The mutation spectrum in RECQL4 diseases

Siitonen, H. Annika; Sotkasiira, Jenni; Biervliet, Martine; Benmansour, Abdelmadjid; Capri, Yline; Cormier‐Daire, Valérie; Crandall, Barbara F.; Hannula-Jouppi, Katariina; Hennekam, Raoul C. M.; Herzog, Denise; Keymolen, Kathelijn; Lipsanen‐Nyman, Marita; Miny, Peter; Plon, Sharon E.; Riedl, Stefan; Sarkar, Ajoy K.; Vargas, Fernando; Verloes, Alain; Wang, Lisa L.; Kääriäinen, Helena; Kestilä, Marjo

doi:10.1038/ejhg.2008.154

Cited by 190 publications

(219 citation statements)

References 42 publications

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“…10 Incomplete clinical sensitivity could be explained by: (i) locus heterogeneity; (ii) mutations within the promoter of the gene; or (iii) mutations not identifiable by direct sequencing, such as deletions of entire exons or of the entire gene. Indeed, in a few patients (5 out of 64 listed in Siitonen et al 1 ), only one RECQL4 mutation is detectable.…”

Section: Clinical Sensitivity (Proportion Of Positive Tests If the DImentioning

confidence: 98%

“…More than 60 disease-causing mutations have been reported, of which at least 40 have been detected in RTS patients. 1,2 The types of observed mutations are as follows, in order of decreasing prevalence: nonsense or frameshift mutations; splicing alterations, including substitutions at canonical splice junctions or at splice-site consensus sequences and subtle intronic deletions that reduce intron size below the threshold (o80 bp) required for correct splicing; 3,4 and missense mutations. There are a few recurrent mutations, among which the most common, exon 9 c.1573delT (p.Cys525AlafsX33), has been detected in patients with all three RECQL4-associated diseases.…”

Section: Mutational Spectrummentioning

confidence: 99%

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Clinical utility gene card for: Rothmund–Thomson syndrome

2012

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Section: Clinical Sensitivity (Proportion Of Positive Tests If the DImentioning

confidence: 98%

Section: Mutational Spectrummentioning

confidence: 99%

Clinical utility gene card for: Rothmund–Thomson syndrome

2012

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“…Out of 10 patients, 4 developed osteosarcoma. 18 However, the comparison is hard as the mutation was combined with a different truncating mutation in each of the nine heterozygous patients, whereas enhancement of the AltTr, likely driven by the deficit of the transcripts from the second mutant allele, might not occur in the only homozygous patient. Only a prolonged and careful follow-up of the siblings, now 9 years and 3 months old and 1 year and 7 months old, will allow validation of the suggested correlation between their genotype at the RECQL4 locus and the mild clinical presentation.…”

Section: Growth Parametersmentioning

confidence: 99%

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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“…RTS is a rare autosomal-recessive disorder due to compound heterozygous mutations in a DNA helicase gene, known as RECQL4, on chromosome 8q24.3, although in around 40% of patients, no mutations have been identified [52,53]. The skin appears normal at birth and then poikiloderma appears including atrophy, irregular pigmentation and telangiectasias beginning during the first 3-6 months of age.…”

Section: Rothmund-thomson Syndrome (Poikiloderma Congenital Rts)mentioning

confidence: 99%

Premature Greying of Hair (Premature Canities): A Concern for Parent and Child

Nigam¹,

Nigam²

2017

Pigmentary Disorders

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Hair goes grey with chronological aging. Premature hair greying may have significant adverse effects on the appearance, self-esteem, and socio-cultural acceptance of the affected individual. The exact aetiopathogenetic mechanism causing premature greying is still not clear and much speculative. Premature canities may appear alone as an autosomal dominant trait or it may occur in association with certain other disorders. The genes Pax3 and MITE play an important role in melanocyte stem cell maintenance and differentiation. Defective melanosomal transfer to the cortical keratinocytes or melanin incontinence due to melanocyte degeneration is also believed to contribute to greying. Despite the extensive molecular research being carried out to understand the pathogenesis of canities, treatment options still remain far from satisfactory and no effective therapy is available. Premature greying is a feature in a number of well recognised syndromes. A number of other conditions have also been observed to be associated with premature greying of hair.

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The mutation spectrum in RECQL4 diseases

Cited by 190 publications

References 42 publications

Clinical utility gene card for: Rothmund–Thomson syndrome

Clinical utility gene card for: Rothmund–Thomson syndrome

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

Premature Greying of Hair (Premature Canities): A Concern for Parent and Child

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