RNA processing defects of the helicase gene RECQL4 in a compound heterozygous Rothmund-Thomson patient
ABSTRACT Rothmund-Thomson syndrome (RTS) (OMIM 268400) is an autosomal recessive genodermatosis associated with genomic instability and increased risk of mesenchymal cancers. Mutations in the RECQL4 gene, encoding a protein of the family of Werner (WRN) and Bloom (BLM) helicases, have been identified in a subset of RTS patients. Apart from congenital poikiloderma, the clinical presentation of RTS is widely variable, raising the question of the possible existence of a second locus. Results herein reported on a sporadic Caucasian patient emphasize the concept that mutation analyses at both DNA and RNA level complement the genetic defect suggested by clinical and cytogenetic signs. The patient presented with typical congenital poikiloderma and bone defects and exhibited significant genomic instability in the peripheral blood karyotype. By RECQL4 DNA mutation analysis, he was found to carry a 1473delT (mut 5) on one allele and an AG to AC change at the 3'-splice site of exon 13 (a variant of mut 4) on the second allele. RT-PCR analysis of RECQL4 cDNA encompassing the entire helicase domain showed diffuse splicing defects indicating that the loss of a single 3'-splice signal motif disregulates the correct splice-site selection and affects the overall RNA processing. The presence of an unstable minisatellite which ends at 3'-splice site of IVS12 may enhance the mutation at this site. This genomic feature together with a number of short introns in the RECQL4 gene may account for the common missplicing of RECQL4 mRNA. While it is possible that defects of RECQL4 mRNA processing might account for part of the clinical variability observed for this syndrome, only a thorough analysis at both genomic and RNA level may allow a genotype-phenotype correlation in RTS patients, restricting the search of a second RTS locus to the specific patients.
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ABSTRACT: Rothmund-Thomson syndrome is a rare autosomal recessive disorder characterized by a widely heterogeneous clinical presentation. Only a subset of clinically diagnosed patients carry RECQL4 gene mutations, probably because of their genetic heterogeneity and/or the complexity of molecular testing. We here describe the polymorphic sites of the RECQL4 gene that detail its genomic structure and may be of interest as modulators of the splicing process and gene expression. We characterized two novel and one already described single-nucleotide polymorphism in the coding region of the RECQL4 gene, which were shown by the exonic splicing enhancer (ESE) score matrix to fall into high-score motifs recognized by serine/arginine-rich proteins. We also describe the genomic structure of a G-C rich minisatellite flanking the 3' splice site of IVS12 in the helicase domain of the RECQL4 gene, which may enhance mutations such as those described at the IVS12 acceptor site. RECQL4 polymorphic sites may be useful for identifying alleles associated with missplicing and, more generally, in cancer-susceptibility association studies.Journal of Human Genetics 02/2003; 48(2):107-9. DOI:10.1007/s100380300016 · 2.53 Impact Factor
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ABSTRACT: RecQ helicases are conserved from bacteria to man. Mutations in three of the human RecQ family members give rise to genetic disorders characterized by genomic instability and a predisposition to cancer. RecQ helicases are therefore caretakers of the genome, and although they do not directly regulate tumorigenesis, they influence stability and the rate of accumulation of genetic alterations, which in turn, result in tumorigenesis. Maintenance of genome stability by RecQ helicases likely involves their participation in DNA replication, recombination, and repair pathways.Biochimie 12/2003; 85(11):1185-93. DOI:10.1016/j.biochi.2003.10.006 · 3.12 Impact Factor
- American Journal of Medical Genetics Part A 08/2004; 129A(1):102; author reply 103. DOI:10.1002/ajmg.a.20636 · 2.05 Impact Factor