| First Author | Nair D | Year | 2023 |
| Journal | Am J Med Genet A | Volume | 191 |
| Issue | 10 | Pages | 2508-2517 |
| PubMed ID | 37353954 | Mgi Jnum | J:344893 |
| Mgi Id | MGI:7579466 | Doi | 10.1002/ajmg.a.63320 |
| Citation | Nair D, et al. (2023) Heterozygous variants in TBCK cause a mild neurologic syndrome in humans and mice. Am J Med Genet A 191(10):2508-2517 |
| abstractText | 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. |
