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Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.
- Source :
-
Journal of medical genetics [J Med Genet] 2018 Dec; Vol. 55 (12), pp. 837-846. Date of Electronic Publication: 2018 Oct 15. - Publication Year :
- 2018
-
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.<br />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.<br />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.<br />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.<br />Competing Interests: Competing interests: None declared.<br /> (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)
- Subjects :
- Adult
Amino Acid Sequence
Base Sequence
Computational Biology
Consanguinity
Female
Genotype
Haplotypes
Humans
Male
Models, Molecular
Mutation
Pedigree
Protein Conformation
RNA Polymerase III chemistry
Reproducibility of Results
Sequence Analysis, DNA
Structure-Activity Relationship
Exome Sequencing
Alleles
Fetal Growth Retardation diagnosis
Fetal Growth Retardation genetics
Genetic Association Studies
Genetic Predisposition to Disease
Genetic Variation genetics
Progeria diagnosis
Progeria genetics
RNA Polymerase III genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1468-6244
- Volume :
- 55
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of medical genetics
- Publication Type :
- Academic Journal
- Accession number :
- 30323018
- Full Text :
- https://doi.org/10.1136/jmedgenet-2018-105528