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.
- wiedemann-rautenstrauch syndrome
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BW, MT and RCH contributed equally.
Contributors SP, YL, EA, CEA-B, DC, JA, CM, AN and GY performed biological sample processing, WES data interpretation, sequence data validation and segregation analyses, mutation screening, SNP. array analyses and data curation; EB carried out the structural analyses; DB, LA-G, MA, GA,. GG-K, TK, SM, JO, AS, GV, HA, CL-O and RCH recruited patients, collected biological samples and performed clinical evaluations; FB, AB and AC performed the WES data processing and analyses; BW, MT and RCH conceived the study, analysed and interpreted the data and wrote the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Parental/guardian consent obtained.
Ethics approval Medical Ethics Committee, Academic Medical Center, University of Amsterdam.
Provenance and peer review Not commissioned; externally peer reviewed.