Genomics & Informatics

Korea Genome Organization (한국유전체학회)
권호 표지
DOI QR코드

DOI QR Code

A novel mutation in GJC2 associated with hypomyelinating leukodystrophy type 2 disorder

  • Received : 2022.02.18
  • Accepted : 2022.04.27
  • Published : 2022.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

Hypomyelinating leukodystrophy type 2 (HLD2), is an inherited genetic disease of the central nervous system caused by recessive mutations in the gap junction protein gamma 2 (GJC2/GJA12). HLD2 is characterized by nystagmus, developmental delay, motor impairments, ataxia, severe speech problem, and hypomyelination in the brain. The GJC2 sequence encodes connexin 47 protein (Cx47). Connexins are a group of membrane proteins that oligomerize to construct gap junctions protein. In the present study, a novel missense mutation gene c.760G>A (p.Val254Met) was identified in a patient with HLD2 by performing whole exome sequencing. Following the discovery of the new mutation in the proband, we used Sanger sequencing to analyze his affected sibling and parents. Sanger sequencing verified homozygosity of the mutation in the proband and his affected sibling. The autosomal recessive inheritance pattern was confirmed since Sanger sequencing revealed both healthy parents were heterozygous for the mutation. PolyPhen2, SIFT, PROVEAN, and CADD were used to evaluate the function prediction scores of detected mutations. Cx47 is essential for oligodendrocyte function, including adequate myelination and myelin maintenance in humans. Novel mutation p.Val254Met is located in the second extracellular domain of Cx47, both extracellular loops are highly conserved and probably induce intramolecular disulfide interactions. This novel mutation in the Cx47 gene causes oligodendrocyte dysfunction and HLD2 disorder.

Keywords

Acknowledgement

We are thankful to the patients and their parents who participated in this study.

References

  1. Wolf NI, Ffrench-Constant C, van der Knaap MS. Hypomyelinating leukodystrophies: unravelling myelin biology. Nat Rev Neurol 2021;17:88-103. https://doi.org/10.1038/s41582-020-00432-1
  2. Mahdieh N, Soveizi M, Tavasoli AR, Rabbani A, Ashrafi MR, Kohlschutter A, et al. Genetic testing of leukodystrophies unraveling extensive heterogeneity in a large cohort and report of five common diseases and 38 novel variants. Sci Rep 2021;11:3231. https://doi.org/10.1038/s41598-021-82778-0
  3. Owczarek-Lipska M, Mulahasanovic L, Obermaier CD, Hortnagel K, Neubauer BA, Korenke GC, et al. Novel mutations in the GJC2 gene associated with Pelizaeus-Merzbacher-like disease. Mol Biol Rep 2019;46:4507-4516. https://doi.org/10.1007/s11033-019-04906-4
  4. Uhlenberg B, Schuelke M, Ruschendorf F, Ruf N, Kaindl AM, Henneke M, et al. Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease. Am J Hum Genet 2004;75:251-260. https://doi.org/10.1086/422763
  5. Biancheri R, Rosano C, Denegri L, Lamantea E, Pinto F, Lanza F, et al. Expanded spectrum of Pelizaeus-Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form. Eur J Hum Genet 2013;21:34-39. https://doi.org/10.1038/ejhg.2012.93
  6. Warner A, Clements DK, Parikh S, Evans WH, DeHaan RL. Specific motifs in the external loops of connexin proteins can determine gap junction formation between chick heart myocytes. J Physiol 1995;488(Pt 3):721-728. https://doi.org/10.1113/jphysiol.1995.sp021003
  7. Tanti A, Lutz PE, Kim J, O'Leary L, Theroux JF, Turecki G, et al. Evidence of decreased gap junction coupling between astrocytes and oligodendrocytes in the anterior cingulate cortex of depressed suicides. Neuropsychopharmacology 2019;44:2099-2111. https://doi.org/10.1038/s41386-019-0471-z
  8. Giaume C, Kirchhoff F, Matute C, Reichenbach A, Verkhratsky A. Glia: the fulcrum of brain diseases. Cell Death Differ 2007;14:1324-1335. https://doi.org/10.1038/sj.cdd.4402144
  9. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248-249. https://doi.org/10.1038/nmeth0410-248
  10. Ng PC, Henikoff S. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 2003;31:3812-3814. https://doi.org/10.1093/nar/gkg509
  11. Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 2015;31:2745-2747. https://doi.org/10.1093/bioinformatics/btv195
  12. Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 2014;46:310-315. https://doi.org/10.1038/ng.2892
  13. Haydon PG. GLIA: listening and talking to the synapse. Nat Rev Neurosci 2001;2:185-193. https://doi.org/10.1038/35058528
  14. Philippot C, Griemsmann S, Jabs R, Seifert G, Kettenmann H, Steinhauser C. Astrocytes and oligodendrocytes in the thalamus jointly maintain synaptic activity by supplying metabolites. Cell Rep 2021;34:108642. https://doi.org/10.1016/j.celrep.2020.108642
  15. Vejar S, Oyarzun JE, Retamal MA, Ortiz FC, Orellana JA. Connexin and pannexin-based channels in oligodendrocytes: implications in brain health and disease. Front Cell Neurosci 2019;13:3.
  16. Chen N, Wang J, Jiang Y, Wu Y, Hao H, Ji T. Different mutations of gap junction connexin 47 lead to discrepant activation of unfolded protein response pathway in Pelizaeus-Merzbacher-like disease. Neuropediatrics 2017;48:426-431. https://doi.org/10.1055/s-0037-1603978
  17. Orthmann-Murphy JL, Salsano E, Abrams CK, Bizzi A, Uziel G, Freidin MM, et al. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain 2009;132:426-438. https://doi.org/10.1093/brain/awn328
  18. Orthmann-Murphy JL, Enriquez AD, Abrams CK, Scherer SS. Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus-Merzbacher-like disease. Mol Cell Neurosci 2007;34:629-641. https://doi.org/10.1016/j.mcn.2007.01.010
  19. Zlomuzica A, Tress O, Binder S, Rovira C, Willecke K, Dere E. Changes in object recognition and anxiety-like behaviour in mice expressing a Cx47 mutation that causes Pelizaeus-Merzbacher-like disease. Dev Neurosci 2012;34:277-287. https://doi.org/10.1159/000339305