Una nueva variante de ITPR1 con ganancia de función asociada con un trastorno del movimiento caracterizado por...

The 1,4,5-trisphosphate receptor type 1 (ITPR1) gene encodes an endoplasmic reticulum calcium release channel, in which loss-of-function mutations have been associated with spinocerebellar ataxias and related neurological phenotypes. Only one gain-of-function mutation in the highly conserved suppressor domain of ITPR1 has been previously reported. We report a novel de novo ITPR1 variant (p.(Tyr131His)) detected by whole genome sequencing in a child with an unexplained movement disorder, characterized by tremor and dystonia, concurrent with a second diagnosis of Myhre syndrome. The proband's movement disorder characteristics share much overlap with previously reported individuals with suppressor domain variants; however, she does not have ataxia. We provide functional evidence of this variant's gain-of-function consequence via in vitro experiments of inositol 1,4,5-triphosphate-mediated calcium release. Our findings deepen the knowledge of ITPR1-mediated movement disorders, expanding the phenotypic spectrum to include movement disorders without ataxia.