Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes
Authors: Rinaldi Berardo , Bayat Allan , Zachariassen Linda G , Sun Jia-Hui , Ge Yu-Han , Zhao Dan , Bonde Kristine , Madsen Laura H , Awad Ilham Abdimunim Ali , Bagiran Duygu , Sbeih Amal , Shah Syeda Maidah , El-Sayed Shaymaa , Lyngby Signe M , Pedersen Miriam G , Stenum-Berg Charlotte , Walker Louise Claudia , Krey Ilona , Delahaye-Duriez Andrée , Emrick Lisa T , Sully Krystal , Murali Chaya N , Burrage Lindsay C , Plaud Gonzalez Julie Ana , Parnes Mered , Friedman Jennifer , Isidor Bertrand , Lefranc Jérémie , Redon Sylvia , Heron Delphine , Mignot Cyril , Keren Boris , Fradin Mélanie , Dubourg Christele , Mercier Sandra , Besnard Thomas , Cogne Benjamin , Deb Wallid , Rivier Clotilde , Milani Donatella , Bedeschi Maria Francesca , Di Napoli Claudia , Grilli Federico , Marchisio Paola , Koudijs Suzanna , Veenma Danielle , Argilli Emanuela , Lynch Sally Ann , Au Ping Yee Billie , Ayala Valenzuela Fernando Eduardo , Brown Carolyn , Masser-Frye Diane , Jones Marilyn , Patron Romero Leslie , Li Wenhui Laura , Thorpe Erin , Hecher Laura , Johannsen Jessika , Denecke Jonas , McNiven Vanda , Szuto Anna , Wakeling Emma , Cruz Vincent , Sency Valerie , Wang Heng , Piard Juliette , Kortüm Fanny , Herget Theresia , Bierhals Tatjana , Condell Angelo , Ben-Zeev Bruria , Kaur Simranpreet , Christodoulou John , Piton Amelie , Zweier Christiane , Kraus Cornelia , Micalizzi Alessia , Trivisano Marina , Specchio Nicola , Lesca Gaetan , Møller Rikke S , Tümer Zeynep , Musgaard Maria , Gerard Benedicte , Lemke Johannes R , Shi Yun Stone , Kristensen Anders S 
Published: November 2023

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded by the GRIA1–GRIA4 genes, of which only GRIA3 is X-chromosomal. Increasing numbers of GRIA3 missense variants are reported in patients with neurodevelopmental disorders (NDD), but only a few have been examined functionally.

Here, we evaluated the impact on AMPAR function of one frameshift and 43 rare missense GRIA3 variants identified in patients with NDD by electrophysiological assays. Thirty-one variants alter receptor function and show loss-of-function or gain-of-function properties, whereas 13 appeared neutral.

We collected detailed clinical data from 25 patients (from 23 families) harbouring 17 of these variants. All patients had global developmental impairment, mostly moderate (9/25) or severe (12/25). Twelve patients had seizures, including focal motor (6/12), unknown onset motor (4/12), focal impaired awareness (1/12), (atypical) absence (2/12), myoclonic (5/12) and generalized tonic-clonic (1/12) or atonic (1/12) seizures. The epilepsy syndrome was classified as developmental and epileptic encephalopathy in eight patients, developmental encephalopathy without seizures in 13 patients, and intellectual disability with epilepsy in four patients. Limb muscular hypotonia was reported in 13/25, and hypertonia in 10/25. Movement disorders were reported in 14/25, with hyperekplexia or non-epileptic erratic myoclonus being the most prevalent feature (8/25).

Correlating receptor functional phenotype with clinical features revealed clinical features for GRIA3-associated NDDs and distinct NDD phenotypes for loss-of-function and gain-of-function variants. Gain-of-function variants were associated with more severe outcomes: patients were younger at the time of seizure onset (median age: 1 month), hypertonic and more often had movement disorders, including hyperekplexia. Patients with loss-of-function variants were older at the time of seizure onset (median age: 16 months), hypotonic and had sleeping disturbances. Loss-of-function and gain-of-function variants were disease-causing in both sexes but affected males often carried de novo or hemizygous loss-of-function variants inherited from healthy mothers, whereas affected females had mostly de novo heterozygous gain-of-function variants.