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Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders.
Borgia, Paola; Baldassari, Simona; Pedemonte, Nicoletta; Alkhunaizi, Ebba; D'Onofrio, Gianluca; Tortora, Domenico; Calì, Elisa; Scudieri, Paolo; Balagura, Ganna; Musante, Ilaria; Diana, Maria Cristina; Pedemonte, Marina; Vari, Maria Stella; Iacomino, Michele; Riva, Antonella; Chimenz, Roberto; Mangano, Giuseppe D; Mohammadi, Mohammad Hasan; Toosi, Mehran Beiraghi; Ashrafzadeh, Farah; Imannezhad, Shima; Karimiani, Ehsan Ghayoor; Accogli, Andrea; Schiaffino, Maria Cristina; Maghnie, Mohamad; Soler, Miguel Angel; Echiverri, Karl; Abrams, Charles K; Striano, Pasquale; Fortuna, Sara; Maroofian, Reza; Houlden, Henry; Zara, Federico; Fiorillo, Chiara; Salpietro, Vincenzo.
Afiliación
  • Borgia P; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132, Genoa, Italy.
  • Baldassari S; Pediatric Neurology and Muscular Diseases Unit, IRCCS Giannina Gaslini Institute, 16147, Genoa, Italy.
  • Pedemonte N; Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.
  • Alkhunaizi E; Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.
  • D'Onofrio G; Department of Genetics, North York General Hospital, University of Toronto, Toronto, ON, Canada.
  • Tortora D; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132, Genoa, Italy.
  • Calì E; Pediatric Neurology and Muscular Diseases Unit, IRCCS Giannina Gaslini Institute, 16147, Genoa, Italy.
  • Scudieri P; Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.
  • Balagura G; Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.
  • Musante I; Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.
  • Diana MC; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132, Genoa, Italy.
  • Pedemonte M; Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.
  • Vari MS; Pediatric Neurology and Muscular Diseases Unit, IRCCS Giannina Gaslini Institute, 16147, Genoa, Italy.
  • Iacomino M; Pediatric Neurology and Muscular Diseases Unit, IRCCS Giannina Gaslini Institute, 16147, Genoa, Italy.
  • Riva A; Pediatric Neurology and Muscular Diseases Unit, IRCCS Giannina Gaslini Institute, 16147, Genoa, Italy.
  • Chimenz R; Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.
  • Mangano GD; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132, Genoa, Italy.
  • Mohammadi MH; Pediatric Neurology and Muscular Diseases Unit, IRCCS Giannina Gaslini Institute, 16147, Genoa, Italy.
  • Toosi MB; Unit of Pediatric Nephrology and Dialysis, Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Via Consolare Valeria 1, 98125, Messina, Italy.
  • Ashrafzadeh F; Department Pro.M.I.S.E. "G. D'Alessandro", University of Palermo, Palermo, Italy.
  • Imannezhad S; Department of Pediatrics, Zabol University of Medical Sciences, Zabol, Iran.
  • Karimiani EG; Pediatric Neurology Department, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.
  • Accogli A; Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
  • Schiaffino MC; Pediatric Neurology Department, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.
  • Maghnie M; Molecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace, London, SW170RE, UK.
  • Soler MA; Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, Iran.
  • Echiverri K; Division of Medical Genetics, Department of Specialized Medicine, Montreal Children's Hospital, McGill University Health Centre (MUHC), Montreal, QC, H4A 3J1, Canada.
  • Abrams CK; Department of Human Genetics, McGill University, Montreal, QC, Canada.
  • Striano P; Pediatric Clinic and Endocrinology Unit, Department of General and Specialist Pediatric Sciences, University of Genoa, 16147, Genoa, Italy.
  • Fortuna S; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132, Genoa, Italy.
  • Maroofian R; Pediatric Clinic and Endocrinology Unit, Department of General and Specialist Pediatric Sciences, University of Genoa, 16147, Genoa, Italy.
  • Houlden H; Computational Modelling of Nanoscale and Biophysical Systems Laboratory, Italian Institute of Technology, 16163, Genoa, Italy.
  • Zara F; Departments of Neurology and Ophthalmology, University of Kentucky, Lexington, 40506, USA.
  • Fiorillo C; Department of Neurology and Rehabilitation, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60607, USA.
  • Salpietro V; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132, Genoa, Italy.
Orphanet J Rare Dis ; 17(1): 286, 2022 07 19.
Article en En | MEDLINE | ID: mdl-35854306
BACKGROUND: Pathogenic variants in PEX-genes can affect peroxisome assembly and function and cause Zellweger spectrum disorders (ZSDs), characterized by variable phenotypes in terms of disease severity, age of onset and clinical presentations. So far, defects in at least 15 PEX-genes have been implicated in Mendelian diseases, but in some of the ultra-rare ZSD subtypes genotype-phenotype correlations and disease mechanisms remain elusive. METHODS: We report five families carrying biallelic variants in PEX13. The identified variants were initially evaluated by using a combination of computational approaches. Immunofluorescence and complementation studies on patient-derived fibroblasts were performed in two patients to investigate the cellular impact of the identified mutations. RESULTS: Three out of five families carried a recurrent p.Arg294Trp non-synonymous variant. Individuals affected with PEX13-related ZSD presented heterogeneous clinical features, including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy. Computational predictions highlighted the involvement of the Arg294 residue in PEX13 homodimerization, and the analysis of blind docking predicted that the p.Arg294Trp variant alters the formation of dimers, impairing the stability of the PEX13/PEX14 translocation module. Studies on muscle tissues and patient-derived fibroblasts revealed biochemical alterations of mitochondrial function and identified mislocalized mitochondria and a reduced number of peroxisomes with abnormal PEX13 concentration. CONCLUSIONS: This study expands the phenotypic and mutational spectrum of PEX13-related ZSDs and also highlight a variety of disease mechanisms contributing to PEX13-related clinical phenotypes, including the emerging contribution of secondary mitochondrial dysfunction to the pathophysiology of ZSDs.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de Zellweger Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Orphanet J Rare Dis Asunto de la revista: MEDICINA Año: 2022 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de Zellweger Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Orphanet J Rare Dis Asunto de la revista: MEDICINA Año: 2022 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido