Abstract
Background Wiedemann-Rautenstrauch syndrome (WRS) is a form of segmental progeria presenting neonatally, characterised by growth retardation, sparse scalp hair, generalised lipodystrophy with characteristic local fatty tissue accumulations and unusual face. We aimed to understand its molecular cause. Methods We performed exome sequencing in two families, targeted sequencing in 10 other families and performed in silico modelling studies and transcript processing analyses to explore the structural and functional consequences of the identified variants. Results Biallelic POLR3A variants were identified in eight affected individuals and monoallelic variants of the same gene in four other individuals. In the latter, lack of genetic material precluded further analyses. Multiple variants were found to affect POLR3A transcript processing and were mostly located in deep intronic regions, making clinical suspicion fundamental to detection. While biallelic POLR3A variants have been previously reported in 4H syndrome and adolescentonset progressive spastic ataxia, recurrent haplotypes specifically occurring in individuals with WRS were detected. All WRS-associated POLR3A amino acid changes were predicted to perturb substantially POLR3A structure/function. Conclusion Biallelic mutations in POLR3A, which encodes for the largest subunit of the DNA-dependent RNA polymerase III, underlie WRS. No isolated functional sites in POLR3A explain the phenotype variability in POLR3A-related disorders. We suggest that specific combinations of compound heterozygous variants must be present to cause the WRS phenotype. Our findings expand the molecular mechanisms contributing to progeroid disorders.
| Original language | English |
|---|---|
| Journal | Journal of Medical Genetics |
| Volume | 55 |
| Issue number | 12 |
| Pages (from-to) | 837-846 |
| Number of pages | 10 |
| ISSN | 0022-2593 |
| DOIs | |
| Publication status | Published - 01.12.2018 |
Funding
7Department of Paediatric, college of Medicine and Health Science, United arab emirates University, al ain, United arab emirates 8Department of clinical genetics, academic Medical centre, University of amsterdam, amsterdam, the netherlands 9cologne centre for genomics and centre for Molecular Medicine cologne, University of cologne, cologne, germany 10Department of internal Medicine i, University Hospital cologne, cologne, germany 11Dipartimento di Oncologia e Medicina Molecolare, istituto Superiore di Sanità, rome, italy 12institute of Human genetics, University of lübeck, lübeck, germany 13Department of Dermatology, University Hospital cologne, cologne, germany 14Department of clinical genetics, guy’s Hospital, london, UK 15Department of Paediatrics, amsterdam UMc – location aMc, University of amsterdam, amsterdam, the netherlands Acknowledgements the authors are pleased to thank all participating families and referring physicians for their generous collaboration and Serenella Venanzi (istituto Superiore di Sanità, rome) for technical assistance. this work received support from the Deutsche Forschungsgemeinschaft (SFB1002 project D02 to BW), italian Ministry of Health (ricerca corrente 2016 and 2017 to an and Mt) and Fondazione Bambino gesù (Vite coraggiose to Mt). The authors are pleased to thank all participating families and referring physicians for their generous collaboration and Serenella Venanzi (Istituto Superiore di Sanita, Rome) for technical assistance. This work received support from the Deutsche Forschungsgemeinschaft (SFB1002 project D02 to BW), Italian Ministry of Health (Ricerca Corrente 2016 and 2017 to AN and MT) and Fondazione Bambino Gesu (Vite Coraggiose to MT).
Research Areas and Centers
- Research Area: Medical Genetics
