Rothmund-Thomson syndrome and RECQL4 defect: Splitting and lumping

Division of Medical Genetics, San Paolo School of Medicine, University of Milan, Via A. di Rudinì, 8, 20142 Milano, Italy.
Cancer Letters (Impact Factor: 5.62). 02/2006; 232(1):107-20. DOI: 10.1016/j.canlet.2005.07.042
Source: PubMed


Rothmund-Thomson Syndrome (RTS) is a rare autosomal recessive genodermatosis with a heterogeneous clinical profile. Mutations in RECQL4, encoding a RecQ DNA helicase, are present in a large fraction, but not all clinically diagnosed patients, allowing to classify RTS among the RecQ helicase chromosomal instability defects including Bloom's and Werner's syndromes. Results of RECQL4 test coupled to the variable clinical presentation favored the splitting of RTS clinical phenotype into nosological entities under distinct genetic control. In parallel, lumping of the RECQL4 gene to two other diseases, RAPADILINO and Baller-Gerold has paved the way to unravel through allelic heterogeneity complex genotype-phenotype correlations. Recql4 knockout mice provided crucial insights into the comprehension of the functional role of RECQL4 helicase, which have been corroborated by the initial biochemical characterization of RECQL4 protein and its acting pathway and by studies on RECQL4 homologs in yeast and Xenopus. A role for RECQL4 in initiation of DNA replication and in sister chromatid cohesion has been proposed, which currently fits the pieces of evidence achieved by different approaches. Further work is needed to define the specific and shared functions of RECQL4 in relation to other RecQ helicases and to connect RECQL4 diseases to other genomic instability syndromes with birth defects and cancer predisposition.

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Available from: Lidia Larizza, Sep 30, 2015
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    • "Syndromes that are characterized by genomic instability often show increased sensitivity to radiotherapy and chemotherapy. RTS patients have a higher risk of secondary malignancies than patients without a cancer predisposition, and several studies demonstrated increased sensitivity of RTS-derived cells to radiation due to reduced DNA repair abilities.[1227] Hence, for cases in which postoperative radiotherapy is needed, this risk factor should be taken into account. "
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    ABSTRACT: Background: Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by genomic instability and increased risk of various malignancies, especially osteosarcoma and squamous cell carcinoma. We report the first RTS patient who developed a central nervous system (CNS)-related neoplasm. Case description: A 28-year-old male, previously diagnosed with RTS , developed a massive parasagital lesion, detected by magnetic resonance imaging. The tumor was surgically removed and histologically diagnosed as atypical meningioma. Preoperative symptoms were dramatically improved. Conclusions: This is the first description of a CNS-related malignancy in RTS patients. Although rare, the genomic instability and additional risk factors of this syndrome should be considered in choosing the course of treatment.
    Full-text · Article · Dec 2012 · Surgical Neurology International
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    • "Rothmund –Thomson syndrome, Baller-Gerold syndrome and RAPADILINO syndrome are three recessive genetic disorders which are characterised by a disparate array of symptoms including skin degeneration, growth deficiency, skeletal abnormalities and high predisposition to osteosarcomas. Although the precise mechanism by which these symptoms are generated is unclear, one protein which has been seen to be mutated in a high percentage of cases is the RecQ4 protein [1], [2]. "
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    ABSTRACT: The RecQ4 protein shows homology to both the S.cerevisiae DNA replication protein Sld2 and the DNA repair related RecQ helicases. Experimental data also suggest replication and repair functions for RecQ4, but the precise details of its involvement remain to be clarified. Here we show that depletion of DmRecQ4 by dsRNA interference in S2 cells causes defects consistent with a replication function for the protein. The cells show reduced proliferation associated with an S phase block, reduced BrdU incorporation, and an increase in cells with a subG1 DNA content. At the molecular level we observe reduced chromatin association of DNA polymerase-alpha and PCNA. We also observe increased chromatin association of phosphorylated H2AvD - consistent with the presence of DNA damage and increased apoptosis. Analysis of DmRecQ4 repair function suggests a direct role in NER, as the protein shows rapid but transient nuclear localisation after UV treatment. Re-localisation is not observed after etoposide or H2O2 treatment, indicating that the involvement of DmRecQ4 in repair is likely to be pathway specific. Deletion analysis of DmRecQ4 suggests that the SLD2 domain was essential, but not sufficient, for replication function. In addition a DmRecQ4 N-terminal deletion could efficiently re-localise on UV treatment, suggesting that the determinants for this response are contained in the C terminus of the protein. Finally several deletions show differential rescue of dsRNA generated replication and proliferation phenotypes. These will be useful for a molecular analysis of the specific role of DmRecQ4 in different cellular pathways.
    Full-text · Article · Nov 2012 · PLoS ONE
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    • "RTS, RAPADILINO and Baller- Gerold syndrome have a significant overlap of symptoms (Fig. 1), all occurring in tissues with a high proliferation rate. The absence of a strong correlation between specific mutations in RecQ4 and specific phenotypes (reviewed in Larizza et al., 2006 and Siitonen et al., 2009) has led some to propose that the three syndromes be reclassified as a single one (Van Maldergem et al., 2006). "
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    ABSTRACT: Recent work has greatly contributed to the understanding of the biology and biochemistry of RecQ4. It plays an essential non-enzymatic role in the formation of the CMG complex, and thus replication initiation, by means of its Sld2 homologous domain. The helicase domain of RecQ4 has now been demonstrated to possess 3'-5' DNA helicase activity, like the other members of the RecQ family. The biological purpose of this activity is still unclear, but helicase-dead mutants are unable to restore viability in the absence of wildtype RecQ4. This indicates that RecQ4 performs a second role, which requires helicase activity and is implicated in replication and DNA repair. Thus, it is clear that two helicases, RecQ4 and Mcm2-7, are integral to replication. The nature of the simultaneous involvement of these two helicases remains to be determined, and possible models will be proposed.
    Preview · Article · Jun 2010 · Critical Reviews in Biochemistry and Molecular Biology
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