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 - Altmüller, Janine
AU - Arboleda, Gonzalo
AU - Beleggia, Filippo
AU - Bruselles, Alessandro
AU - Ciolfi, Andrea
AU - Gillessen-Kaesbach, Gabriele
AU - Krieg, Thomas
AU - Mohammed, Shehla
AU - Müller, Christian
AU - Novelli, Antonio
AU - Ortega, Jenny
AU - Sandoval, Adrian
AU - Velasco, Gloria
AU - Yigit, G. khan
AU - Arboleda, Humberto
AU - Lopez-Otin, Carlos
AU - Wollnik, Bernd
AU - Tartaglia, Marco
AU - Hennekam, Raoul C.
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 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.
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 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85054960143&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30323018
U2 - https://doi.org/10.1136/jmedgenet-2018-105528
DO - https://doi.org/10.1136/jmedgenet-2018-105528
M3 - Article
C2 - 30323018
SN - 0022-2593
VL - 55
SP - 837
EP - 846
JO - Journal of medical genetics
JF - Journal of medical genetics
IS - 12
ER -