Heterozygous variants in TBCK cause a mild neurologic syndrome in humans and mice.

Autor: Nair D; Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Diaz-Rosado A; Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.; Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA., Varella-Branco E; Centro de Estudos do Genoma Humano e Células-Tronco, Universidade de São Paulo, São Paulo, Brazil., Ramos I; Centro de Estudos do Genoma Humano e Células-Tronco, Universidade de São Paulo, São Paulo, Brazil., Black A; Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Angireddy R; Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Park J; Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA., Murali S; Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.; Department of Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Yoon A; Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Ciesielski B; ITMAT, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, USA., O'Brien WT; ITMAT, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, USA., Passos-Bueno MR; ITMAT, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, USA., Bhoj E; Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2023 Oct; Vol. 191 (10), pp. 2508-2517. Date of Electronic Publication: 2023 Jun 23.
DOI: 10.1002/ajmg.a.63320
Abstrakt: 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.
(© 2023 Wiley Periodicals LLC.)
Databáze: MEDLINE
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