Identification of a de novo Mutation in TMEM106B in a Saudi Child Causes Hypomyelination Leukodystrophy

Abstract

Hypomyelinating leukodystrophies are one of the white matter disorders caused by a lack of myelin deposition in the central nervous system (CNS). Here, we report the first case of hypomyelinating leukodystrophy in the Middle East and Saudi Arabia. This condition is caused by a mutation in the TMEM106B gene (HLD16; MIM 617964). Hypotonia, congenital nystagmus, delayed motor development, and delayed speech are the main clinical manifestations. The affected patient has mild pyramidal syndrome, a mild intellectual disability, ataxic gait, hyperreflexia, intention tremor, dysmetria, and other motor difficulties. Findings from neuroimaging reveal severe, ongoing, and diffuse hypomyelination identified via the whole exome sequencing, a harmful missense mutation in the TMEM106B gene that is heterozygous. The patient is the offspring of two unrelated persons. The protein's cytoplasmic domain contains a variation that is located in highly conserved residues. In an oligodendroglial cell line, the mutant protein significantly lowered the mRNA production of important myelin genes, decreased branching, and increased cell mortality. TMEM106B is abundantly expressed in neurons and oligodendrocytes in the CNS and is localized in the late endosome and lysosome compartments. TMEM106B levels can be controlled at the transcriptional level through chromatin modification, at the mRNA level through miRNAs, and at the protein level through lysosomal functions. Our findings reveal a novel role of zinc homeostasis in oligodendrocyte development and myelin production and show that variations in TMEM163 induce hypomyelination leukodystrophy.

Keywords

TMEM106 - Exome - hypomyelinating leukodystrophies - mutation

Publication History

Article published online:
20 March 2023

• References

• 1 Feng T, Lacrampe A, Hu F. Physiological and pathological functions of TMEM106B: a gene associated with brain aging and multiple brain disorders. Acta Neuropathol 2021; 141 (03) 327-339
• 2 van der Knaap MS, Schiffmann R, Mochel F, Wolf NI. Diagnosis, prognosis, and treatment of leukodystrophies. Lancet Neurol 2019; 18 (10) 962-972
• 3 van der Knaap MS, Bugiani M. Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol 2017; 134 (03) 351-382
• 4 Wolf NI, Ffrench-Constant C, van der Knaap MS. Hypomyelinating leukodystrophies: unravelling myelin biology. Nat Rev Neurol 2021; 17 (02) 88-103
• 5 Pouwels PJ, Vanderver A, Bernard G. et al. Hypomyelinating leukodystrophies: translational research progress and prospects. Ann Neurol 2014; 76 (01) 5-19
• 6 Chelban V, Patel N, Vandrovcova J. et al; SYNAPSE Study Group. Mutations in NKX6–2 cause progressive spastic ataxia and hypomyelination. Am J Hum Genet 2017; 100 (06) 969-977
• 7 Kevelam SH, Steenweg ME, Srivastava S. et al. Update on leukodystrophies: a historical perspective and adapted definition. Neuropediatrics 2016; 47 (06) 349-354
• 8 Lang CM, Fellerer K, Schwenk BM. et al. Membrane orientation and subcellular localization of transmembrane protein 106B (TMEM106B), a major risk factor for frontotemporal lobar degeneration. J Biol Chem 2012; 287 (23) 19355-19365
• 9 Stagi M, Klein ZA, Gould TJ, Bewersdorf J, Strittmatter SM. Lysosome size, motility and stress response regulated by fronto-temporal dementia modifier TMEM106B. Mol Cell Neurosci 2014; 61: 226-240
• 10 Klein ZA, Takahashi H, Ma M. et al. Loss of TMEM106B ameliorates lysosomal and frontotemporal dementia-related phenotypes in progranulin-deficient mice. Neuron 2017; 95 (02) 281-296.e6
• 11 Van Deerlin VM, Sleiman PMA, Martinez-Lage M. et al. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 2010; 42 (03) 234-239