Rothmund-Thomson syndrome due toRECQ4 helicase mutations: Report and clinical and molecular comparisons with Bloom syndrome and Werner syndrome

Lindor, Noralane M.; Furuichi, Yasuhiro; Kitao, Saori; Shimamoto, Akiro; Arndt, Carola A.S.; Jalal, Syed M.

doi:10.1002/(sici)1096-8628(20000131)90:3<223::aid-ajmg7>3.0.co;2-z

Cited by 164 publications

(106 citation statements)

References 33 publications

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“…This amino acid substitution is not found in the SNP database and may be specifically linked to the p.Cys525AlafsX33 mutation or represent a rare haplotype. 3,5,6 It is difficult to interpret the effects of the amino acid substitutions because there is no crystallographic model for RECQL4 and the exact physiological role of this protein is unknown. However, bioinformatics tool can be used to predict the significance of the amino acid substitution on the protein.…”

Section: Recql4 Mutationsmentioning

confidence: 73%

The mutation spectrum in RECQL4 diseases

et al. 2008

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Mutations in the RECQL4 gene can lead to three clinical phenotypes with overlapping features. All these syndromes, Rothmund-Thomson (RTS), RAPADILINO and Baller-Gerold (BGS), are characterized by growth retardation and radial defects, but RAPADILINO syndrome lacks the main dermal manifestation, poikiloderma that is a hallmark feature in both RTS and BGS. It has been previously shown that RTS patients with RECQL4 mutations are at increased risk of osteosarcoma, but the precise incidence of cancer in RAPADILINO and BGS has not been determined. Here, we report that RAPADILINO patients identified as carriers of the c.1390 þ 2delT mutation (p.Ala420_Ala463del) are at increased risk to develop lymphoma or osteosarcoma (6 out of 15 patients). We also summarize all the published RECQL4 mutations and their associated cancer cases and provide an update of 14 novel RECQL4 mutations with accompanying clinical data.

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Section: Recql4 Mutationsmentioning

confidence: 73%

The mutation spectrum in RECQL4 diseases

et al. 2008

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“…Our recent studies demonstrate that BLM and WRN are structurespecific helicases that demonstrate a marked similarity in DNA substrate preference (13). Also, WS and BS patients share a number of phenotypic characteristics (14), indicating a possible "cross-talk" in the intracellular pathways in which BLM and WRN function. In this context, as mentioned above, both helicases have common interacting partners (p53, RPA).…”

mentioning

confidence: 99%

Colocalization, Physical, and Functional Interaction between Werner and Bloom Syndrome Proteins

Kobbe¹,

Karmakar²,

Dawut³

et al. 2002

Journal of Biological Chemistry

124

104

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The RecQ helicase family comprises a conserved group of proteins implicated in several aspects of DNA metabolism. Three of the family members are defective in heritable diseases characterized by abnormal growth, premature aging, and predisposition to malignancies. These include the WRN and BLM gene products that are defective in Werner and Bloom syndromes, disorders which share many phenotypic and cellular characteristics including spontaneous genomic instability. Here, we report a physical and functional interaction between BLM and WRN. These proteins were coimmunoprecipitated from a nuclear matrix-solubilized fraction, and the purified recombinant proteins were shown to interact directly. Moreover, BLM and WRN colocalized to nuclear foci in three human cell lines. Two regions of WRN that mediate interaction with BLM were identified, and one of these was localized to the exonuclease domain of WRN. Functionally, BLM inhibited the exonuclease activity of WRN. This is the first demonstration of a physical and functional interaction between RecQ helicases. Our observation that RecQ family members interact provides new insights into the complex phenotypic manifestations resulting from the loss of these proteins. Werner syndrome (WS)1 is a hallmark premature aging syndrome associated with increased malignancies and genomic instability (1). The protein defective in WS, Werner syndrome protein (WRN), is an ATP-dependent 3Ј-5Ј-helicase and also has a 3Ј-5Ј-exonuclease activity (2). Recently, a number of protein partners for WRN have been identified. These include proliferating cell nuclear antigen (3), replication protein A (RPA) (4), DNA topoisomerase I (3), the Ku heterodimer (5, 6), DNA polymerase ␦ (7), and p53 (8). Some of these interactions are not only physical but are also functional. Each of these binding proteins is involved in some form of DNA metabolism, such as DNA recombination, replication, and repair, and in the resolution of alternative DNA structures (1, 2). This suggests that WRN plays a role in a number of key DNA metabolic pathways. Bloom syndrome (BS) is a highly cancer-prone disease associated with increased genomic instability and elevated sister chromatid exchanges. The protein defective in this disorder, Bloom syndrome protein (BLM), is a 3Ј-5Ј-helicase (9). BLM binds to RPA, p53, topoisomerase III␣, and RAD51 and is a component of the BRCA1-associated genome surveillance complex (10). This links BLM with proteins implicated in several aspects of DNA metabolism (DNA recombination, replication, and repair).BLM and WRN both belong to the RecQ family of helicases, which are conserved from Escherichia coli to human (11). WRN is unique among the human RecQ helicases in having an exonuclease domain in the N-terminal region of the protein. A number of the RecQ helicases have been purified, and their biochemical properties have been characterized (11). There is considerable interest in the substrate specificities of each of these enzymes and in possible differences between them. However, so far there h...

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“…Genomic instability is a common feature found in cells from these diseases. This is manifested as a high rate of sister chromatid exchanges in BS cells as well as acquired chromosomal mosaicism in WS and RTS cells (52).…”

Section: Recq Family Helicases: Wrn and Blmmentioning

confidence: 99%

p53-Mediated Apoptosis and Genomic Instability Diseases

Robles

2001

Acta Oncologica

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Rothmund-Thomson syndrome due toRECQ4 helicase mutations: Report and clinical and molecular comparisons with Bloom syndrome and Werner syndrome

Cited by 164 publications

References 33 publications

The mutation spectrum in RECQL4 diseases

The mutation spectrum in RECQL4 diseases

Colocalization, Physical, and Functional Interaction between Werner and Bloom Syndrome Proteins

p53-Mediated Apoptosis and Genomic Instability Diseases

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