Lysosomal dysfunction in TMEM106B hypomyelinating leukodystrophy.

Abstract

Transmembrane protein 106B ( TMEM106B ; NM_001134232) was recently identified as a gene responsible for a form of hypomyelinating leukodystrophy (HLD).1,2 All 5 cases identified to date carry the identical c.754 G > A, (p.Asp252Asn) mutation.1,2 Although the exact function is unknown,3 studies of TMEM106B in the context of frontotemporal lobar degeneration with 43-kD TAR DNA-binding protein (TDP-43) pathology (FTLD-TDP) indicate that TMEM106B likely acts as a lysosomal regulator and can modify risk for FTLD-TDP.4 However, the molecular effects of the (p.Asp252Asn) substitution have not yet been reported for TMEM106B -associated HLD. The HLDs are heterogeneous conditions, with the known disease genes playing roles in myelin sheath structure (e.g., PLP1 ) and other cellular functions that are not oligodendrocyte specific, including protein translation, molecular chaperoning, and cytoskeletal regulation.5 We set out to assess if this recurrent TMEM106B substitution was affecting lysosome biology or had an alternate role underlying the HLD pathogenesis. Implication of lysosome biology in HLD provides exciting new advances in our understanding of the molecular underpinnings of this condition and the complexities of neurodevelopment. The authors would like to thank the patient and family; without whom this work would not be possible. The authors also wish to acknowledge Dr. Wendy Mears for her tissue culture expertise. This work was supported by the Care4Rare Canada Consortium funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec, and the Children's Hospital of Eastern Ontario Foundation.