Upstream open reading frame-introducing variants in patients with primary familial brain calcification.

Autor: Rovelet-Lecrux A; Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics, CNRMAJ and Reference Center for Neurogenetics Disorders, F-76000, Rouen, France., Bonnevalle A; Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Neurology, CNRMAJ and Reference Center for Neurogenetics Disorders, F-76000, Rouen, France., Quenez O; Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics, CNRMAJ and Reference Center for Neurogenetics Disorders, F-76000, Rouen, France., Delcroix W; Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics, CNRMAJ and Reference Center for Neurogenetics Disorders, F-76000, Rouen, France., Cassinari K; Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics, CNRMAJ and Reference Center for Neurogenetics Disorders, F-76000, Rouen, France., Richard AC; Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics, CNRMAJ and Reference Center for Neurogenetics Disorders, F-76000, Rouen, France., Boland A; Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057, Evry, France., Deleuze JF; Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057, Evry, France., Goizet C; Department of Medical Genetics, National Reference Center for Rare Diseases 'Neurogenetic', Pellegrin Hospital, Bordeaux University Hospital, and University of Bordeaux, CNRS, INCIA, UMR 5287, NRGen Team, Bordeaux, France., Rucar A; Department of Neurology, University-Hospital of Angers, 49933, Angers, France.; Unité MitoVasc, UMR CNRS 6015, INSERM U1083, 49933, Angers, France., Verny C; Department of Neurology, University-Hospital of Angers, 49933, Angers, France.; Unité MitoVasc, UMR CNRS 6015, INSERM U1083, 49933, Angers, France., Nguyen K; AP-HM, Hôpital Timone, Département de Génétique Médicale, Marseille, France., Lecourtois M; Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics, CNRMAJ and Reference Center for Neurogenetics Disorders, F-76000, Rouen, France., Nicolas G; Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics, CNRMAJ and Reference Center for Neurogenetics Disorders, F-76000, Rouen, France. gaelnicolas@hotmail.com.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2024 Jul; Vol. 32 (7), pp. 779-785. Date of Electronic Publication: 2024 Mar 04.
DOI: 10.1038/s41431-024-01580-4
Abstrakt: More than 50% of patients with primary familial brain calcification (PFBC), a rare neurological disorder, remain genetically unexplained. While some causative genes are yet to be identified, variants in non-coding regions of known genes may represent a source of missed diagnoses. We hypothesized that 5'-Untranslated Region (UTR) variants introducing an AUG codon may initiate mRNA translation and result in a loss of function in some of the PFBC genes. After reannotation of exome sequencing data of 113 unrelated PFBC probands, we identified two upstream AUG-introducing variants in the 5'UTR of PDGFB. One, NM_002608.4:c.-373C>G, segregated with PFBC in the family. It was predicted to create an upstream open reading frame (ORF). The other one, NM_002608.4:c.-318C>T, was found in a simplex case. It was predicted to result in an ORF overlapping the natural ORF with a frameshift. In a GFP reporter assay, both variants were associated with a dramatic decrease in GFP levels, and, after restoring the reading frame with the GFP sequence, the c.-318C>T variant was associated with a strong initiation of translation as measured by western blotting. Overall, we found upstream AUG-introducing variants in the 5'UTR of PDGFB in 2/113 (1.7%) undiagnosed PFBC cases. Such variants thus represent a source of putative pathogenic variants.
(© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)
Databáze: MEDLINE
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