Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms

Kishore R Kumar; Gautam Wali; Ryan L Davis; Amali C Mallawaarachchi; Elizabeth E Palmer; Velimir Gayevskiy; Andre E Minoche; David Veivers; Marcel E Dinger; Alan Mackay-Sim; Mark J Cowley; Carolyn M Sue

doi:10.1016/j.ymgmr.2018.07.003

Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms

Mol Genet Metab Rep. 2018 Jul 20:16:46-51. doi: 10.1016/j.ymgmr.2018.07.003. eCollection 2018 Sep.

Authors

Kishore R Kumar^{1

2}, Gautam Wali², Ryan L Davis², Amali C Mallawaarachchi³, Elizabeth E Palmer^{3

4

5

6}, Velimir Gayevskiy¹, Andre E Minoche¹, David Veivers⁷, Marcel E Dinger^{1

8}, Alan Mackay-Sim⁹, Mark J Cowley^{1

8}, Carolyn M Sue²

Affiliations

¹ Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.
² Department of Neurogenetics, Kolling Institute, Royal North Shore Hospital, St. Leonards, NSW, Australia.
³ Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁴ Sydney Children's Hospital, Randwick, NSW, Australia.
⁵ School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, Sydney, NSW, Australia.
⁶ Genetics of Learning Disability Service, Waratah, NSW, Australia.
⁷ ENT Department, Royal North Shore Hospital, St Leonards, NSW, Australia.
⁸ St Vincent's Hospital Clinical School, University of New South Wales, Sydney, NSW, Australia.
⁹ Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia.

Abstract

Zellweger syndrome spectrum disorders are caused by mutations in any of at least 12 different PEX genes. This includes PEX16, an important regulator of peroxisome biogenesis. Using whole genome sequencing, we detected previously unreported, biallelic variants in PEX16 [NM_004813.2:c.658G>A, p.(Ala220Thr) and NM_004813.2:c.830G>A, p.(Arg277Gln)] in an individual with leukodystrophy, spastic paraplegia, cerebellar ataxia, and craniocervical dystonia with normal plasma very long chain fatty acids. Using olfactory-neurosphere derived cells, a population of neural stem cells, we showed patient cells had reduced peroxisome density and increased peroxisome size, replicating previously reported findings in PEX16 cell lines. Along with alterations in peroxisome morphology, patient cells also had impaired peroxisome function with reduced catalase activity. Furthermore, patient cells had reduced oxidative stress levels after exposure to hydrogen-peroxide (H₂O₂), which may be a result of compensation by H₂O₂ metabolising enzymes other than catalase to preserve peroxisome-related cell functions. Our findings of impaired catalase activity and altered oxidative stress response are novel. Our study expands the phenotype of PEX16 mutations by including dystonia and provides further insights into the pathological mechanisms underlying PEX16-associated disorders. Additional studies of the full spectrum of peroxisomal dysfunction could improve our understanding of the mechanism underlying PEX16-associated disorders.

Keywords: Dystonia; Leukodystrophy; PEX16; Peroxisomes; Whole genome sequencing.