RNA processing defects of the helicase gene RECQL4 in a compound heterozygous Rothmund-Thomson patient

University of Milan, Milano, Lombardy, Italy
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 07/2003; 120A(3):395-9. DOI: 10.1002/ajmg.a.20154
Source: PubMed


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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    • "About two-third of RTS patients suffers from symmetrical growth retardation, of which in most cases the levels of growth hormone are normal.[1333] Sporadic case reports documented RTS patients who presented with other manifestations such as deafness,[1] gastrointestinal tract malformations,[2] and symptoms in the respiratory and hematological systems.[192128] "
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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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    • "No homozygous patient has been ever detected, raising the suspicion that this truncating mutation may have severe consequences. Indeed, we know by transcript analysis that the c.1573del T allele is not transcribed [30]. "
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    ABSTRACT: Rothmund-Thomson syndrome (RTS) is a genodermatosis presenting with a characteristic facial rash (poikiloderma) associated with short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, juvenile cataracts, skeletal abnormalities, radial ray defects, premature aging and a predisposition to cancer. The prevalence is unknown but around 300 cases have been reported in the literature so far. The diagnostic hallmark is facial erythema, which spreads to the extremities but spares the trunk, and which manifests itself within the first year and then develops into poikiloderma. Two clinical subforms of RTS have been defined: RTSI characterised by poikiloderma, ectodermal dysplasia and juvenile cataracts, and RTSII characterised by poikiloderma, congenital bone defects and an increased risk of osteosarcoma in childhood and skin cancer later in life. The skeletal abnormalities may be overt (frontal bossing, saddle nose and congenital radial ray defects), and/or subtle (visible only by radiographic analysis). Gastrointestinal, respiratory and haematological signs have been reported in a few patients. RTS is transmitted in an autosomal recessive manner and is genetically heterogeneous: RTSII is caused by homozygous or compound heterozygous mutations in the RECQL4 helicase gene (detected in 60-65% of RTS patients), whereas the aetiology in RTSI remains unknown. Diagnosis is based on clinical findings (primarily on the age of onset, spreading and appearance of the poikiloderma) and molecular analysis for RECQL4 mutations. Missense mutations are rare, while frameshift, nonsense mutations and splice-site mutations prevail. A fully informative test requires transcript analysis not to overlook intronic deletions causing missplicing. The diagnosis of RTS should be considered in all patients with osteosarcoma, particularly if associated with skin changes. The differential diagnosis should include other causes of childhood poikiloderma (including dyskeratosis congenita, Kindler syndrome and Poikiloderma with Neutropaenia), other rare genodermatoses with prominent telangiectasias (including Bloom syndrome, Werner syndrome and Ataxia-telangiectasia) and the allelic disorders, RAPADILINO syndrome and Baller-Gerold syndrome, which also share some clinical features. A few mutations recur in all three RECQL4 diseases. Genetic counselling should be provided for RTS patients and their families, together with a recommendation for cancer surveillance for all patients with RTSII. Patients should be managed by a multidisciplinary team and offered long term follow-up. Treatment includes the use of pulsed dye laser photocoagulation to improve the telangiectatic component of the rash, surgical removal of the cataracts and standard treatment for individuals who develop cancer. Although some clinical signs suggest precocious aging, life expectancy is not impaired in RTS patients if they do not develop cancer. Outcomes in patients with osteosarcoma are similar in RTS and non-RTS patients, with a five-year survival rate of 60-70%. The sensitivity of RTS cells to genotoxic agents exploiting cells with a known RECQL4 status is being elucidated and is aimed at optimizing the chemotherapeutic regimen for osteosarcoma.
    Full-text · Article · Jan 2010 · Orphanet Journal of Rare Diseases
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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.
    Full-text · Article · Feb 2003 · Journal of Human Genetics
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