Abstract
Original language | English |
---|---|
Pages (from-to) | 837-846 |
Number of pages | 10 |
Journal | Journal of Medical Genetics |
Volume | 55 |
Issue number | 12 |
DOIs | |
Publication status | Published - 2018 |
Keywords
- DNA
- polr3a protein
- protein
- unclassified drug
- adolescent
- allele
- Article
- ataxia
- clinical article
- computer model
- family
- female
- gene identification
- gene location
- genetic variability
- haplotype
- human
- male
- priority journal
- progeria
- spasticity
- whole exome sequencing
- wiedemann rautenstrauch syndrome
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Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome. / Paolacci, S.; Li, Y.; Agolini, E. et al.
In: Journal of Medical Genetics, Vol. 55, No. 12, 2018, p. 837-846.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome
AU - Paolacci, S.
AU - Li, Y.
AU - Agolini, E.
AU - Bellacchio, E.
AU - Arboleda-Bustos, C.E.
AU - Carrero, D.
AU - Bertola, D.
AU - Al-Gazali, L.
AU - Alders, M.
AU - Altmuller, J.
AU - Arboleda, G.
AU - Beleggia, F.
AU - Bruselles, A.
AU - Ciolfi, A.
AU - Gillessen-Kaesbach, G.
AU - Krieg, T.
AU - Mohammed, S.
AU - Muller, C.
AU - Novelli, A.
AU - Ortega, J.
AU - Sandoval, A.
AU - Velasco, G.
AU - Yigit, G.
AU - Arboleda, H.
AU - Lopez-Otin, C.
AU - Wollnik, B.
AU - Tartaglia, M.
AU - Hennekam, R.C.
N1 - Cited By :2 Export Date: 11 April 2019 CODEN: JMDGA Correspondence Address: Hennekam, R.C.; Department of Paediatrics, Amsterdam UMC - Location AMC, University of AmsterdamNetherlands; email: r.c.hennekam@amc.uva.nl Chemicals/CAS: DNA, 9007-49-2; protein, 67254-75-5 Funding details: Deutsche Forschungsgemeinschaft, D02, SFB1002 Funding details: Ministry of Health Funding text 1: 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). 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PY - 2018
Y1 - 2018
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. © Author(s) (or their employer(s)) 2018.
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. © Author(s) (or their employer(s)) 2018.
KW - DNA
KW - polr3a protein
KW - protein
KW - unclassified drug
KW - adolescent
KW - allele
KW - Article
KW - ataxia
KW - clinical article
KW - computer model
KW - family
KW - female
KW - gene identification
KW - gene location
KW - genetic variability
KW - haplotype
KW - human
KW - male
KW - priority journal
KW - progeria
KW - spasticity
KW - whole exome sequencing
KW - wiedemann rautenstrauch syndrome
U2 - 10.1136/jmedgenet-2018-105528
DO - 10.1136/jmedgenet-2018-105528
M3 - Article
VL - 55
SP - 837
EP - 846
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
SN - 0022-2593
IS - 12
ER -