Molecular characterization of <i>PRKN</i> structural variations identified through whole‐genome sequencing

Bravo, Paloma; Darvish, Hossein; Tafakhori, Abbas; Azcona, Luís; Johari, Amir Hossein; Jamali, Faezeh; Paisán-Ruı́z, Coro

doi:10.1002/mgg3.482

Cited by 6 publications

(6 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, examples of specific mechanisms directly linking TEs with detrimental processes in neurons are also known [ 470 , 471 ]. There are also case reports about very specific TE insertions affecting certain genes relevant for neuropathology [ 363 , 472 , 473 , 474 ].…”

Section: The Role Of Neuronal Tes In Pathologymentioning

confidence: 99%

See 1 more Smart Citation

The Role of Transposable Elements of the Human Genome in Neuronal Function and Pathology

Чеснокова

Beletskiy

Kolosov

2022

IJMS

View full text Add to dashboard Cite

Transposable elements (TEs) have been extensively studied for decades. In recent years, the introduction of whole-genome and whole-transcriptome approaches, as well as single-cell resolution techniques, provided a breakthrough that uncovered TE involvement in host gene expression regulation underlying multiple normal and pathological processes. Of particular interest is increased TE activity in neuronal tissue, and specifically in the hippocampus, that was repeatedly demonstrated in multiple experiments. On the other hand, numerous neuropathologies are associated with TE dysregulation. Here, we provide a comprehensive review of literature about the role of TEs in neurons published over the last three decades. The first chapter of the present review describes known mechanisms of TE interaction with host genomes in general, with the focus on mammalian and human TEs; the second chapter provides examples of TE exaptation in normal neuronal tissue, including TE involvement in neuronal differentiation and plasticity; and the last chapter lists TE-related neuropathologies. We sought to provide specific molecular mechanisms of TE involvement in neuron-specific processes whenever possible; however, in many cases, only phenomenological reports were available. This underscores the importance of further studies in this area.

show abstract

Section: The Role Of Neuronal Tes In Pathologymentioning

confidence: 99%

“…Whole-genome sequencing of three families with early onset PD revealed five structural variations in the PRKN gene; retrotransposon sequences were identified within 1–2 Kb of the deletions’ break points, suggesting that all identified variations might originate through retrotransposition events [ 472 ].…”

Section: The Role Of Neuronal Tes In Pathologymentioning

confidence: 99%

The Role of Transposable Elements of the Human Genome in Neuronal Function and Pathology

Чеснокова

Beletskiy

Kolosov

2022

IJMS

View full text Add to dashboard Cite

show abstract

“…Structural variation formation is proposed to occur with non-allelic homologous recombination. LTR and non-LTR retrotransposon sequences were identified within two kilobases of the deletion break point, suggesting that the deletions may have originated due to retrotransposition events (124). The link between retroelement activation in neurodegenerative disorders is present but not fully established.…”

Section: Mobile Elements and Neurodegenerative Disordersmentioning

confidence: 99%

Transposable Elements, Inflammation, and Neurological Disease

2019

View full text Add to dashboard Cite

Transposable Elements (TE) are mobile DNA elements that can replicate and insert themselves into different locations within the host genome. Their propensity to self-propagate has a myriad of consequences and yet their biological significance is not well-understood. Indeed, retrotransposons have evaded evolutionary attempts at repression and may contribute to somatic mosaicism. Retrotransposons are emerging as potent regulatory elements within the human genome. In the diseased state, there is mounting evidence that endogenous retroelements play a role in etiopathogenesis of inflammatory diseases, with a disposition for both autoimmune and neurological disorders. We postulate that active mobile genetic elements contribute more to human disease pathogenesis than previously thought.

show abstract

“…By using use whole genome sequencing, we found that the analyzed patient carries a large deletion encompassing exon 5 and two deep intronic variants, which leads to PARKIN loss. While other exon 5 deletions were previously described in PD patients 67,68 , to our knowledge the pathogenicity of deep intronic variants in the PRKN gene was never demonstrated before. The only described splicing variants (see HGMD® Professional 2023.2) are either located at the canonical splice site or within 20 nucleotides from the intron/exon junction.…”

Section: Discussionmentioning

confidence: 65%

Parkin is not required to sustain OXPHOS function in adult mammalian tissues

Filograna,

Gerlach,

Choi

et al. 2023

Preprint

View full text Add to dashboard Cite

Loss-of-function variants in thePRKNgene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson’s disease (PD). Extensivein vitroandin vivostudies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditionalParkinknockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development ofParkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygousPRKNpathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.

show abstract

Molecular characterization of PRKN structural variations identified through whole‐genome sequencing

Cited by 6 publications

References 17 publications

The Role of Transposable Elements of the Human Genome in Neuronal Function and Pathology

The Role of Transposable Elements of the Human Genome in Neuronal Function and Pathology

Transposable Elements, Inflammation, and Neurological Disease

Parkin is not required to sustain OXPHOS function in adult mammalian tissues

Contact Info

Product

Resources

About