2. Academic Validation
  3. Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness

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

  • Brain. 2021 Nov 29;144(10):3020-3035. doi: 10.1093/brain/awab185.
Antonella Sferra 1,  Paola Fortugno 2 3,  Marialetizia Motta 1,  Chiara Aiello 1,  Stefania Petrini 4,  Andrea Ciolfi 1,  Francesca Cipressa 5,  Isabella Moroni 6,  Vincenzo Leuzzi 7,  Luisa Pieroni 8,  Federica Marini 9 10,  Odile Boespflug Tanguy 11 12,  Eleonore Eymard-Pierre 13,  Federica Rachele Danti 6,  Claudia Compagnucci 1,  Giovanna Zambruno 1,  Alfredo Brusco 14,  Filippo M Santorelli 15,  Luisa Chiapparini 16,  Paola Francalanci 17,  Anna Livia Loizzo 18,  Marco Tartaglia 1,  Gianluca Cestra 5 8 19,  Enrico Bertini 1
Affiliations

Affiliations

  • 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.
PMID: 33964137 DOI: 10.1093/brain/awab185
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.

Keywords

fibrotic cardiomyopathy; hepatopathy; laminopathies; leukodystrophy; sensorineural-deafness.

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