Abstract
Myelin pathologies are an important cause of multifactorial, e.g., multiple sclerosis, and Mendelian, e.g., leukodystrophy, neurological disorders. CNP encodes a major component of myelin and its CNS expression is exclusive to myelin-forming oligodendrocytes. Deficiency of CNP in mouse causes a lethal white matter neurodegenerative phenotype. However, a corresponding human phenotype has not been described to date. Here, we describe a multiplex consanguineous family from Oman in which multiple affected members display a remarkably consistent phenotype of neuroregression with profound brain white matter loss. A novel homozygous missense variant in CNP was identified by combined autozygome/exome analysis. Immunoblot analysis suggests that this is a null allele in patient fibroblasts, which display abnormal F-actin organization. Our results suggest the establishment of a novel CNP-related hypomyelinating leukodystrophy in humans.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alazami AM, Patel N, Shamseldin HE, Anazi S, Al-Dosari MS, Alzahrani F, Hijazi H, Alshammari M, Aldahmesh MA, Salih MA (2015) Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep 10:148–161
Anazi S, Maddirevula S, Salpietro V, Asi YT, Alsahli S, Alhashem A, Shamseldin HE, AlZahrani F, Patel N, Ibrahim N (2017) Expanding the genetic heterogeneity of intellectual disability. Hum Genet 136:1419–1429
Banik NL (1995) A multidisciplinary approach to myelin diseases II (NATO AS1 Series A: Life Sciences, Vol. 258). Neurology 45:403–404
Bifulco M, Laezza C, Stingo S, Wolff J (2002) 2′,3′-Cyclic nucleotide 3′-phosphodiesterase: a membrane-bound, microtubule-associated protein and membrane anchor for tubulin. Proc Natl Acad Sci 99:1807–1812
Braun P, De Angelis D, Shtybel W, Bernier L (1991) Isoprenoid modification permits 2′,3′-cyclic nucleotide 3′-phosphodiesterase to bind to membranes. J Neurosci Res 30:540–544
Chelban V, Patel N, Vandrovcova J, Zanetti MN, Lynch DS, Ryten M, Botía JA, Bello O, Tribollet E, Efthymiou S (2017) Mutations in NKX6-2 cause progressive spastic ataxia and hypomyelination. Am J Human Genet 100:969–977
Dobson R, Giovannoni G (2019) Multiple sclerosis—a review. Eur J Neurol 26:27–40
Fields RD (2015) A new mechanism of nervous system plasticity: activity-dependent myelination. Nat Rev Neurosci 16:756–767
Fünfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J, Brinkmann BG, Kassmann CM, Tzvetanova ID, Möbius W (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485:517–521
Gravel M, Peterson J, Yong VW, Kottis V, Trapp B, Braun PE (1996) Overexpression of 2′,3′-cyclic nucleotide 3′-phosphodiesterase in transgenic mice alters oligodendrocyte development and produces aberrant myelination. Mol Cell Neurosci 7:453–466
Griffiths I, Klugmann M, Anderson T, Yool D, Thomson C, Schwab MH, Schneider A, Zimmermann F, McCulloch M, Nadon N (1998) Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280:1610–1613
Jahn O, Tenzer S, Werner HB (2009) Myelin proteomics: molecular anatomy of an insulating sheath. Mol Neurobiol 40:55–72
Kurihara T, Tsukada Y (1967) The regional and subcellular distribution of 2′,3′-cyclic nucleotide 3′-phosphohydrolase in the central nervous system. J Neurochem 14:1167–1174
Laezza C, Wolff J, Bifulco M (1997) Identification of a 48-kDa prenylated protein that associates with microtubules as 2′,3′-cyclic nucleotide 3′-phosphodiesterase in FRTL-5 cells. FEBS Lett 413:260–264
Lappe-Siefke C, Goebbels S, Gravel M, Nicksch E, Lee J, Braun PE, Griffiths IR, Nave K-A (2003) Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat Genet 33:366–374
Lee J, Gravel M, Zhang R, Thibault P, Braun PE (2005) Process outgrowth in oligodendrocytes is mediated by CNP, a novel microtubule assembly myelin protein. J Cell Biol 170:661–673
Lu Y, Oura S, Matsumura T, Oji A, Sakurai N, Fujihara Y, Shimada K, Miyata H, Tobita T, Noda T (2019) CRISPR/Cas9-mediated genome editing reveals 30 testis-enriched genes dispensable for male fertility in mice. Biol Reprod 101:501–511
Mitne-Neto M, Machado-Costa M, Marchetto MC, Bengtson MH, Joazeiro CA, Tsuda H, Bellen HJ, Silva HC, Oliveira AS, Lazar M (2011) Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients. Hum Mol Genet 20:3642–3652
Möbius W, Cooper B, Kaufmann WA, Imig C, Ruhwedel T, Snaidero N, Saab AS, Varoqueaux F (2010) Electron microscopy of the mouse central nervous system. Methods in cell biology, vol 96. Elsevier, Oxford, pp 475–512
Monies D, Maddirevula S, Kurdi W, Alanazy MH, Alkhalidi H, Al-Owain M, Sulaiman RA, Faqeih E, Goljan E, Ibrahim N (2017) Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation. Genet Med 19:1144–1150
Monies D, Abouelhoda M, Assoum M, Moghrabi N, Rafiullah R, Almontashiri N, Alowain M, Alzaidan H, Alsayed M, Subhani S (2019) Lessons learned from large-scale, first-tier clinical exome sequencing in a highly consanguineous population. Am J Human Genet 104:1182–1201
Saugier-Veber P, Munnich A, Bonneau D, Rozet J-M, Le Merrer M, Gil R, Boespflug-Tanguy O (1994) X-linked spastic paraplegia and Pelizaeus–Merzbacher disease are allelic disorders at the proteolipid protein locus. Nat Genet 6:257
Snaidero N, Velte C, Myllykoski M, Raasakka A, Ignatev A, Werner HB, Erwig MS, Möbius W, Kursula P, Nave K-A (2017) Antagonistic functions of MBP and CNP establish cytosolic channels in CNS myelin. Cell Rep 18:314–323
Stassart RM, Möbius W, Nave KA, Edgar JM (2018) The axon-myelin unit in development and degenerative disease. Front Neurosci 12:467. https://doi.org/10.3389/fnins.2018.00467
Trapp BD, Bernier L, Andrews SB, Colman DR (1988) Cellular and subcellular distribution of 2′,3′-cyclic nucleotide 3′-phosphodiesterase and its mRNA in the rat central nervous system. J Neurochem 51:859–868
Yu W-P, Collarini EJ, Pringle NP, Richardson WD (1994) Embryonic expression of myelin genes: evidence for a focal source of oligodendrocyte precursors in the ventricular zone of the neural tube. Neuron 12:1353–1362
Acknowledgements
We thank the study family for their enthusiastic participation. We also thank the Genotyping and Sequencing Core Facilities at KFSRHC for their technical help.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Authors declare no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Al-Abdi, L., Al Murshedi, F., Elmanzalawy, A. et al. CNP deficiency causes severe hypomyelinating leukodystrophy in humans. Hum Genet 139, 615–622 (2020). https://doi.org/10.1007/s00439-020-02144-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-020-02144-4