Heterozygous variants in TBCK cause a mild neurologic syndrome in humans and mice. Academic Article uri icon

Overview

abstract

  • TBCK-related encephalopathy is a rare pediatric neurodegenerative disorder caused by biallelic loss-of-function variants in the TBCK gene. After receiving anecdotal reports of neurologic phenotypes in both human and mouse TBCK heterozygotes, we quantified if TBCK haploinsufficiency causes a phenotype in mice and humans. Using the tbck+/- mouse model, we performed a battery of behavioral assays and mTOR pathway analysis to investigate potential alterations in neurophysiology. We conducted as well a phenome-wide association study (PheWAS) analysis in a large adult biobank to determine the presence of potential phenotypes associated to this variant. The tbck+/- mouse model demonstrates a reduction of exploratory behavior in animals with significant sex and genotype interactions. The concurrent PheWAS analysis of 10,900 unrelated individuals showed that patients with one copy of a TBCK loss-of-function allele had a significantly higher rate of acquired toe and foot deformities, likely indicative of a mild peripheral neuropathy phenotype. This study presents an example of what may be the underappreciated occurrence of mild neurogenic symptoms in heterozygote individuals of recessive neurogenetic syndromes.

publication date

  • June 23, 2023

Research

keywords

  • Brain Diseases
  • Protein Serine-Threonine Kinases

Identity

PubMed Central ID

  • PMC10524953

Scopus Document Identifier

  • 85162869397

Digital Object Identifier (DOI)

  • 10.1002/ajmg.a.63320

PubMed ID

  • 37353954

Additional Document Info

volume

  • 191

issue

  • 10