Kathleen J Sweadner1, Elena Arystarkhova1, John T Penniston1, Kathryn J Swoboda1, Allison Brashear1, Laurie J Ozelius1. 1. Department of Neurosurgery (K.J. Sweadner, E.A., J.T.P.), Center for Human Genetics Research (K.J. Swoboda), and Department of Neurology, (K.J. Swoboda, L.J.O.) Massachusetts General Hospital, Boston; and the Department of Neurology (A.B.), Wake Forest School of Medicine, Winston-Salem, NC.
Abstract
OBJECTIVE: We tested the assumption that closely related genes should have similar pathogenic variants by analyzing >200 pathogenic variants in a gene family with high neurologic impact and high sequence identity, the Na,K-ATPases ATP1A1, ATP1A2, and ATP1A3. METHODS: Data sets of disease-associated variants were compared. Their equivalent positions in protein crystal structures were used for insights into pathogenicity and correlated with the phenotype and conservation of homology. RESULTS: Relatively few mutations affected the corresponding amino acids in 2 genes. In the membrane domain of ATP1A3 (primarily expressed in neurons), variants producing milder neurologic phenotypes had different structural positions than variants producing severe phenotypes. In ATP1A2 (primarily expressed in astrocytes), membrane domain variants characteristic of severe phenotypes in ATP1A3 were absent from patient data. The known variants in ATP1A1 fell into 2 distinct groups. Sequence conservation was an imperfect indicator: it varied among structural domains, and some variants with demonstrated pathogenicity were in low conservation sites. CONCLUSIONS: Pathogenic variants varied between genes despite high sequence identity, and there is a genotype-structure-phenotype relationship in ATP1A3 that correlates with neurologic outcomes. The absence of "severe" pathogenic variants in ATP1A2 patients predicts that they will manifest either in a different tissue or by death in utero and that new ATP1A1 variants will produce additional phenotypes. It is important that some variants in poorly conserved amino acids are nonetheless pathogenic and could be incorrectly predicted to be benign.
OBJECTIVE: We tested the assumption that closely related genes should have similar pathogenic variants by analyzing >200 pathogenic variants in a gene family with high neurologic impact and high sequence identity, the Na,K-ATPases ATP1A1, ATP1A2, and ATP1A3. METHODS: Data sets of disease-associated variants were compared. Their equivalent positions in protein crystal structures were used for insights into pathogenicity and correlated with the phenotype and conservation of homology. RESULTS: Relatively few mutations affected the corresponding amino acids in 2 genes. In the membrane domain of ATP1A3 (primarily expressed in neurons), variants producing milder neurologic phenotypes had different structural positions than variants producing severe phenotypes. In ATP1A2 (primarily expressed in astrocytes), membrane domain variants characteristic of severe phenotypes in ATP1A3 were absent from patient data. The known variants in ATP1A1 fell into 2 distinct groups. Sequence conservation was an imperfect indicator: it varied among structural domains, and some variants with demonstrated pathogenicity were in low conservation sites. CONCLUSIONS: Pathogenic variants varied between genes despite high sequence identity, and there is a genotype-structure-phenotype relationship in ATP1A3 that correlates with neurologic outcomes. The absence of "severe" pathogenic variants in ATP1A2 patients predicts that they will manifest either in a different tissue or by death in utero and that new ATP1A1 variants will produce additional phenotypes. It is important that some variants in poorly conserved amino acids are nonetheless pathogenic and could be incorrectly predicted to be benign.
Authors: Amy E Moseley; Steve P Lieske; Randall K Wetzel; Paul F James; Suiwen He; Daniel A Shelly; Richard J Paul; Gregory P Boivin; David P Witte; Jan Marino Ramirez; Kathleen J Sweadner; Jerry B Lingrel Journal: J Biol Chem Date: 2002-11-27 Impact factor: 5.157
Authors: Unda Todt; Martin Dichgans; Karin Jurkat-Rott; Axel Heinze; Giovanni Zifarelli; Jan B Koenderink; Ingrid Goebel; Vera Zumbroich; Anne Stiller; Alfredo Ramirez; Thomas Friedrich; Hartmut Göbel; Christian Kubisch Journal: Hum Mutat Date: 2005-10 Impact factor: 4.878
Authors: Amy E Moseley; Michael T Williams; Tori L Schaefer; Cynthia S Bohanan; Jon C Neumann; Michael M Behbehani; Charles V Vorhees; Jerry B Lingrel Journal: J Neurosci Date: 2007-01-17 Impact factor: 6.167
Authors: Patricia de Carvalho Aguiar; Kathleen J Sweadner; John T Penniston; Jacek Zaremba; Liu Liu; Marsha Caton; Gurutz Linazasoro; Michel Borg; Marina A J Tijssen; Susan B Bressman; William B Dobyns; Allison Brashear; Laurie J Ozelius Journal: Neuron Date: 2004-07-22 Impact factor: 17.173
Authors: Mary E Moya-Mendez; Chiagoziem Ogbonna; Jordan E Ezekian; Michael B Rosamilia; Lyndsey Prange; Caridad de la Uz; Jeffrey J Kim; Taylor Howard; John Garcia; Robert Nussbaum; Rebecca Truty; Thomas E Callis; Emily Funk; Matthew Heyes; Guy de Lisle Dear; Michael P Carboni; Salim F Idriss; Mohamad A Mikati; Andrew P Landstrom Journal: J Am Heart Assoc Date: 2021-08-28 Impact factor: 5.501