Telomere healing following DNA polymerase arrest-induced breakages is likely the main mechanism generating chromosome 4p terminal deletions

Hannes, Femke; Houdt, Jeroen Van; Quarrell, Oliver; Poot, Martin; Hochstenbach, Ron; Vermeesch, Joris Robert

doi:10.1002/humu.21368

Cited by 21 publications

(18 citation statements)

References 57 publications

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“…Our work describes for the first time a set of mitochondrial phenotypes in WHS-patient-derived LCLs that also segregate with seizure development in the small cohort examined. This is notable because LCL C(355), which does not present with any of the aberrant mitochondrial phenotypes identified here, has a deletion that incorporates CTBP1 and CPLX1 , yet this individual is seizure free (Hannes et al, 2010). Furthermore, we can model some of the mitochondrial phenotypes identified in the LCLs by manipulating LETM1 expression in cell lines of neuronal (Neuro2A) and glial (T98G) origin (Fig.…”

Section: Discussionmentioning

confidence: 78%

“…1. All of these lines are derived from patients previously described in the literature (Engbers et al, 2009; Hannes et al, 2010; Maas et al, 2008; Rauch et al, 2001). Of note, FN4367 is an LCL derived from the patient described by Rauch and colleagues involving one of the smallest deletions catalogued in 4p16.3 in a patient exhibiting mild WHS phenotypes, but without seizures (Rauch et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…This is an interstitial 191.5 kb deletion encompassing WHSCR1, and not involving LETM1 (Rauch et al, 2001). LCL C(355) is from a WHS-like individual with a terminal deletion up to and including SLBP , thereby preserving LETM1 and the WHSCRs (Engbers et al, 2009; Hannes et al, 2010). This individual has not presented with seizures (Engbers et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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LETM1 haploinsufficiency causes mitochondrial defects in Wolf-Hirschhorn syndrome patient cells: implications for dissecting underlying pathomechanisms in this condition

Hart

Rauch

Carr

et al. 2014

Disease Models &Amp; Mechanisms

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Wolf-Hirschhorn syndrome (WHS) represents an archetypical example of a contiguous gene deletion disorder – a condition comprising a complex set of developmental phenotypes with a multigenic origin. Epileptic seizures, intellectual disability, growth restriction, motor delay and hypotonia are major co-morbidities in WHS. Haploinsufficiency of LETM1, which encodes a mitochondrial inner-membrane protein functioning in ion transport, has been proposed as an underlying pathomechanism, principally for seizures but also for other core features of WHS, including growth and motor delay. Growing evidence derived from several model organisms suggests that reduced LETM1 expression is associated with some element of mitochondrial dysfunction. Surprisingly, LETM1-dependent mitochondrial functional deficits have not previously been described in cells from individuals with WHS. Here, using a unique panel of WHS-patient-derived cell lines with deletions of differing sizes, incorporating LETM1 or not, we show, for the first time, that LETM1 expression is reduced in mitochondria isolated from WHS-patient cells. Furthermore, we show that this is associated with distinct mitochondrial phenotypes, including altered intracellular [Ca2+] levels, dysfunctional mitochondrial transition-pore opening, hyperpolarization and superoxide leakage from resting mitochondria. Interestingly, we find that these phenotypes segregate with seizures in our WHS cohort. Our findings identify novel cellular phenotypes in WHS attributable to a 50% reduction in LETM1 expression level; these phenotypes could underlie and/or contribute to some of the core clinical features of this condition.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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LETM1 haploinsufficiency causes mitochondrial defects in Wolf-Hirschhorn syndrome patient cells: implications for dissecting underlying pathomechanisms in this condition

Hart

Rauch

Carr

et al. 2014

Disease Models &Amp; Mechanisms

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“…Extensive homology present at the telomere and subtelomere of most chromosomes 29 can trigger breakage–fusion–bridge (BFB) cycles 133,134 by forming dicentric chromosomes, intrachromosomal or interchromosomal ectopic recombination 135 and secondary structures that can render these regions prone to breaks 136 . NHEJ is likely to be a predominant mechanism of repair 137 , although recurrent NAHR between interchromosomal LCRs also occurs 51,135,138 .…”

Section: The Role Of Genomic Architecturementioning

confidence: 99%

Mechanisms underlying structural variant formation in genomic disorders

2016

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With the recent burst of technological developments in genomics, and the clinical implementation of genome-wide assays, our understanding of the molecular basis of genomic disorders, specifically the contribution of structural variation to disease burden, is evolving quickly. Ongoing studies have revealed a ubiquitous role for genome architecture in the formation of structural variants at a given locus, both in DNA recombination-based processes and in replication-based processes. These reports showcase the influence of repeat sequences on genomic stability and structural variant complexity and also highlight the tremendous plasticity and dynamic nature of our genome in evolution, health and disease susceptibility.

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“…Indeed, other mechanisms may be responsible for the observed pattern of scattered amplification. Recent studies have demonstrated that telomere crisis and telomere healing can have dramatic and multiple effects on the genome [46, 47]. These include polyploidization as well as chromosome instability that may lead to kataegis or chromothripsis-like aberrations.…”

Section: Discussionmentioning

confidence: 99%

Scattered genomic amplification in dedifferentiated liposarcoma

et al. 2017

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Background: Atypical lipomatous tumor (ALT), well differentiated liposarcoma (WDLS) and dedifferentiated liposarcoma (DDLS) are cytogenetically characterized by near-diploid karyotypes with no or few other aberrations than supernumerary ring or giant marker chromosomes, although DDLS tend to have somewhat more complex rearrangements. In contrast, pleomorphic liposarcomas (PLS) have highly aberrant and heterogeneous karyotypes. The ring and giant marker chromosomes contain discontinuous amplicons, in particular including multiple copies of the target genes CDK4, HMGA2 and MDM2 from 12q, but often also sequences from other chromosomes.Results: The present study presents a DDLS with an atypical hypertriploid karyotype without any ring or giant marker chromosomes. SNP array analyses revealed amplification of almost the entire 5p and discontinuous amplicons of 12q including the classical target genes, in particular CDK4. In addition, amplicons from 1q, 3q, 7p, 9p, 11q and 20q, covering from 2 to 14 Mb, were present. FISH analyses showed that sequences from 5p and 12q were scattered, separately or together, over more than 10 chromosomes of varying size. At RNA sequencing, significantly elevated expression, compared to myxoid liposarcomas, was seen for TRIO and AMACR in 5p and of CDK4, HMGA2 and MDM2 in 12q. Conclusions: The observed pattern of scattered amplification does not show the characteristics of chromothripsis, but is novel and differs from the well known cytogenetic manifestations of amplification, i.e., double minutes, homogeneously staining regions and ring chromosomes. Possible explanations for this unusual distribution of amplified sequences might be the mechanism of alternative lengthening of telomeres that is frequently active in DDLS and events associated with telomere crisis.

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Telomere healing following DNA polymerase arrest-induced breakages is likely the main mechanism generating chromosome 4p terminal deletions

Cited by 21 publications

References 57 publications

LETM1 haploinsufficiency causes mitochondrial defects in Wolf-Hirschhorn syndrome patient cells: implications for dissecting underlying pathomechanisms in this condition

LETM1 haploinsufficiency causes mitochondrial defects in Wolf-Hirschhorn syndrome patient cells: implications for dissecting underlying pathomechanisms in this condition

Mechanisms underlying structural variant formation in genomic disorders

Scattered genomic amplification in dedifferentiated liposarcoma

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