Novel Autosomal Recessivec10orf2Mutations Causing Infantile-Onset Spinocerebellar Ataxia

Recessive mutations in genes encoding mitochondrial DNA replication machinery lead to mitochondrial DNA depletion syndromes. This genetically and phenotypically heterogeneous group includes infantile onset spinocerebellar ataxia (OMIM# 271245) a neurodegenerative disease caused by mutations in the mtDNA helicase gene,c10orf2, with an increased frequency in the Finnish population due to a founder mutation. We describe a child of English descent who presented with a severe phenotype of IOSCA as a result of two-novel mutations in thec10orf2gene. This paper expands the phenotypic spectrum of IOSCA and adds further evidence for the presence of a genotype-phenotype correlation among patients with recessive mutations in this gene.

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A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool

International Journal of Molecular Sciences ◽

10.3390/ijms222212223 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12223

Author(s):

Giulia di Punzio ◽

Micol Gilberti ◽

Enrico Baruffini ◽

Tiziana Lodi ◽

Claudia Donnini ◽

...

Keyword(s):

Mitochondrial Dna ◽

Physiological Role ◽

Homologous Gene ◽

Inner Mitochondrial Membrane ◽

Dntp Pool ◽

Recessive Mutations ◽

Mitochondrial Dna Depletion ◽

Mtdna Deletion ◽

Selective Channel ◽

Deoxyribonucleoside Triphosphate

Mitochondrial DNA depletion syndromes (MDS) are clinically heterogenous and often severe diseases, characterized by a reduction of the number of copies of mitochondrial DNA (mtDNA) in affected tissues. In the context of MDS, yeast has proved to be both an excellent model for the study of the mechanisms underlying mitochondrial pathologies and for the discovery of new therapies via high-throughput assays. Among the several genes involved in MDS, it has been shown that recessive mutations in MPV17 cause a hepatocerebral form of MDS and Navajo neurohepatopathy. MPV17 encodes a non selective channel in the inner mitochondrial membrane, but its physiological role and the nature of its cargo remains elusive. In this study we identify ten drugs active against MPV17 disorder, modelled in yeast using the homologous gene SYM1. All ten of the identified molecules cause a concomitant increase of both the mitochondrial deoxyribonucleoside triphosphate (mtdNTP) pool and mtDNA stability, which suggests that the reduced availability of DNA synthesis precursors is the cause for the mtDNA deletion and depletion associated with Sym1 deficiency. We finally evaluated the effect of these molecules on mtDNA stability in two other MDS yeast models, extending the potential use of these drugs to a wider range of MDS patients.

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Faculty Opinions recommendation of Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1086992.539949 ◽

2007 ◽

Author(s):

Michio Hirano

Keyword(s):

Mitochondrial Dna ◽

Ribonucleotide Reductase ◽

Mitochondrial Dna Depletion

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Faculty Opinions recommendation of MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.12481.469965 ◽

2006 ◽

Author(s):

Michio Hirano

Keyword(s):

Mitochondrial Dna ◽

Membrane Protein ◽

Mitochondrial Membrane ◽

Inner Mitochondrial Membrane ◽

Mitochondrial Dna Depletion ◽

Mitochondrial Membrane Protein

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Mitochondrial DNA depletion syndrome with a mutation in SLC25A4 developing epileptic encephalopathy: A case report

Brain and Development ◽

10.1016/j.braindev.2021.08.005 ◽

2021 ◽

Author(s):

Tomoko Kashiki ◽

Jun Kido ◽

Ken Momosaki ◽

Shouichirou Kusunoki ◽

Shiro Ozasa ◽

...

Keyword(s):

Mitochondrial Dna ◽

Case Report ◽

Epileptic Encephalopathy ◽

Mitochondrial Dna Depletion ◽

Mitochondrial Dna Depletion Syndrome

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Age-Related Mitochondrial DNA Depletion and the Impact on Pancreatic Beta Cell Function

PLoS ONE ◽

10.1371/journal.pone.0115433 ◽

2014 ◽

Vol 9 (12) ◽

pp. e115433 ◽

Cited By ~ 23

Author(s):

Donna L. Nile ◽

Audrey E. Brown ◽

Meutia A. Kumaheri ◽

Helen R. Blair ◽

Alison Heggie ◽

...

Keyword(s):

Mitochondrial Dna ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Age Related ◽

Mitochondrial Dna Depletion ◽

Pancreatic Beta Cell Function ◽

The Impact

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Mitochondrial DNA depletion analysis by pseudogene ratioing

Journal of Neuroscience Methods ◽

10.1016/j.jneumeth.2005.06.023 ◽

2006 ◽

Vol 150 (2) ◽

pp. 265-271 ◽

Cited By ~ 6

Author(s):

Russell H. Swerdlow ◽

Gerard T. Redpath ◽

Daniel R. Binder ◽

John N. Davis ◽

Scott R. VandenBerg

Keyword(s):

Mitochondrial Dna ◽

Mitochondrial Dna Depletion

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Delineating the Clinical Spectrum Associated With Xq25q26.2 Duplications: Report of 2 Families and Review of the Literature

Journal of Child Neurology ◽

10.1177/0883073818811454 ◽

2018 ◽

Vol 34 (2) ◽

pp. 86-93 ◽

Cited By ~ 2

Author(s):

John C. Herriges ◽

Ellen M. Arch ◽

Pamela A. Burgio ◽

Erin E. Baldwin ◽

Danielle LaGrave ◽

...

Keyword(s):

Intellectual Disability ◽

Learning Difficulties ◽

Growth Failure ◽

Speech Delay ◽

Review Of The Literature ◽

Phenotype Correlation ◽

Additional Insight ◽

Dysmorphic Features ◽

Phenotypic Spectrum ◽

Insight Into

To date, 13 patients with interstitial microduplications involving Xq25q26.2 have been reported. Here, we report 6 additional patients from 2 families with duplications involving Xq25q26.2. Family I carries a 5.3-Mb duplication involving 26 genes. This duplication was identified in 3 patients and was associated with microcephaly, growth failure, developmental delay, and dysmorphic features. Family II carries an overlapping 791-kb duplication that involves 3 genes. This duplication was identified in 3 patients and was associated with learning disability and speech delay. The size and gene content of published overlapping Xq25q26.2 duplications vary, making it difficult to define a critical region or establish a genotype-phenotype correlation. However, patients with overlapping duplications have been found to share common clinical features including microcephaly, growth failure, intellectual disability, learning difficulties, and dysmorphic features. The 2 families presented here provide additional insight into the phenotypic spectrum and clinical significance of duplications in this region.

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