosynthesis. Three out of four patients tested showed a low endogenous pool of CoQ10 in their fibroblasts or lymphoblasts, and two out of three patients showed impaired ubiquinone synthesis, strongly suggesting that ADCK3 is also involved in CoQ10 biosynthesis. The deleterious nature of the three identified missense changes was confirmed by the introduction of them at the corresponding positions of the yeast COQ8 gene. Finally, a phylogenetic analysis shows that ADCK3 belongs to the family of atypical kinases, which includes phosphoinositide and choline kinases, suggesting that ADCK3 plays an indirect regulatory role in ubiquinone biosynthesis possibly as part of a feedback loop that regulates ATP production.
316 citations
Morgridge Institute for Research1, University of Wisconsin-Madison2, University of Strasbourg3, French Institute of Health and Medical Research4, Collège de France5, Centre national de la recherche scientifique6, University of Georgia7, École Polytechnique Fédérale de Lausanne8, Swiss Institute of Bioinformatics9, University of Grenoble10
TL;DR: Although COQ8 was predicted to be aprotein kinase, it is demonstrated that it lacks canonical protein kinase activity in trans and has ATPase activity and interacts with lipid CoQ intermediates, functions that are likely conserved across all domains of life.
113 citations
TL;DR: The results indicate that CABC1 is an important candidate for mutation analysis in progressive cerebellar ataxia and atrophy on MRI to identify those patients, who may benefit from CoQ10 treatment.
77 citations
TL;DR: A novel homozygous frameshift mutation in ADCK3, which results in the loss of the stop codon, is identified in both siblings and broadens the phenotypic spectrum associated with ADCk3 mutations and provides further understanding of their pathogenic mechanism.
Abstract: Background The autosomal-recessive cerebellar ataxias (ARCA) are a clinically and genetically heterogeneous group of neurodegenerative disorders. The large number of ARCA genes leads to delay and difficulties obtaining an exact diagnosis in many patients and families. Ubiquinone (CoQ10) deficiency is one of the potentially treatable causes of ARCAs as some patients respond to CoQ10 supplementation. The AarF domain containing kinase 3 gene ( ADCK3 ) is one of several genes associated with CoQ10 deficiency. ADCK3 encodes a mitochondrial protein which functions as an electron-transfer membrane protein complex in the mitochondrial respiratory chain (MRC). Methods We report two siblings from a consanguineous Pakistani family who presented with cerebellar ataxia and severe myoclonus from adolescence. Whole exome sequencing and biochemical assessment of fibroblasts were performed in the index patient. Results A novel homozygous frameshift mutation in ADCK3 (p.Ser616Leufs*114), was identified in both siblings. This frameshift mutation results in the loss of the stop codon, extending the coding protein by 81 amino acids. Significant CoQ10 deficiency and reduced MRC enzyme activities in the index patient9s fibroblasts suggested that the mutant protein may reduce the efficiency of mitochondrial electron transfer. CoQ10 supplementation was initiated following these genetic and biochemical analyses. She gained substantial improvement in myoclonic movements, ataxic gait and dysarthric speech after treatment. Conclusion This study highlights the importance of diagnosing ADCK3 mutations and the potential benefit of treatment for patients. The identification of this new mutation broadens the phenotypic spectrum associated with ADCK3 mutations and provides further understanding of their pathogenic mechanism.
54 citations
TL;DR: The importance of investigating mitochondrial function and, in particular, muscle CoQ10 levels, in patients with adult‐onset cerebellar ataxia is suggested, including a 48 year old man, who presented with dysarthria and walking difficulties.
Abstract: Inherited ataxias are a group of heterogeneous disorders in children or adults but their genetic definition remains still undetermined in almost half of the patients. However, CoQ10 deficiency is a rare cause of cerebellar ataxia and ADCK3 is the most frequent gene associated with this defect. We herein report a 48 year old man, who presented with dysarthria and walking difficulties. Brain magnetic resonance imaging showed a marked cerebellar atrophy. Serum lactate was elevated. Tissues obtained by muscle and skin biopsies were studied for biochemical and genetic characterization. Skeletal muscle biochemistry revealed decreased activities of complexes I+III and II+III and a severe reduction of CoQ10 , while skin fibroblasts showed normal CoQ10 levels. A mild loss of maximal respiration capacity was also found by high-resolution respirometry. Molecular studies identified a novel homozygous deletion (c.504del_CT) in ADCK3, causing a premature stop codon. Western blot analysis revealed marked reduction of ADCK3 protein levels. Treatment with CoQ10 was started and, after 1 year follow-up, patient neurological condition slightly improved. This report suggests the importance of investigating mitochondrial function and, in particular, muscle CoQ10 levels, in patients with adult-onset cerebellar ataxia. Moreover, clinical stabilization by CoQ10 supplementation emphasizes the importance of an early diagnosis.
42 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 1 |
| 2019 | 1 |
| 2018 | 1 |
| 2017 | 1 |
| 2016 | 5 |
| 2015 | 1 |