Biallelic EPB41L3 variants underlie a developmental disorder with seizures and myelination defects.

Autor: Werren EA; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Advanced Precision Medicine Laboratory, The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA., Rodriguez Bey G; Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA., Majethia P; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, India., Kaur P; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, India., Patil SJ; Division of Medical Genetics, Narayana Health-Mazumdar Shaw Medical Center, Narayana Health, Bangalore 560099, India., Kekatpure M; Department of Neurology, Division of Pediatric Neurology, Narayana Health-Mazumdar Shaw Medical Center, Narayana Health, Bangalore 560099, India., Afenjar A; Reference Center for Malformations and Congenital Diseases of the Cerebellum and Unit of Molecular Genetics, Trousseau Hospital, Department of Genetics, APHP Sorbonne University, Paris 75012, France., Qebibo L; Reference Center for Malformations and Congenital Diseases of the Cerebellum and Unit of Molecular Genetics, Trousseau Hospital, Department of Genetics, APHP Sorbonne University, Paris 75012, France.; Developmental Brain Disorders Laboratory, Imagine Institute, Paris 75015, France., Burglen L; Reference Center for Malformations and Congenital Diseases of the Cerebellum and Unit of Molecular Genetics, Trousseau Hospital, Department of Genetics, APHP Sorbonne University, Paris 75012, France.; Developmental Brain Disorders Laboratory, Imagine Institute, Paris 75015, France., Tomoum H; Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo 11591, Egypt., Demurger F; Department of Clinical Genetics, Vannes Hospital, Vannes 56017, France., Duborg C; Service de Génétique Moléculaire, CHU Rennes, Hôpital Sud, CLAD Ouest, Rennes 40770, France., Siddiqui S; Department of Neuroimaging and Interventional Radiology, STAR Institute of Neurosciences, STAR Hospitals, Hyderabad 500034, India., Tsan YC; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Abdullah U; University Institute of Biochemistry and Biotechnology (UIBB), PMAS-Arid Agriculture University Rawalpindi, Rawalpindi 46300, Pakistan., Ali Z; Centre for Biotechnology and Microbiology, University of Swat, Charbagh, Swat, Khyber Pakhtunkhwa 19120, Pakistan., Saadi SM; Human Molecular Genetics Laboratory, NIBGE-PIEAS, Faisalabad 61010, Pakistan., Baig SM; Faculty of Life Sciences, Health Services Academy, Park Road, Islamabad 44000, Pakistan.; Department of Biological and Biomedical Sciences, Aga Khan University, Karachi 74800, Pakistan., Houlden H; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK., Maroofian R; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK., Padiath QS; Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA.; Department of Neurobiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA., Bielas SL; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Shukla A; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, India.
Jazyk: angličtina
Zdroj: Brain : a journal of neurology [Brain] 2024 Sep 18. Date of Electronic Publication: 2024 Sep 18.
DOI: 10.1093/brain/awae299
Abstrakt: Erythrocyte Membrane Protein Band 4.1 Like 3 (EPB41L3: NM_012307.5), also known as DAL-1, encodes the ubiquitously expressed, neuronally enriched 4.1B protein, part of the 4.1 superfamily of membrane-cytoskeleton adaptors. 4.1B plays key roles in cell spreading, migration, and cytoskeletal scaffolding that support oligodendrocyte axon adhesions essential for proper myelination. We herein describe six individuals from five unrelated families with global developmental delay, intellectual disability, seizures, hypotonia, neuroregression, and delayed myelination. Exome sequencing identified biallelic variants in EPB41L3 in all affected individuals: two nonsense (c.466C>T, p.(R156*); c.2776C>T, p.(R926*)) and three frameshift (c.666delT, p.(F222Lfs*46); c.2289dupC, p.(V764Rfs*19); c.948_949delTG, p.(A317Kfs*33)). Quantitative-real time PCR and Western blot analysis in human fibroblasts harbouring EPB41L3:c.666delT, p.(F222Lfs*46) indicate ablation of EPB41L3 mRNA and 4.1B protein expression. Inhibition of the nonsense mediated decay (NMD) pathway led to an upregulation of EPB41L3:c.666delT transcripts, supporting NMD as a pathogenic mechanism. Epb41l3-deficient mouse oligodendroglia cells showed significant reduction in mRNA expression of key myelin genes, reduced branching, and increased apoptosis. Our report provides the first clinical description of an autosomal recessive disorder associated with variants in EPB41L3, which we refer to as EPB41L3-associated developmental disorder (EADD). Moreover, our functional studies substantiate the pathogenicity of EPB41L3 hypothesized loss-of-function variants.
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Databáze: MEDLINE
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