Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia
Elizabeth J. Bhoj
(1)
,
Dong Li
(2)
,
Margaret Harr
,
Shimon Edvardson
,
Orly Elpeleg
(3)
,
Elizabeth Chisholm
,
Jane Juusola
(4)
,
Ganka Douglas
,
Maria Guillen Sacoto
,
Karine Siquier-Pernet
(5, 6, 7, 8)
,
Abdelkrim Saadi
,
Christine Bole-Feysot
(9, 5, 6, 7)
,
Patrick Nitschke
(5, 10, 6, 7)
,
Alekhya Narravula
,
Maria Walke
,
Peter Horner
,
Peter Day-Salvatore
,
Parul Jayakar
,
Samantha Vergano
,
Mark Tarnopolsky
(11)
,
Madhuri Hegde
,
Laurence Colleaux
,
Peter Crino
,
Hakon Hakonarson
(12)
,
Elizabeth j. Bhoj
,
Maria j. Guillen Sacoto
,
Michele b. Horner
,
Debra-Lynn Day-Salvatore
,
Samantha a. schrier Vergano
,
Mark a. Tarnopolsky
1
The Center for Applied Genomics [Philadelphia, PA, USA]
2 UBC Mathematics - Department of Mathematics [Vancouver]
3 Department of Genetics and Metabolic Diseases and the Monique and Jacques Roboh Department of Genetic Research
4 GeneDx [Gaithersburg, MD, USA]
5 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
6 UPD5 - Université Paris Descartes - Paris 5
7 USPC - Université Sorbonne Paris Cité
8 Hôpital Necker - Enfants Malades [AP-HP]
9 Plateforme de génomique [SFR Necker]
10 BIP-D - Plateforme Bioinformatique [SFR Necker]
11 McMaster University [Hamilton, Ontario]
12 CHOP - Children’s Hospital of Philadelphia
2 UBC Mathematics - Department of Mathematics [Vancouver]
3 Department of Genetics and Metabolic Diseases and the Monique and Jacques Roboh Department of Genetic Research
4 GeneDx [Gaithersburg, MD, USA]
5 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
6 UPD5 - Université Paris Descartes - Paris 5
7 USPC - Université Sorbonne Paris Cité
8 Hôpital Necker - Enfants Malades [AP-HP]
9 Plateforme de génomique [SFR Necker]
10 BIP-D - Plateforme Bioinformatique [SFR Necker]
11 McMaster University [Hamilton, Ontario]
12 CHOP - Children’s Hospital of Philadelphia
Margaret Harr
- Fonction : Auteur
Shimon Edvardson
- Fonction : Auteur
Orly Elpeleg
- Fonction : Auteur
- PersonId : 1194018
- ORCID : 0000-0002-5041-7272
Elizabeth Chisholm
- Fonction : Auteur
Ganka Douglas
- Fonction : Auteur
Maria Guillen Sacoto
- Fonction : Auteur
Abdelkrim Saadi
- Fonction : Auteur
Alekhya Narravula
- Fonction : Auteur
Maria Walke
- Fonction : Auteur
Peter Horner
- Fonction : Auteur
Peter Day-Salvatore
- Fonction : Auteur
Parul Jayakar
- Fonction : Auteur
Samantha Vergano
- Fonction : Auteur
Madhuri Hegde
- Fonction : Auteur
Laurence Colleaux
- Fonction : Auteur
- PersonId : 184021
- IdHAL : laurence-colleaux
- ORCID : 0000-0002-0987-7648
- IdRef : 033661782
Peter Crino
- Fonction : Auteur
Hakon Hakonarson
- Fonction : Auteur
- PersonId : 763145
- ORCID : 0000-0003-2814-7461
Elizabeth j. Bhoj
- Fonction : Auteur
Maria j. Guillen Sacoto
- Fonction : Auteur
Michele b. Horner
- Fonction : Auteur
Debra-Lynn Day-Salvatore
- Fonction : Auteur
Samantha a. schrier Vergano
- Fonction : Auteur
Mark a. Tarnopolsky
- Fonction : Auteur
Résumé
Through an international multi-center collaboration, 13 individuals from nine unrelated families and affected by likely pathogenic biallelic variants in TBC1-domain-containing kinase (TBCK) were identified through whole-exome sequencing. All affected individuals were found to share a core phenotype of intellectual disability and hypotonia, and many had seizures and showed brain atrophy and white-matter changes on neuroimaging. Minor non-specific facial dysmorphism was also noted in some individuals, including multiple older children who developed coarse features similar to those of storage disorders. TBCK has been shown to regulate the mammalian target of rapamycin (mTOR) signaling pathway, which is also stimulated by exogenous leucine supplementation. TBCK was absent in cells from affected individuals, and decreased phosphorylation of phospho-ribosomal protein S6 was also observed, a finding suggestive of downregulation of mTOR signaling. Lastly, we demonstrated that activation of the mTOR pathway in response to L-leucine supplementation was retained, suggesting a possible avenue for directed therapies for this condition.