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01.05.2013 | Original Article

MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways

verfasst von: Alex R. Paciorkowski, Ryan N. Traylor, Jill A. Rosenfeld, Jacqueline M. Hoover, Catharine J. Harris, Susan Winter, Yves Lacassie, Martin Bialer, Allen N. Lamb, Roger A. Schultz, Elizabeth Berry-Kravis, Brenda E. Porter, Marni Falk, Anu Venkat, Rena J. Vanzo, Julie S. Cohen, Ali Fatemi, William B. Dobyns, Lisa G. Shaffer, Blake C. Ballif, Eric D. Marsh

Erschienen in: Neurogenetics | Ausgabe 2/2013

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Abstract

MEF2C haploinsufficiency syndrome is an emerging neurodevelopmental disorder associated with intellectual disability, autistic features, epilepsy, and abnormal movements. We report 16 new patients with MEF2C haploinsufficiency, including the oldest reported patient with MEF2C deletion at 5q14.3. We detail the neurobehavioral phenotype, epilepsy, and abnormal movements, and compare our subjects with those previously reported in the literature. We also investigate Mef2c expression in the developing mouse forebrain. A spectrum of neurofunctional deficits emerges, with hyperkinesis a consistent finding. Epilepsy varied from absent to severe, and included intractable myoclonic seizures and infantile spasms. Subjects with partial MEF2C deletion were statistically less likely to have epilepsy. Finally, we confirm that Mef2c is present both in dorsal primary neuroblasts and ventral gamma-aminobutyric acid(GABA)ergic interneurons in the forebrain of the developing mouse. Given interactions with several key neurodevelopmental genes such as ARX, FMR1, MECP2, and TBR1, it appears that MEF2C plays a role in several developmental stages of both dorsal and ventral neuronal cell types.

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Berland S, Houge G (2010) Late-onset gain of skills and peculiar jugular pit in an 11-year-old girl with 5q14.3 microdeletion including MEF2C. Clin Dysmorphol 19(4):222–224PubMedCrossRef

Carr CW, Zimmerman HH, Martin CL, Vikkula M, Byrd AC, Abdul-Rahman OA (2011) 5q14.3 neurocutaneous syndrome: a novel continguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C. Am. J. Med. Genet. A 155A(7):1640–1645PubMed

Engels H, Wohlleber E, Zink A, Hoyer J, Ludwig KU, Brockschmidt FF et al (2009) A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients. Eur J Hum Genet 17(12):1592–1599PubMedCrossRef

Le Meur N, Holder-Espinasse M, Jaillard S, Goldenberg A, Joriot S, Amati-Bonneau P et al (2010) MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations. J Med Genet 47(1):22–29PubMedCrossRef

Novara F, Beri S, Giorda R, Ortibus E, Nageshappa S, Darra F et al (2010) Refining the phenotype associated with MEF2C haploinsufficiency. Clin Genet 78(5):471–477PubMedCrossRef

Nowakowska BA, Obersztyn E, Szymańska K, Bekiesińska-Figatowska M, Xia Z, Ricks CB et al (2010) Severe mental retardation, seizures, and hypotonia due to deletions of MEF2C. Am J Med Genet B Neuropsychiatr Genet 153B(5):1042–1051PubMed

Zweier M, Gregor A, Zweier C, Engels H, Sticht H, Wohlleber E et al (2010) Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression. Hum Mutat 31(6):722–733PubMedCrossRef

Mikhail FM, Lose EJ, Robin NH, Descartes MD, Rutledge KD, Rutledge SL et al (2011) Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental retardation, and/or autism spectrum disorders. Am J Med Genet A 155A(10):2386–2396PubMed

Zweier M, Rauch A (2012) The MEF2C-related and 5q14.3q15 microdeletion syndrome. Mol Syndromol 2(3–5):164–70PubMed

10.

Li Z, McKercher SR, Cui J, Nie Z, Soussou W, Roberts AJ et al (2008) Myocyte enhancer factor 2C as a neurogenic and antiapoptotic transcription factor in murine embryonic stem cells. J Neurosci 28(26):6557–6568PubMedCrossRef

11.

Potthoff MJ, Olson EN (2007) MEF2: a central regulator of diverse developmental programs. Development 134(23):4131–4140PubMedCrossRef

12.

Leifer D, Krainc D, Yu YT, McDermott J, Breitbart RE, Heng J et al (1993) MEF2C, a MADS/MEF2-family transcription factor expressed in a laminar distribution in cerebral cortex. Proc Natl Acad Sci U S A 90(4):1546–1550PubMedCrossRef

13.

Lyons GE, Micales BK, Schwarz J, Martin JF, Olson EN (1995) Expression of mef2 genes in the mouse central nervous system suggests a role in neuronal maturation. J Neurosci 15(8):5727–5738PubMed

14.

Janson CG, Chen Y, Li Y, Leifer D (2001) Functional regulatory regions of human transcription factor MEF2C. Brain Res Mol Brain Res 97(1):70–82PubMedCrossRef

15.

Sekiyama Y, Suzuki H, Tsukahara T (2012) Functional gene expression analysis of tissue-specific isoforms of Mef2c. Cell Mol Neurobiol 32(1):129–139PubMedCrossRef

16.

Li H, Radford JC, Ragusa MJ, Shea KL, McKercher SR, Zaremba JD et al (2008) Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo. Proc Natl Acad Sci U S A 105(27):9397–9402PubMedCrossRef

17.

Barbosa AC, Kim M-S, Ertunc M, Adachi M, Nelson ED, McAnally J et al (2008) MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function. Proc Natl Acad Sci U S A 105(27):9391–9396PubMedCrossRef

18.

Bedogni F, Hodge RD, Elsen GE, Nelson BR, Daza RAM, Beyer RP et al (2010) Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex. Proc Natl Acad Sci U S A 107(29):13129–13134PubMedCrossRef

19.

Fulp CT, Cho G, Marsh ED, Nasrallah IM, Labosky PA, Golden JA (2008) Identification of Arx transcriptional targets in the developing basal forebrain. Hum Mol Genet 17(23):3740–3760PubMedCrossRef

20.

Long JE, Cobos I, Potter GB, Rubenstein JLR (2009) Dlx1&2 and Mash1 transcription factors control MGE and CGE patterning and differentiation through parallel and overlapping pathways. Cereb Cortex 19(Suppl 1):i96–i106PubMedCrossRef

21.

Battini R, Sgandurra G, Petacchi E, Guzzetta A, Di Pietro R, Giannini MT et al (2008) Movement disorder-childhood rating scale: reliability and validity. Pediatr Neurol 39(4):259–265PubMedCrossRef

22.

Sanger TD, Chen D, Fehlings DL, Hallett M, Lang AE, Mink JW et al (2010) Definition and classification of hyperkinetic movements in childhood. Mov Disord 25(11):1538–1549PubMedCrossRef

23.

Ballif BC, Theisen A, McDonald-McGinn DM, Zackai EH, Hersh JH, Bejjani BA et al (2008) Identification of a previously unrecognized microdeletion syndrome of 16q11.2q12.2. Clin Genet 74(5):469–475PubMedCrossRef

24.

Marsh ED, Minarcik J, Campbell K, Brooks-Kayal AR, Golden JA (2008) FACS-array gene expression analysis during early development of mouse telencephalic interneurons. Dev Neurobiol 68(4):434–445PubMedCrossRef

25.

Batista-Brito R, Machold R, Klein C, Fishell G (2008) Gene expression in cortical interneuron precursors is prescient of their mature function. Cereb Cortex 18(10):2306–2317PubMedCrossRef

26.

Winden KD, Oldham MC, Mirnics K, Ebert PJ, Swan CH, Levitt P et al (2009) The organization of the transcriptional network in specific neuronal classes. Mol Syst Biol 5:291PubMedCrossRef

27.

Chahrour M, Jung SY, Shaw C, Zhou X, Wong STC, Qin J et al (2008) MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320(5880):1224–1229PubMedCrossRef

28.

Cardoso C, Boys A, Parrini E, Mignon-Ravix C, McMahon JM, Khantane S et al (2009) Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletion. Neurology 72(9):784–792PubMedCrossRef

29.

Saitsu H, Igarashi N, Kato M, Okada I, Kosho T, Shimokawa O et al (2011) De novo 5q14.3 translocation 121.5-kb upstream of MEF2C in a patient with severe intellectual disability and early-onset epileptic encephalopathy. Am J Med Genet A 155(11):2879–84CrossRef

30.

Toral-López J, Buentello-Volante B, Balderas-Minor MM, Amezcua-Herrera C, Valdes-Miranda JM, González-Huerta LM et al (2012) An intellectually disabled patient with the 5q14.3q15 microdeletion syndrome associated with an apparently de novo t(2;5)(q13;q14). Am J Med Genet A 158A(4):942–946PubMedCrossRef

31.

Strømme P, Mangelsdorf ME, Scheffer IE, Gécz J (2002) Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX. Brain Dev 24(5):266–268PubMedCrossRef

32.

Guerrini R, Moro F, Kato M, Barkovich AJ, Shiihara T, McShane MA et al (2007) Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus. Neurology 69(5):427–433PubMedCrossRef

33.

Brunetti-Pierri N, Paciorkowski AR, Ciccone R, Mina ED, Bonaglia MC, Borgatti R et al (2011) Duplications of FOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment. Eur J Hum Genet 19(1):102–107PubMedCrossRef

34.

Kortüm F, Das S, Flindt M, Morris-Rosendahl DJ, Stefanova I, Goldstein A et al (2011) The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis. J Med Genet 48(6):396–406PubMedCrossRef

35.

Percy AK (2002) Rett syndrome. Current status and new vistas. Neurol Clin 20(4):1125–1141PubMedCrossRef

36.

Neul JL, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Bahi-Buisson N et al (2010) Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol 68(6):944–950PubMedCrossRef

37.

Pfeiffer BE, Zang T, Wilkerson JR, Taniguchi M, Maksimova MA, Smith LN et al (2010) Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2. Neuron 66(2):191–197PubMedCrossRef

38.

Tonk V, Kyhm JH, Gibson CE, Wilson GN (2011) Interstitial deletion 5q14.3q21.3 with MEF2C haploinsufficiency and mild phenotype: when more is less. Am J Med Genet A 155A(6):1437–1441PubMed

39.

Bienvenu T, Diebold B, Chelly J, Isidor B (2012) Refining the phenotype associated with MEF2C point mutations. Neurogenetics. doi:10.1007/s10048-012-0344-7

Titel: MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways
verfasst von: Alex R. Paciorkowski
Ryan N. Traylor
Jill A. Rosenfeld
Jacqueline M. Hoover
Catharine J. Harris
Susan Winter
Yves Lacassie
Martin Bialer
Allen N. Lamb
Roger A. Schultz
Elizabeth Berry-Kravis
Brenda E. Porter
Marni Falk
Anu Venkat
Rena J. Vanzo
Julie S. Cohen
Ali Fatemi
William B. Dobyns
Lisa G. Shaffer
Blake C. Ballif
Eric D. Marsh
Publikationsdatum: 01.05.2013
Verlag: Springer-Verlag
Erschienen in: Neurogenetics / Ausgabe 2/2013
Print ISSN: 1364-6745
Elektronische ISSN: 1364-6753
DOI: https://doi.org/10.1007/s10048-013-0356-y

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MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways

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