Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome

Bertelsen, Birgitte; Melchior, Linea; Jensen, Lars Riff; Groth, Camilla; Glenthøj, Birte; Rizzo, Renata; Debes, Nanette Mol; Skov, Liselotte; Brøndum‐Nielsen, Karen; Paschou, Peristera; Silahtaroglu, Asli; Tümer, Zeynep

doi:10.1038/ejhg.2014.24

Cited by 65 publications

(63 citation statements)

References 40 publications

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“…Additionally, USP30 has been linked to Parkinson disease owing to its ability to oppose parkin-mediated mitophagy 96 , whereas the oligopeptidase PITRM1 has been implicated in Alzheimer disease, being the main peptidase involved in the degradation of mitochondrial amyloid-β aggregates 45 . Moreover, intragenic deletions in IMMP2L cause Tourette syndrome, whereas several SNPs and copy number variations in this gene have been associated with autism and a wide range of other neurodevelopmental disorders [131][132][133] .…”

Section: Mitoproteases and Human Diseasesmentioning

confidence: 99%

“…Notably, USP30 inhibitors have also been shown to promote mitochondrial fusion and to restore the mitochondrial network and oxidative respiration in cells that are deficient in mitofusins 81 . There are also cases in which the clinical applications must be based on the restoration of the activity of mitoproteases that are downregulated or inactivated in the development or progression of certain pathologies, including many hereditary diseases of mitochondrial proteolysis 131,143,148 . Consequently, either pharmacological activation or inhibition of mitoproteases will be required to treat these conditions.…”

Section: Box 1 | Clinical Implications Derived From Studies On Mitoprmentioning

confidence: 99%

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New roles for mitochondrial proteases in health, ageing and disease

Quirós

Langer

López-Otı́n

2015

Nat Rev Mol Cell Biol

439

406

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Recent advances in mitochondrial biology have revealed the high diversity and complexity of proteolytic enzymes that regulate mitochondrial function. We have classified mitochondrial proteases, or mitoproteases, on the basis of their function and location, and defined the human mitochondrial degradome as the complete set of mitoproteases that are encoded by the human genome. In addition to their nonspecific degradative functions, mitoproteases perform highly regulated proteolytic reactions that are important in mitochondrial function, integrity and homeostasis. These include protein synthesis, quality control, mitochondrial biogenesis and dynamics, mitophagy and apoptosis. Impaired or dysregulated function of mitoproteases is associated with ageing and with many pathological conditions such as neurodegenerative disorders, metabolic syndromes and cancer. A better understanding of the mitochondrial proteolytic landscape and its modulation may contribute to improving human lifespan and 'healthspan'.

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Section: Mitoproteases and Human Diseasesmentioning

confidence: 99%

Section: Box 1 | Clinical Implications Derived From Studies On Mitoprmentioning

confidence: 99%

New roles for mitochondrial proteases in health, ageing and disease

Quirós

Langer

López-Otı́n

2015

Nat Rev Mol Cell Biol

439

406

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“…IMMP2L is a candidate for behavioral disorders, including Gilles de la Tourette syndrome (OMIM #137580) [Bertelsen et al, 2014;Gimelli et al, 2014]. In this condition multiple motor and vocal tics are described that impact language processing [Frank, 1978].…”

Section: Sz and (The Evolution Of) Human Languagementioning

confidence: 99%

Schizophrenia and Human Self-Domestication: An Evolutionary Linguistics Approach

et al. 2017

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Schizophrenia (SZ) is a pervasive neurodevelopmental disorder that entails social and cognitive deficits, including marked language problems. Its complex multifactorial etiopathogenesis, including genetic and environmental factors, is still widely uncertain. SZ incidence has always been high and quite stable in human populations, across time and regardless of cultural implications, for unclear reasons. It has been hypothesized that SZ pathophysiology may involve the biological components that changed during the recent human evolutionary history, and led to our distinctive mode of cognition, which includes language skills. In this paper we explore this hypothesis, focusing on the self-domestication of the human species. This has been claimed to account for many human-specific distinctive traits, including aspects of our behavior and cognition, and to favor the emergence of complex languages through cultural evolution. The “domestication syndrome” in mammals comprises the constellation of traits exhibited by domesticated strains, seemingly resulting from the hypofunction of the neural crest. It is our intention to show that people with SZ exhibit more marked domesticated traits at the morphological, physiological, and behavioral levels. We also show that genes involved in domestication and neural crest development and function comprise nearly 20% of SZ candidates, most of which exhibit altered expression profiles in the brain of SZ patients, specifically in areas involved in language processing. Based on these observations, we conclude that SZ may represent an abnormal ontogenetic itinerary for the human faculty of language, resulting, at least in part, from changes in genes important for the domestication syndrome and primarily involving the neural crest.

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“…Intragenic losses may also affect the expression of alternative splicing variants and consequently alter cellular phenotypes [Bertelsen et al, 2014;Wang et al, 2014]. Thus, a de novo heterozygous 677-kb loss in a patient with ASD ( figs.…”

Section: Gene Truncation and Loss Of Alternative Transcriptsmentioning

confidence: 99%

Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders

Poot¹

2015

Mol Syndromol

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Based on genomic rearrangements and copy number variations, the contactin-associated protein-like 2 gene (CNTNAP2) has been implicated in neurodevelopmental disorders such as Gilles de la Tourette syndrome, intellectual disability, obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, and attention deficit hyperactivity disorder. To explain the phenotypic pleiotropy of CNTNAP2 alterations, several hypotheses have been put forward. Those include gene disruption, loss of a gene copy by a heterozygous deletion, altered regulation of gene expression due to loss of transcription factor binding and DNA methylation sites, and mutations in the amino acid sequence of the encoded protein which may provoke altered interactions of the CNTNAP2-encoded protein, Caspr2, with other proteins. Also exome sequencing, which covers <0.2% of the CNTNAP2 genomic DNA, has revealed numerous single nucleotide variants in healthy individuals and in patients with neurodevelopmental disorders. In some of these disorders, disruption of CNTNAP2 may be interpreted as a susceptibility factor rather than a directly causative mutation. In addition to being associated with impaired development of language, CNTNAP2 may turn out to be a central node in the molecular networks controlling neurodevelopment. This review discusses the impact of CNTNAP2 mutations on its functioning at multiple levels of the combinatorial genetic networks that govern brain development. In addition, recommendations for genomic testing in the context of clinical genetic management of patients with neurodevelopmental disorders and their families are put forward.

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Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome

Cited by 65 publications

References 40 publications

New roles for mitochondrial proteases in health, ageing and disease

New roles for mitochondrial proteases in health, ageing and disease

Schizophrenia and Human Self-Domestication: An Evolutionary Linguistics Approach

Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders

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