An unusual mutation in RECQ4 gene leading to Rothmund–Thomson syndrome

Balraj, Pauline; Concannon, Patrick; Jamal, A. Rahman A.; Beghini, Alessandro; Hoe, T S; Khoo, Alan Soo‐Beng; Volpi, L.

doi:10.1016/s0027-5107(02)00189-6

Cited by 34 publications

(27 citation statements)

References 8 publications

(10 reference statements)

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“…The region is required for the initiation of DNA replication, in particular for chromatin binding of DNA polymerase ␣. In humans, mutations in RecQ4 are responsible for some cases of Rothmund-Thomson syndrome (2,16,20), suggesting that RecQ4 is important for preventing genome instability and that mutations in it might lead to cancer or premature aging (1,7,9). Here we report that vertebrate RecQ4 performs an essential role in the formation of replication machinery through interaction with Cut5.…”

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confidence: 73%

“…1A). A further database search with the full-length Xenopus sequence revealed that it shares the highest similarity with mammalian RecQ4, whose mutation has been implicated in the generation of some cases of Rothmund-Thomson syndrome in humans (2,16,20). Because the sequence shows greater similarity to that of metazoan RecQ4 than to that of yeast Sld2/Drc1, we hereafter call this gene product Xenopus RecQ4.…”

Section: Resultsmentioning

confidence: 99%

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The N-Terminal Noncatalytic Region of Xenopus RecQ4 Is Required for Chromatin Binding of DNA Polymerase α in the Initiation of DNA Replication

Matsuno

Kumano

Kubota

et al. 2006

Molecular and Cellular Biology

162

200

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Recruitment of DNA polymerases onto replication origins is a crucial step in the assembly of eukaryotic replication machinery. A previous study in budding yeast suggests that Dpb11 controls the recruitment of DNA polymerases ␣ and onto the origins. Sld2 is an essential replication protein that interacts with Dpb11, but no metazoan homolog has yet been identified. We isolated Xenopus RecQ4 as a candidate Sld2 homolog. RecQ4 is a member of the metazoan RecQ helicase family, and its N-terminal region shows sequence similarity with Sld2. In Xenopus egg extracts, RecQ4 is essential for the initiation of DNA replication, in particular for chromatin binding of DNA polymerase ␣. An N-terminal fragment of RecQ4 devoid of the helicase domain could rescue the replication activity of RecQ4-depleted extracts, and antibody against the fragment inhibited DNA replication and chromatin binding of the polymerase. Further, N-terminal fragments of RecQ4 physically interacted with Cut5, a Xenopus homolog of Dpb11, and their ability to bind to Cut5 closely correlated with their ability to rescue the replication activity of the depleted extracts. Our data suggest that RecQ4 performs an essential role in the assembly of replication machinery through interaction with Cut5 in vertebrates.

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confidence: 73%

Section: Resultsmentioning

confidence: 99%

The N-Terminal Noncatalytic Region of Xenopus RecQ4 Is Required for Chromatin Binding of DNA Polymerase α in the Initiation of DNA Replication

Matsuno

Kumano

Kubota

et al. 2006

Molecular and Cellular Biology

162

200

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“…2,19 Molecular characterisation of transcripts has occasionally disclosed the effect of RECQL4 mutations overlooked by DNA analysis. 20 The current study shows that the functional effects of mutations identified by DNA analysis may be better interpreted by RNA analysis. Because of the above considerations, the clinical utility gene card for RTS 21 recommends that the characterisation of RECQL4 mutations should always include RNA analysis.…”

Section: Growth Parametersmentioning

confidence: 73%

Novel physiological RECQL4 alternative transcript disclosed by molecular characterisation of Rothmund–Thomson Syndrome sibs with mild phenotype

et al. 2014

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Rothmund-Thomson syndrome is a rare genodermatosis caused by biallelic mutations of the RECQL4 gene and is characterised by poikiloderma, sparse hair, eyelashes and/or eyebrows, small stature, skeletal and dental abnormalities and cancer predisposition. Mutations predicted to result in the loss of RECQL4 protein have been associated with osteosarcoma risk, but mutation(s)-phenotype correlations are better addressed by combined DNA and RNA analyses. We describe two siblings with a mild phenotype, mainly restricted to the skin, who carry the unreported paternal c.2272C4T alteration in exon 14 and the previously reported maternal exon 15 c.2492_2493delAT, both predicted to result in premature termination codons (p.(Arg758*), p.(His831Argfs*52)). However real-time and transcript analysis showed, in the carrier father and affected daughter, increased levels of a novel RECQL4 physiological alternative transcript with partial in-frame skipping of exon 14, generated by increased usage of a weak cryptic splice site. This alternative transcript is expressed in all controls and tested tissues, its upregulation is specific to the paternal c.2272C4T mutation and depends on the abrogation of the binding motifs for SF2 and SRp55 serine/arginine-rich proteins with bypass of the mutation site located in the skipped exon 14 portion. Moreover, in the proband the increased levels of the alternative transcript, likely encoding a protein isoform with residual activity, may compensate for the dearth of the canonical transcript with the c.2492_2493delAT, accounting for the mild clinical phenotype of the siblings. Our results emphasise the value of RNA analysis to better predict the effects of RECQL4 mutations on the clinical phenotype. Keywords: Rothmund-Thomson; mild phenotype; RECQL4; alternative splicing; exonic splicing enhancer; hypomorphic mutation INTRODUCTION Rothmund-Thomson syndrome (RTS, MIM#268400) is a clinically and genetically heterogeneous autosomal recessive disorder caused by biallelic mutations of the RECQL4 gene (MIM*603780) 1 in up to 66% of patients. 2 To date, more than 60 different RECQL4 mutations, only a few recurrent, have been described in RECQL4-related diseases, 45 of which were in patients with RTS, defined as RTS type II. 3-6 RECQL4-negative patients are classified as RTS type I. 3 The relationship between RECQL4 genotype and syndromic phenotype depends on mutation type and intragenic position and the specific combination of two different mutations, which makes (with a few exceptions) each case incomparable to others previously described. It has been proposed that in RTS patients, 'deleterious' RECQL4 mutations, predicted to lead to truncated proteins, predispose to osteosarcoma 2 and skeletal malformations. 7 Until functional studies, currently available for a restricted number of RECQL4 mutations, 8 unravel possible genotype-phenotype correlations, the analysis of mutant alleles at the transcript level may complement DNA analysis in predicting the effect of mutations on the clinical phenotype, includi...

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“…Identification of two novel RECQL4 exonic SNPs and genomic characterization of the IVS12 minisatellite Received: October 24, 2002/ Accepted: November 21, 2002 MIM#268400; Kitao et al 1999b;Lindor et al 2000;Wang et al 2002;Balraj et al 2002), a rare autosomal recessive genodermatosis, which, in addition to the poikilodermatous rash, has a variable clinical presentation and is associated with genomic instability and predisposition to malignancy (Wang et al 2001).…”

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confidence: 99%

“…During RECQL4 gene mutation screenings of patients with a clinical diagnosis of RTS, we identified in the RECQL4 coding region two novel and one already described (Balraj et al 2002) single-nucleotide polymorphism (SNP) falling into predicted functional exonic splicing enhancers (ESEs). ESEs are cis-acting elements that function as binding sites for serine/arginine-rich (SR) proteins, a family of essential splicing factors that are also involved in alternative splicing regulation (Cartegni et al 2002).…”

mentioning

confidence: 99%

Identification of two novel RECQL4 exonic SNPs and genomic characterization of the IVS12 minisatellite

Roversi¹,

Beghini²,

Zambruno

et al. 2003

J Hum Genet

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An unusual mutation in RECQ4 gene leading to Rothmund–Thomson syndrome

Cited by 34 publications

References 8 publications

The N-Terminal Noncatalytic Region of Xenopus RecQ4 Is Required for Chromatin Binding of DNA Polymerase α in the Initiation of DNA Replication

The N-Terminal Noncatalytic Region of Xenopus RecQ4 Is Required for Chromatin Binding of DNA Polymerase α in the Initiation of DNA Replication

Novel physiological RECQL4 alternative transcript disclosed by molecular characterisation of Rothmund–Thomson Syndrome sibs with mild phenotype

Identification of two novel RECQL4 exonic SNPs and genomic characterization of the IVS12 minisatellite

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