Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia

Am J Hum Genet. 2016 Apr 7;98(4):782-8. doi: 10.1016/j.ajhg.2016.03.016.

Elizabeth J Bhoj ¹, Dong Li ², Margaret Harr ³, Shimon Edvardson ⁴, Orly Elpeleg ⁵, Elizabeth Chisholm ⁶, Jane Juusola ⁷, Ganka Douglas ⁷, Maria J Guillen Sacoto ⁷, Karine Siquier-Pernet ⁸, Abdelkrim Saadi ⁹, Christine Bole-Feysot ¹⁰, Patrick Nitschke ¹¹, Alekhya Narravula ¹², Maria Walke ¹³, Michele B Horner ¹⁴, Debra-Lynn Day-Salvatore ¹⁴, Parul Jayakar ¹³, Samantha A Schrier Vergano ⁶, Mark A Tarnopolsky ¹⁵, Madhuri Hegde ¹², Laurence Colleaux ⁸, Peter Crino ¹⁶, Hakon Hakonarson ²

Affiliations

1 Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: [email protected].
2 Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
3 Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
4 Pediatric Neurology Unit, Hadassah University Hospital, Mount Scopus, Jerusalem 91120, Israel; Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
5 Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
6 Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA 23507, USA.
7 GeneDx, Gaithersburg, MD 20877, USA.
8 INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Necker-Enfants Malades Hospital, 75015 Paris, France.
9 Département de Neurologie, Etablissement Hospitalier Spécialisé de Benaknoun, Algers, Algeria.
10 Genomic Platform, INSERM UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
11 Plateforme de Bioinformatique, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
12 Emory Genetics Laboratory, Emory University, Decatur, GA 30033, USA.
13 Nicklaus Children's Hospital, Miami, FL, 33155, USA.
14 Department of Medical Genetics & Genomic Medicine, St. Peter's University Hospital, New Brunswick, NJ 08901, USA.
15 Department of Pediatrics, McMaster University Medical Center, Hamilton, ON L8N 3Z5, Canada.
16 Department of Neurology, Temple University, Philadelphia, PA 19122, USA.

PMID: 27040691 DOI: 10.1016/j.ajhg.2016.03.016

Abstract

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.

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