Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy
Por:
Verdura, E, Rodriguez-Palmero, A, Velez-Santamaria, V, Planas-Serra, L, de la Calle, I, Raspall-Chaure, M, Roubertie, A, Benkirane, M, Saettini, F, Pavinato, L, Mandrile, G, O'Leary, M, O'Heir, E, Barredo, E, Chacon, A, Michaud, V, Goizet, C, Ruiz, M, Schluter, A, Rouvet, I, Sala-Coromina, J, Fossati, C, Iascone, M, Canonico, F, Marce-Grau, A, de Souza, P, Adams, DR, Casasnovas, C, Rehm, HL, Mefford, HC, Gutierrez-Solana, LG, Brusco, A, Koenig, M, Macaya, A and Pujol, A
Publicada:
1 sep 2021
Ahead of Print:
1 ago 2021
Resumen:
Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life.
Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells.
In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.
Filiaciones:
Verdura, E:
Bellvitge Biomed Res Inst IDIBELL, Neurometab Dis Lab, Barcelona 08908, Catalonia, Spain
Inst Salud Carlos III, Ctr Biomed Res Network Rare Dis CIBERER, Madrid 28029, Spain
:
Bellvitge Biomed Res Inst IDIBELL, Neurometab Dis Lab, Barcelona 08908, Catalonia, Spain
Univ Autonoma Barcelona, Hosp Univ Germans Trias i Pujol, Dept Pediat, Pediat Neurol Unit, Catalonia, Spain
Velez-Santamaria, V:
Bellvitge Biomed Res Inst IDIBELL, Neurometab Dis Lab, Barcelona 08908, Catalonia, Spain
Univ Barcelona, Hosp Univ Bellvitge, Neurol Dept, Neuromuscular Unit, Barcelona, Spain
Planas-Serra, L:
Bellvitge Biomed Res Inst IDIBELL, Neurometab Dis Lab, Barcelona 08908, Catalonia, Spain
Inst Salud Carlos III, Ctr Biomed Res Network Rare Dis CIBERER, Madrid 28029, Spain
de la Calle, I:
Bellvitge Biomed Res Inst IDIBELL, Neurometab Dis Lab, Barcelona 08908, Catalonia, Spain
Raspall-Chaure, M:
Univ Autonoma Barcelona, Vall dHebron Res Inst, Neurol Res Grp, Barcelona, Spain
Vall dHebron Univ Hosp, Dept Paediat Neurol, Barcelona, Spain
Roubertie, A:
Hop Gui de Chauliac, Dept Neuropediat, Pole Neurosci Tete & Cou, Montpellier, France
Inst Neurosci Montpellier, INSERM U1051, Montpellier, France
Benkirane, M:
Univ Montpellier, Inst Univ Rech Clin, Lab Genet Malad Rares EA7402, CHU Montpellier, F-34295 Montpellier 5, France
Saettini, F:
Univ Milano Bicocca, Fdn MBBM, Paediat Hematol Dept, Monza, Italy
Pavinato, L:
Univ Torino, Dept Med Sci, I-10126 Turin, Italy
Mandrile, G:
San Luigi Gonzaga Univ Hosp, Thalassemia Ctr, Orbassano, Italy
San Luigi Gonzaga Univ Hosp, Med Genet Unit, Orbassano, Italy
O'Leary, M:
Broad Inst MIT & Harvard, Ctr Mendelian Genom, Program Med & Populat Genet, Cambridge, MA 02142 USA
O'Heir, E:
Broad Inst MIT & Harvard, Ctr Mendelian Genom, Program Med & Populat Genet, Cambridge, MA 02142 USA
Barredo, E:
Hosp Univ Gregorio Maranon, Neuropediat Dept, Madrid, Spain
Chacon, A:
Hosp Univ Gregorio Maranon, Neuropediat Dept, Madrid, Spain
Michaud, V:
Bordeaux Univ Hosp, Mol Genet Lab, Bordeaux, Aquitaine, France
Univ Bordeaux, Rare Dis Lab Genet & Metab, INSERM U1211, Talence, Aquitaine, France
Goizet, C:
Univ Bordeaux, Rare Dis Lab Genet & Metab, INSERM U1211, Talence, Aquitaine, France
Univ Hosp Ctr Bordeaux, Reference Ctr Rare Neurogenet Dis, Dept Med Genet, Pellegrin Hosp Grp, Bordeaux, Aquitaine, France
Ruiz, M:
Bellvitge Biomed Res Inst IDIBELL, Neurometab Dis Lab, Barcelona 08908, Catalonia, Spain
Inst Salud Carlos III, Ctr Biomed Res Network Rare Dis CIBERER, Madrid 28029, Spain
Schluter, A:
Bellvitge Biomed Res Inst IDIBELL, Neurometab Dis Lab, Barcelona 08908, Catalonia, Spain
Inst Salud Carlos III, Ctr Biomed Res Network Rare Dis CIBERER, Madrid 28029, Spain
Rouvet, I:
CHU Lyon, Cellular Biotechnol Dept, Hosp Civils Lyon, Lyon, France
CHU Lyon, Biobank, Hosp Civils Lyon, Lyon, France
Sala-Coromina, J:
Univ Autonoma Barcelona, Vall dHebron Res Inst, Neurol Res Grp, Barcelona, Spain
Vall dHebron Univ Hosp, Dept Paediat Neurol, Barcelona, Spain
Fossati, C:
Fdn MBBM, Dept Paediat, Monza, Italy
Iascone, M:
Papa Giovanni XXIII Hosp, Mol Genet Lab, USSD LGM, Bergamo, Italy
Canonico, F:
Univ Milano Bicocca, San Gerardo Hosp, Dept Neuroradiol, ASST Monza, Monza, Italy
Marce-Grau, A:
Univ Autonoma Barcelona, Vall dHebron Res Inst, Neurol Res Grp, Barcelona, Spain
de Souza, P:
NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA
Adams, DR:
NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA
NIH, Undiagnosed Dis Program, Common Fund, Bldg 10, Bethesda, MD 20892 USA
Casasnovas, C:
Bellvitge Biomed Res Inst IDIBELL, Neurometab Dis Lab, Barcelona 08908, Catalonia, Spain
Inst Salud Carlos III, Ctr Biomed Res Network Rare Dis CIBERER, Madrid 28029, Spain
Univ Barcelona, Hosp Univ Bellvitge, Neurol Dept, Neuromuscular Unit, Barcelona, Spain
Rehm, HL:
Broad Inst MIT & Harvard, Ctr Mendelian Genom, Program Med & Populat Genet, Cambridge, MA 02142 USA
Mefford, HC:
Univ Washington, Dept Paediat, Div Genet Med, Seattle, WA 98195 USA
Gutierrez-Solana, LG:
Inst Salud Carlos III, Ctr Biomed Res Network Rare Dis CIBERER, Madrid 28029, Spain
Hosp Infantil Univ Nino Jesus, Pediat Neurol, Madrid, Spain
Brusco, A:
Univ Torino, Dept Med Sci, I-10126 Turin, Italy
Univ Hosp, Med Genet Unit, Citta Salute & Sci, I-10126 Turin, Italy
Koenig, M:
Univ Montpellier, Inst Univ Rech Clin, Lab Genet Malad Rares EA7402, CHU Montpellier, F-34295 Montpellier 5, France
Macaya, A:
Univ Autonoma Barcelona, Vall dHebron Res Inst, Neurol Res Grp, Barcelona, Spain
Vall dHebron Univ Hosp, Dept Paediat Neurol, Barcelona, Spain
Pujol, A:
Bellvitge Biomed Res Inst IDIBELL, Neurometab Dis Lab, Barcelona 08908, Catalonia, Spain
Inst Salud Carlos III, Ctr Biomed Res Network Rare Dis CIBERER, Madrid 28029, Spain
Catalan Inst Res & Adv Studies ICREA, Barcelona, Catalonia, Spain
Green Submitted, Green Published, hybrid
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