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

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 R...

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Published in:	European journal of human genetics : EJHG 2014-11, Vol.22 (11), p.1298-1304
Main Authors:	Colombo, Elisa Adele, Fontana, Laura, Roversi, Gaia, Negri, Gloria, Castiglia, Daniele, Paradisi, Mauro, Zambruno, Giovanna, Larizza, Lidia
Format:	Article
Language:	eng
Subjects:	Alleles Amino Acid Sequence Arginine Cancer Cell Line Child Codon, Nonsense - genetics Codon, Nonsense - metabolism Codons Deoxyribonucleic acid DNA DNA, Complementary - genetics DNA, Complementary - isolation & purification Exons Female Gene expression Genetic testing Genetics Genodermatosis Genotype Genotype & phenotype Hair Humans Infant Male Molecular Sequence Data Mutation Osteosarcoma Patients Pedigree Phenotype Phenotypes Physiology Proteins RecQ Helicases - genetics RecQ Helicases - metabolism Ribonucleic acid RNA Rothmund-Thomson syndrome Rothmund-Thomson Syndrome - diagnosis Rothmund-Thomson Syndrome - genetics Sequence Analysis, DNA Serine Siblings Skin Skin - metabolism Transcription
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Summary:	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.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.(Arg758), p.(His831Argfs52)). 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.
ISSN:	1018-4813 1476-5438