Paolacci, Stefano ORCID: 0000-0002-5551-7520, Li, Yun, Agolini, Emanuele ORCID: 0000-0001-6543-6225, Bellacchio, Emanuele ORCID: 0000-0002-2757-849X, Arboleda-Bustos, Carlos E., Carrero, Dido, Bertola, Debora, Al-Gazali, Lihadh, Alders, Mariel, Altmueller, Janine, Arboleda, Gonzalo, Beleggia, Filippo ORCID: 0000-0003-0234-7094, Bruselles, Alessandro ORCID: 0000-0002-1556-4998, Ciolfi, Andrea, Gillessen-Kaesbach, Gabriele, Krieg, Thomas, Mohammed, Shehla, Mueller, Christian, Noyelli, Antonio, Ortega, Jenny, Sandoval, Adrian, Velasco, Gloria, Yigit, Goekhan, Arboleda, Humberto, Lopez-Otin, Carlos ORCID: 0000-0001-6964-1904, Wollnik, Bernd, Tartaglia, Marco ORCID: 0000-0001-7736-9672 and Hennekam, Raoul C. (2018). Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome. J. Med. Genet., 55 (12). S. 837 - 846. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-6244

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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 adolescent-onset 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Paolacci, StefanoUNSPECIFIEDorcid.org/0000-0002-5551-7520UNSPECIFIED
Li, YunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Agolini, EmanueleUNSPECIFIEDorcid.org/0000-0001-6543-6225UNSPECIFIED
Bellacchio, EmanueleUNSPECIFIEDorcid.org/0000-0002-2757-849XUNSPECIFIED
Arboleda-Bustos, Carlos E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carrero, DidoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bertola, DeboraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al-Gazali, LihadhUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alders, MarielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arboleda, GonzaloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beleggia, FilippoUNSPECIFIEDorcid.org/0000-0003-0234-7094UNSPECIFIED
Bruselles, AlessandroUNSPECIFIEDorcid.org/0000-0002-1556-4998UNSPECIFIED
Ciolfi, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gillessen-Kaesbach, GabrieleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krieg, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mohammed, ShehlaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noyelli, AntonioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ortega, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sandoval, AdrianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Velasco, GloriaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yigit, GoekhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arboleda, HumbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopez-Otin, CarlosUNSPECIFIEDorcid.org/0000-0001-6964-1904UNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tartaglia, MarcoUNSPECIFIEDorcid.org/0000-0001-7736-9672UNSPECIFIED
Hennekam, Raoul C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-164023
DOI: 10.1136/jmedgenet-2018-105528
Journal or Publication Title: J. Med. Genet.
Volume: 55
Number: 12
Page Range: S. 837 - 846
Date: 2018
Publisher: BMJ PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1468-6244
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NEONATAL PROGEROID SYNDROME; FREQUENT CAUSE; MUTATIONS; GENE; PHENOTYPE; SUBUNIT; GENOMEMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/16402

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