Rothmund-Thomson Syndrome is a rare genodermatosis caused by biallelic mutations of the RECQL4 gene and 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.2272C>T alteration in exon 14 and the previously reported maternal exon 15 c.2492_2493delAT, both predicted to result in premature termination codons (p.R758*, p.H831Rfs51*). 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.2272C>T 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.
|Titolo:||Novel physiological RECQL4 alternative transcript disclosed by molecular characterisation of Rothmund-Thomson Syndrome sibs with mild phenotype|
|Parole Chiave:||Rothmund-Thomson; mild phenotype; RECQL4; alternative splicing; exonic splicing enhancer; hypomorphic mutation|
|Settore Scientifico Disciplinare:||Settore MED/03 - Genetica Medica|
|Data di pubblicazione:||nov-2014|
|Data ahead of print / Data di stampa:||12-feb-2014|
|Digital Object Identifier (DOI):||10.1038/ejhg.2014.18|
|Appare nelle tipologie:||01 - Articolo su periodico|