Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness

Author:

Sferra Antonella1,Fortugno Paola23,Motta Marialetizia1,Aiello Chiara1,Petrini Stefania4,Ciolfi Andrea1,Cipressa Francesca5,Moroni Isabella6,Leuzzi Vincenzo7ORCID,Pieroni Luisa8ORCID,Marini Federica910,Boespflug Tanguy Odile1112,Eymard-Pierre Eleonore13,Danti Federica Rachele6,Compagnucci Claudia1ORCID,Zambruno Giovanna1,Brusco Alfredo14ORCID,Santorelli Filippo M15,Chiapparini Luisa16,Francalanci Paola17,Loizzo Anna Livia18,Tartaglia Marco1ORCID,Cestra Gianluca5819,Bertini Enrico1ORCID

Affiliation:

1. Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy

2. Department of Life, Health and Environmental Sciences University of L’Aquila, 00167 Rome, Italy

3. Human Functional Genomics, IRCCS San Raffaele Pisana, 00166 Rome, Italy

4. Confocal Microscopy Core Facility, Research Laboratories, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy

5. University of Rome “Sapienza”, Department of Biology and Biotechnology, 00185 Rome, Italy

6. Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy

7. Department of Human Neuroscience, Unit of Child Neurology and Psychiatry, Sapienza University, 00185 Rome, Italy

8. Santa Lucia IRCCS Foundation, 00179 Rome, Italy

9. Institute of Biochemistry and Clinical Biochemistry, Università Cattolica del Sacro Cuore, 00168 Rome, Italy

10. Department of Laboratory Diagnostic and Infectious Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy

11. Service de Neurologie Pédiatrique, Centre de reference leucodystrophies et leucoencephalopathies de cause rare (LEUKOFRANCE), APHP Hopital Robert-Debré, 75019 Paris, France

12. Université de Paris, NeuroDiderot, UMR 1141 INSERM 75651 Paris, France

13. Service de Cytogénétique Médicale CHU de Clermont Ferrand, Hopital ESTAING 63003 Clermont Ferrand, France

14. Department of Medical Sciences, University of Torino, 10124 Turin, Italy

15. Molecular Medicine, IRCCS Stella Maris Foundation, 56128 Pisa, Italy

16. Neuroradiology Department, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy

17. Department of Laboratories, Pathology Unit, IRCCS Bambino Gesù Children's Hospital, 00165 Rome, Italy

18. DIDASCO Società Cooperativa Sociale- Centro di riabilitazione, 00185 Rome, Italy

19. Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), 00185 Rome, Italy

Abstract

Abstract Leukodystrophies are a heterogeneous group of rare inherited disorders that mostly involve the white matter of the CNS. These conditions are characterized by primary glial cell and myelin sheath pathology of variable aetiology, which causes secondary axonal degeneration, generally emerging with disease progression. Whole exome sequencing performed in five large consanguineous nuclear families allowed us to identify homozygosity for two recurrent missense variants affecting highly conserved residues of RNF220 as the causative event underlying a novel form of leukodystrophy with ataxia and sensorineural deafness. We report these two homozygous missense variants (p.R363Q and p.R365Q) in the ubiquitin E3 ligase RNF220 as the underlying cause of this novel form of leukodystrophy with ataxia and sensorineural deafness that includes fibrotic cardiomyopathy and hepatopathy as associated features in seven consanguineous families. Mass spectrometry analysis identified lamin B1 as the RNF220 binding protein and co-immunoprecipitation experiments demonstrated reduced binding of both RNF220 mutants to lamin B1. We demonstrate that RNF220 silencing in Drosophila melanogaster specifically affects proper localization of lamin Dm0, the fly lamin B1 orthologue, promotes its aggregation and causes a neurodegenerative phenotype, strongly supporting the functional link between RNF220 and lamin B1. Finally, we demonstrate that RNF220 plays a crucial role in the maintenance of nuclear morphology; mutations in primary skin fibroblasts determine nuclear abnormalities such as blebs, herniations and invaginations, which are typically observed in cells of patients affected by laminopathies. Overall, our data identify RNF220 as a gene implicated in leukodystrophy with ataxia and sensorineural deafness and document a critical role of RNF220 in the regulation of nuclear lamina. Our findings provide further evidence on the direct link between nuclear lamina dysfunction and neurodegeneration.

Funder

Italian Ministry of Health

Foundation for Myopathic Research

European Leukodystrophy Association

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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