Autosomal-Recessive Mutations in the tRNA Splicing Endonuclease Subunit TSEN15 Cause Pontocerebellar Hypoplasia and Progressive Microcephaly

Am J Hum Genet. 2016 Jul 7;99(1):228-35. doi: 10.1016/j.ajhg.2016.05.023.

Martin W Breuss ¹, Tipu Sultan ², Kiely N James ¹, Rasim O Rosti ¹, Eric Scott ¹, Damir Musaev ¹, Bansri Furia ³, André Reis ⁴, Heinrich Sticht ⁵, Mohammed Al-Owain ⁶, Fowzan S Alkuraya ⁷, Miriam S Reuter ⁴, Rami Abou Jamra ⁸, Christopher R Trotta ³, Joseph G Gleeson ⁹

Affiliations

1 Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92025, USA.
2 Department of Pediatric Neurology, Institute of Child Health & The Children's Hospital, Lahore 54000, Pakistan.
3 PTC Therapeutics, South Plainfield, NJ 07080, USA.
4 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91054, Germany.
5 Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91054, Germany.
6 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11211, Saudi Arabia; Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
7 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11211, Saudi Arabia; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 11211, Saudi Arabia.
8 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91054, Germany; Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig 04103, Germany.
9 Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92025, USA. Electronic address: jogleeson@ucsd.edu.

PMID: 27392077 DOI: 10.1016/j.ajhg.2016.05.023

Abstract

The tRNA splicing Endonuclease is a highly evolutionarily conserved protein complex, involved in the cleavage of intron-containing tRNAs. In human it consists of the catalytic subunits TSEN2 and TSEN34, as well as the non-catalytic TSEN54 and TSEN15. Recessive mutations in the corresponding genes of the first three are known to cause pontocerebellar hypoplasia (PCH) types 2A-C, 4, and 5. Here, we report three homozygous TSEN15 variants that cause a milder version of PCH2. The affected individuals showed progressive microcephaly, delayed developmental milestones, intellectual disability, and, in two out of four cases, epilepsy. None, however, displayed the central visual failure seen in PCH case subjects where other subunits of the TSEN are mutated, and only one was affected by the extensive motor defects that are typical in other forms of PCH2. The three amino acid substitutions impacted the protein level of TSEN15 and the stoichiometry of the interacting subunits in different ways, but all resulted in an almost complete loss of in vitro tRNA cleavage activity. Taken together, our results demonstrate that mutations in any known subunit of the TSEN complex can cause PCH and progressive microcephaly, emphasizing the importance of its function during brain development.

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