Abstract
De novo mutations in the IRF2BPL gene have been identified to date in 18 patients presenting with neuromotor regression, epilepsy and variable neurological signs. Here, we report a female child carrying a novel heterozygous truncating variant in IRF2BPL. Following normal development for two and half years, she developed a progressive neurological condition with psychomotor regression, dystonic tetraparesis with hyperkinetic movements, but no overt epilepsy. Skin biopsy revealed enlarged lysosomes containing granular and tubular material, suggestive of a lysosomal storage disorder. This case expands the IRF2BPL phenotypic spectrum, for the first time providing evidence of endolysosomal storage.
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References
Marcogliese PC, Shashi V, Spillmann RC, Stong N, Rosenfeld JA, Koenig MK, Martinez-Agosto JA, Herzog M, Chen AH, Dickson PI, Lin HJ et al (2018) IRF2BPL is associated with neurological phenotypes. Am J Hum Genet 103(2):245–260
Tran Mau-Them F, Guibaud L, Duplomb L, Keren B, Lindstrom K, Marey I, Mochel F, van den Boogaard MJ, Oegema R, Nava C, Masurel A, Jouan T, Jansen FE, Au M, Chen AH, Cho M, Duffourd Y, Lozier E, Konovalov F, Sharkov A, Korostelev S, Urteaga B, Dickson P, Vera M, Martinez-Agosto JA, Begemann A, Zweier M, Schmitt-Mechelke T, Rauch A, Philippe C, van Gassen K, Nelson S, Graham JM Jr, Friedman J, Faivre L, Lin HJ, Thauvin-Robinet C, Vitobello A (2019) De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy. Genet Med 21(4):1008–1014. https://doi.org/10.1038/s41436-018-0143-0
Rampazzo A, Pivotto F, Occhi G, Tiso N, Bortoluzzi S, Rowen L, Hood L, Nava A, Danieli GA (2000) Characterization of C14orf4, a novel intronless human gene containing a polyglutamine repeat, mapped to the ARVD1 critical region. Biochem Biophys Res Commun 278(3):766–774. https://doi.org/10.1006/bbrc.2000.3883
Anderson GW, Goebel HH, Simonati A (2013) Human pathology in NCL. Biochim Biophys Acta 11:1807–1826. https://doi.org/10.1016/j.bbadis.2012.11.014
Beck-Wodl S, Harzer K, Sturm M, Buchert R, Riess O, Mennel HD, Latta E, Pagenstecher A, Keber U (2018) Homozygous TBC1 domain-containing kinase (TBCK) mutation causes a novel lysosomal storage disease—a new type of neuronal ceroid lipofuscinosis (CLN15)? Acta Neuropathol Commun 6(1):145. https://doi.org/10.1186/s40478-018-0646-6
Heger S, Mastronardi C, Dissen GA, Lomniczi A, Cabrera R, Roth CL, Jung H, Galimi F, Sippell W, Ojeda SR (2007) Enhanced at puberty 1 (EAP1) is a new transcriptional regulator of the female neuroendocrine reproductive axis. J Clin Invest 117(8):2145–2154. https://doi.org/10.1172/JCI31752
Higashimori A, Dong Y, Zhang Y, Kang W, Nakatsu G, Ng SSM, Arakawa T, Sung JJY, Chan FKL, Yu J (2018) Forkhead box F2 suppresses gastric cancer through a novel FOXF2-IRF2BPL-beta-catenin signaling axis. Cancer Res 78(7):1643–1656. https://doi.org/10.1158/0008-5472.CAN-17-2403
Brocke KS, Neu-Yilik G, Gehring NH, Hentze MW, Kulozik AE (2002) The human intronless melanocortin 4-receptor gene is NMD insensitive. Hum Mol Genet 11(3):331–335
Cusack BP, Arndt PF, Duret L, Roest Crollius H (2011) Preventing dangerous nonsense: selection for robustness to transcriptional error in human genes. PLoS Genet 7(10):e1002276. https://doi.org/10.1371/journal.pgen.1002276
Zheng Q, Huang T, Zhang L, Zhou Y, Luo H, Xu H, Wang X (2016) Dysregulation of ubiquitin-proteasome system in neurodegenerative diseases. Front Aging Neurosci 8:303. https://doi.org/10.3389/fnagi.2016.00303
Staropoli JF, Karaa A, Lim ET, Kirby A, Elbalalesy N, Romansky SG, Leydiker KB, Coppel SH, Barone R, Xin W, MacDonald ME, Abdenur JE, Daly MJ, Sims KB, Cotman SL (2012) A homozygous mutation in KCTD7 links neuronal ceroid lipofuscinosis to the ubiquitin-proteasome system. Am J Hum Genet 91(1):202–208. https://doi.org/10.1016/j.ajhg.2012.05.023
Seranova E, Connolly KJ, Zatyka M, Rosenstock TR, Barrett T, Tuxworth RI, Sarkar S (2017) Dysregulation of autophagy as a common mechanism in lysosomal storage diseases. Essays Biochem 61(6):733–749. https://doi.org/10.1042/EBC20170055
Funding
This work was funded by the European Research Council (ERC Starting Grant 260888), the Pierfranco and Luisa Mariani Foundation (PADAPORT project) and the Italian Ministry of Health (Ricerca Finalizzata 2013 NET-2013-02356160, Ricerca Corrente ‘Neuroscienze Sperimentali’ and 5x1000 Anno 2016 to Fondazione Santa Lucia).
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Monia Ginevrino and Roberta Battini have equally contributed to this work.
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Ginevrino, M., Battini, R., Nuovo, S. et al. A novel IRF2BPL truncating variant is associated with endolysosomal storage. Mol Biol Rep 47, 711–714 (2020). https://doi.org/10.1007/s11033-019-05109-7
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DOI: https://doi.org/10.1007/s11033-019-05109-7