Clinical and Molecular Profiling in GNAO1 Permits Phenotype-Genotype Correlation
Por:
Lasa-Aranzasti, A, Larasati, YA, Cardoso, JD, Solis, GP, Koval, A, Cazurro-Gutiérrez, A, Ortigoza-Escobar JD, Miranda, MC, De la Casa-Fages, B, Moreno-Galdó, A, Tizzano E, Gómez-Andrés, D, Verdura, E, Katanaev, VL and Pérez-Dueñas, B
Publicada:
1 sep 2024
Ahead of Print:
1 jun 2024
Resumen:
Background Defects in GNAO1, the gene encoding the major neuronal G-protein G alpha o, are related to neurodevelopmental disorders, epilepsy, and movement disorders. Nevertheless, there is a poor understanding of how molecular mechanisms explain the different phenotypes. ObjectivesWe aimed to analyze the clinical phenotype and the molecular characterization of GNAO1-related disorders. Methods Patients were recruited in collaboration with the Spanish GNAO1 Association. For patient phenotyping, direct clinical evaluation, analysis of homemade-videos, and an online questionnaire completed by families were analyzed. We studied G alpha o cellular expression, the interactions of the partner proteins, and binding to guanosine triphosphate (GTP) and G-protein-coupled receptors (GPCRs). Results Eighteen patients with GNAO1 genetic defects had a complex neurodevelopmental disorder, epilepsy, central hypotonia, and movement disorders. Eleven patients showed neurological deterioration, recurrent hyperkinetic crisis with partial recovery, and secondary complications leading to death in three cases. Deep brain stimulation improved hyperkinetic crisis, but had inconsistent benefits in dystonia. The molecular defects caused by pathogenic G alpha o were aberrant GTP binding and hydrolysis activities, an inability to interact with cellular binding partners, and reduced coupling to GPCRs. Decreased localization of G alpha o in the plasma membrane was correlated with the phenotype of "developmental and epileptic encephalopathy 17." We observed a genotype-phenotype correlation, pathogenic variants in position 203 were related to developmental and epileptic encephalopathy, whereas those in position 209 were related to neurodevelopmental disorder with involuntary movements. Milder phenotypes were associated with other molecular defects such as del.16q12.2q21 and I344del. Conclusion We highlight the complexity of the motor phenotype, which is characterized by fluctuations throughout the day, and hyperkinetic crisis with a distinct post-hyperkinetic crisis state. We confirm a molecular-based genotype-phenotype correlation for specific variants.
Filiaciones:
Lasa-Aranzasti, A:
Vall Hebron Univ Hosp, Dept Clin & Mol Genet, Barcelona, Spain
Autonomous Univ Barcelona, Vall Hebron Res Inst VHIR, Pediat Neurol Res Grp, Passeig Vall Hebron 119-129, Barcelona 08035, Spain
Autonomous Univ Barcelona, Vall Hebron Res Inst VHIR, Med Genet Grp, Barcelona, Spain
Univ Autonoma Barcelona, Fac Med, Dept Pediat, Barcelona, Spain
European Reference Network Rare Congenital Malform, Paris, France
Larasati, YA:
Univ Geneva, Fac Med, Translat Res Ctr Oncohaematol, Dept Cell Physiol & Metab, Geneva, Switzerland
Cardoso, JD:
Autonomous Univ Barcelona, Vall Hebron Res Inst VHIR, Pediat Neurol Res Grp, Passeig Vall Hebron 119-129, Barcelona 08035, Spain
Ctr Hosp Univ Santo Antonio, Ctr Materno Infantil Norte, Serv Pediat, Porto, Portugal
Solis, GP:
Univ Geneva, Fac Med, Translat Res Ctr Oncohaematol, Dept Cell Physiol & Metab, Geneva, Switzerland
Koval, A:
Univ Geneva, Fac Med, Translat Res Ctr Oncohaematol, Dept Cell Physiol & Metab, Geneva, Switzerland
Cazurro-Gutiérrez, A:
Autonomous Univ Barcelona, Vall Hebron Res Inst VHIR, Pediat Neurol Res Grp, Passeig Vall Hebron 119-129, Barcelona 08035, Spain
Univ Autonoma Barcelona, Fac Med, Dept Pediat, Barcelona, Spain
Ortigoza-Escobar JD:
Inst Recerca Sant Joan de Deu, Dept Child Neurol, Movement Disorders Unit, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Res Rare Dis CIBERER, U 703, Barcelona, Spain
European Reference Network Rare Neurol Dis ERN RND, Barcelona, Spain
Miranda, MC:
European Reference Network Rare Neurol Dis ERN RND, Barcelona, Spain
Hosp Gen Univ Gregorio Maranon, Dept Pediat, Madrid, Spain
Inst Invest Sanitaria Gregorio Maranon, Madrid, Spain
De la Casa-Fages, B:
European Reference Network Rare Neurol Dis ERN RND, Barcelona, Spain
Inst Invest Sanitaria Gregorio Maranon, Madrid, Spain
Hosp Gen Univ Gregorio Maranon, Neurol Dept, Movement Disorders Unit, Madrid, Spain
Moreno-Galdó, A:
Univ Autonoma Barcelona, Dept Pediat, Vall Hebron Barcelona Hosp Campus, Barcelona, Spain
Inst Salud Carlos III ISCIII, CIBER Rare Dis CIBERER, Madrid, Spain
Tizzano E:
Vall Hebron Univ Hosp, Dept Clin & Mol Genet, Barcelona, Spain
Autonomous Univ Barcelona, Vall Hebron Res Inst VHIR, Med Genet Grp, Barcelona, Spain
European Reference Network Rare Congenital Malform, Paris, France
Gómez-Andrés, D:
Autonomous Univ Barcelona, Vall Hebron Res Inst VHIR, Pediat Neurol Res Grp, Passeig Vall Hebron 119-129, Barcelona 08035, Spain
European Reference Network Rare Neurol Dis ERN RND, Barcelona, Spain
Vall Hebron Univ Hosp Barcelona, Dept Neurol, Barcelona, Spain
Verdura, E:
Autonomous Univ Barcelona, Vall Hebron Res Inst VHIR, Pediat Neurol Res Grp, Passeig Vall Hebron 119-129, Barcelona 08035, Spain
Katanaev, VL:
Univ Geneva, Fac Med, Translat Res Ctr Oncohaematol, Dept Cell Physiol & Metab, Geneva, Switzerland
Far Eastern Fed Univ, Sch Med & Life Sci, Vladivostok, Russia
Pérez-Dueñas, B:
Autonomous Univ Barcelona, Vall Hebron Res Inst VHIR, Pediat Neurol Res Grp, Passeig Vall Hebron 119-129, Barcelona 08035, Spain
Univ Autonoma Barcelona, Fac Med, Dept Pediat, Barcelona, Spain
European Reference Network Rare Neurol Dis ERN RND, Barcelona, Spain
Univ Autonoma Barcelona, Dept Pediat, Vall Hebron Barcelona Hosp Campus, Barcelona, Spain
Inst Salud Carlos III ISCIII, CIBER Rare Dis CIBERER, Madrid, Spain
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