A Novel Gain-of-Function ITPR1 Variant Associated With a Movement Disorder Characterized by Tremor and Dystonia

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• The 1,4,5-trisphosphate receptor type 1 (ITPR1) gene encodes a calcium release channel implicated in neurological disorders.
• Loss-of-function mutations in ITPR1 are linked to spinocerebellar ataxias.
• Previously, only one gain-of-function mutation in the ITPR1 suppressor domain was identified.

Purpose of the Study:

• To identify the genetic cause of an unexplained movement disorder in a child.
• To characterize a novel de novo ITPR1 variant and its functional consequences.
• To expand the understanding of ITPR1-associated neurological phenotypes.

Main Methods:

• Whole genome sequencing to detect genetic variants.
• Clinical assessment of a child with tremor, dystonia, and Myhre syndrome.
• In vitro experiments to assess inositol 1,4,5-triphosphate-mediated calcium release.

Main Results:

• A novel de novo ITPR1 variant (p.(Tyr131His)) was identified in the patient.
• The patient presented with tremor and dystonia, but not ataxia.
• Functional studies confirmed the variant causes a gain-of-function effect on calcium release.

Conclusions:

• The identified ITPR1 variant is pathogenic and causes a gain-of-function effect.
• This finding expands the phenotypic spectrum of ITPR1-mediated movement disorders.
• Movement disorders associated with ITPR1 can occur without ataxia.