Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome
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Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID : An emerging neurodevelopmental syndrome. / Ismail, Vardha; Zachariassen, Linda G.; Godwin, Annie; Sahakian, Mane; Ellard, Sian; Stals, Karen L.; Baple, Emma; Brown, Kate Tatton; Foulds, Nicola; Wheway, Gabrielle; Parker, Matthew O.; Lyngby, Signe M.; Pedersen, Miriam G.; Desir, Julie; Bayat, Allan; Musgaard, Maria; Guille, Matthew; Kristensen, Anders S.; Baralle, Diana.
I: American Journal of Human Genetics, Bind 109, Nr. 7, 2022, s. 1217-1241.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID
T2 - An emerging neurodevelopmental syndrome
AU - Ismail, Vardha
AU - Zachariassen, Linda G.
AU - Godwin, Annie
AU - Sahakian, Mane
AU - Ellard, Sian
AU - Stals, Karen L.
AU - Baple, Emma
AU - Brown, Kate Tatton
AU - Foulds, Nicola
AU - Wheway, Gabrielle
AU - Parker, Matthew O.
AU - Lyngby, Signe M.
AU - Pedersen, Miriam G.
AU - Desir, Julie
AU - Bayat, Allan
AU - Musgaard, Maria
AU - Guille, Matthew
AU - Kristensen, Anders S.
AU - Baralle, Diana
PY - 2022
Y1 - 2022
N2 - GRIA1 encodes the GluA1 subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, which are ligand-gated ion channels that act as excitatory receptors for the neurotransmitter L-glutamate (Glu). AMPA receptors (AMPARs) are homo- or heteromeric protein complexes with four subunits, each encoded by different genes, GRIA1 to GRIA4. Although GluA1-containing AMPARs have a crucial role in brain function, the human phenotype associated with deleterious GRIA1 sequence variants has not been established. Subjects with de novo missense and nonsense GRIA1 variants were identified through international collaboration. Detailed phenotypic and genetic assessments of the subjects were carried out and the pathogenicity of the variants was evaluated in vitro to characterize changes in AMPAR function and expression. In addition, two Xenopus gria1 CRISPR-Cas9 F-0 models were established to characterize the in vivo consequences. Seven unrelated individuals with rare GRIA1 variants were identified. One individual carried a homozygous nonsense variant (p.Arg377Ter), and six had heterozygous missense variations (p.Arg345Gln, p.Ala636Thr, p.Ile627Thr, and p.Gly745Asp), of which the p.Ala636Thr variant was recurrent in three individuals. The cohort revealed subjects to have a recurrent neurodevelopmental disorder mostly affecting cognition and speech. Functional evaluation of major GluA1-containing AMPAR subtypes carrying the GRIA1 variant mutations showed that three of the four missense variants profoundly perturb receptor function. The homozygous stop-gain variant completely destroys the expression of GluA1-containing AMPARs. The Xenopus gria1 models show transient motor deficits, an intermittent seizure phenotype, and a significant impairment to working memory in mutants. These data support a developmental disorder caused by both heterozygous and homozygous variants in GRIA1 affecting AMPAR function.
AB - GRIA1 encodes the GluA1 subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, which are ligand-gated ion channels that act as excitatory receptors for the neurotransmitter L-glutamate (Glu). AMPA receptors (AMPARs) are homo- or heteromeric protein complexes with four subunits, each encoded by different genes, GRIA1 to GRIA4. Although GluA1-containing AMPARs have a crucial role in brain function, the human phenotype associated with deleterious GRIA1 sequence variants has not been established. Subjects with de novo missense and nonsense GRIA1 variants were identified through international collaboration. Detailed phenotypic and genetic assessments of the subjects were carried out and the pathogenicity of the variants was evaluated in vitro to characterize changes in AMPAR function and expression. In addition, two Xenopus gria1 CRISPR-Cas9 F-0 models were established to characterize the in vivo consequences. Seven unrelated individuals with rare GRIA1 variants were identified. One individual carried a homozygous nonsense variant (p.Arg377Ter), and six had heterozygous missense variations (p.Arg345Gln, p.Ala636Thr, p.Ile627Thr, and p.Gly745Asp), of which the p.Ala636Thr variant was recurrent in three individuals. The cohort revealed subjects to have a recurrent neurodevelopmental disorder mostly affecting cognition and speech. Functional evaluation of major GluA1-containing AMPAR subtypes carrying the GRIA1 variant mutations showed that three of the four missense variants profoundly perturb receptor function. The homozygous stop-gain variant completely destroys the expression of GluA1-containing AMPARs. The Xenopus gria1 models show transient motor deficits, an intermittent seizure phenotype, and a significant impairment to working memory in mutants. These data support a developmental disorder caused by both heterozygous and homozygous variants in GRIA1 affecting AMPAR function.
KW - AMPA-RECEPTOR
KW - GLUTAMATE-RECEPTOR
KW - XENOPUS-LAEVIS
KW - LIGAND-BINDING
KW - SPATIAL MEMORY
KW - INTELLECTUAL DISABILITY
KW - SYNAPTIC PLASTICITY
KW - CHANNEL CONDUCTANCE
KW - CRYSTAL-STRUCTURES
KW - LURCHER MUTATION
U2 - 10.1016/j.ajhg.2022.05.009
DO - 10.1016/j.ajhg.2022.05.009
M3 - Journal article
C2 - 35675825
VL - 109
SP - 1217
EP - 1241
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 7
ER -
ID: 317242836