TY - JOUR
T1 - Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome
AU - Paolacci, Stefano
AU - Li, Yun
AU - Agolini, Emanuele
AU - Bellacchio, Emanuele
AU - Arboleda-Bustos, Carlos E.
AU - Carrero, Dido
AU - Bertola, Debora
AU - Al-Gazali, Lihadh
AU - Alders, Mariel
AU - Altmuller, Janine
AU - Arboleda, Gonzalo
AU - Beleggia, Filippo
AU - Bruselles, Alessandro
AU - Ciolfi, Andrea
AU - Gillessen-Kaesbach, Gabriele
AU - Krieg, Thomas
AU - Mohammed, Shehla
AU - Muller, Christian
AU - Novelli, Antonio
AU - Ortega, Jenny
AU - Sandoval, Adrian
AU - Velasco, Gloria
AU - Yigit, Gokhan
AU - Arboleda, Humberto
AU - Lopez-Otin, Carlos
AU - Wollnik, Bernd
AU - Tartaglia, Marco
AU - Hennekam, Raoul C.
N1 - Funding Information:
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).
Funding Information:
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).
Publisher Copyright:
© Author(s) (or their employer(s)) 2018.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1136/jmedgenet-2018-105528
DO - 10.1136/jmedgenet-2018-105528
M3 - Article
C2 - 30323018
AN - SCOPUS:85054960143
SN - 0022-2593
VL - 55
SP - 837
EP - 846
JO - Journal of medical genetics
JF - Journal of medical genetics
IS - 12
ER -