Neurol Sci. 2021 May 17; doi: 10.1007/s10072-021-05269-0. Epub 2021 May 17.

Identification of a novel mutation in MEF2C gene in an atypical patient with frontotemporal lobar degeneration.

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology

Andreia Adrião, Isabel Santana, Carolina Ribeiro, M Leonor Cancela, Natércia Conceição, Manuela Grazina

PMID: 33999292 DOI: 10.1007/s10072-021-05269-0

Abstract

The MEF2C gene encodes a transcription factor known to play a crucial role in molecular pathways affecting neuronal development. MEF2C mutations were described as a genetic cause of developmental disease (MRD20), and several reports sustain its involvement in dementia-related conditions, such as Alzheimer's disease and amyotrophic lateral sclerosis. These pathologies and frontotemporal degeneration (FTLD) are thought to share common physiopathological pathways. In this exploratory study, we searched for alterations in the DNA sequence of exons and boundaries, including 5'- and 3'-untranslated regions (5'UTR, 3'UTR), of MEF2C gene in 11 patients with clinical phenotypes related with MRD20 or FTLD. We identified a heterozygous deletion of 13 nucleotides in the 5'UTR region of a 69 years old FTLD patient. This alteration was absent in 200 healthy controls, suggesting a contribution to this patient's disease phenotype. In silico analysis of the mutated sequence indicated changes in mRNA secondary structure and stability, thus potentially affecting MEF2C protein levels. Furthermore, in vitro functional analysis of this mutation revealed that the presence of this deletion abolished the transcriptional activity of the gene in human embryonic cells and rat brain neurons, probably by modifying MEF2C expression. Altogether, our results provide evidence for the involvement of MEF2C in FTLD manifesting with seizures.

Keywords: 5′ Untranslated region (5′UTR); Frontotemporal lobar degeneration (FTLD); Mental retardation autosomal dominant syndrome-20 disease (MRD20); Myocyte-specific enhancer factor 2 (MEF2C)

References

1. Leifer D, Krainc D, Yu YT, McDermott J, Breitbart RE, Heng J, Neve RL, Kosofsky B, Nadal-Ginard B, Lipton SA (1993) MEF2C, a MADS/MEF2-family transcription factor expressed in a laminar distribution in cerebral cortex. Proc Natl Acad Sci U S A 90:1546–1550 - PubMed
2. 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 15:5727–5738 - PubMed
3. Li H, Radford JC, Ragusa MJ, Shea KL, McKercher SR, Zaremba JD, Soussou W, Nie Z, Kang YJ, Nakanishi N, Okamoto SI, Roberts AJ, Schwarz JJ, Lipton SA (2008) Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo. Proc Natl Acad Sci U S A 105:9397–9402 - PubMed
4. Akhtar MW, Kim MS, Adachi M et al (2012) In vivo analysis of mef2 transcription factors in synapse regulation and neuronal survival. PLoS One 7:1–10 - PubMed
5. Barbosa AC, Kim M-S, Ertunc M, Adachi M, Nelson ED, McAnally J, Richardson JA, Kavalali ET, Monteggia LM, Bassel-Duby R, Olson EN (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 105:9391–9396 - PubMed
6. Zweier M, Rauch A (2011) The MEF2C-related and 5q14.3q15 microdeletion syndrome. Mol Syndromol 2:164–170 - PubMed
7. Bienvenu T, Diebold B, Chelly J, Isidor B (2012) Refining the phenotype associated with MEF2C point mutations. Neurogenetics 14:71–75 - PubMed
8. Engels H, Wohlleber E, Zink A, Hoyer J, Ludwig KU, Brockschmidt FF, Wieczorek D, Moog U, Hellmann-Mersch B, Weber RG, Willatt L, Kreiß-Nachtsheim M, Firth HV, Rauch A (2009) A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients. Eur J Hum Genet 17:1592–1599 - PubMed
9. Hotz A, Hellenbroich Y, Sperner J, Linder-Lucht M, Tacke U, Walter C, Caliebe A, Nagel I, Saunders DE, Wolff G, Martin P, Morris-Rosendahl DJ (2013) Microdeletion 5q14.3 and anomalies of brain development. Am J Med Genet A 161:2124–2133 - PubMed
10. Paciorkowski AR, Traylor RN, Rosenfeld JA, Hoover JM, Harris CJ, Winter S, Lacassie Y, Bialer M, Lamb AN, Schultz RA, Berry-Kravis E, Porter BE, Falk M, Venkat A, Vanzo RJ, Cohen JS, Fatemi A, Dobyns WB, Shaffer LG, Ballif BC, Marsh ED (2013) MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways. Neurogenetics 14:99–111 - PubMed
11. Zweier M, Gregor A, Zweier C, Engels H, Sticht H, Wohlleber E, Bijlsma EK, Holder SE, Zenker M, Rossier E, Grasshoff U, Johnson DS, Robertson L, Firth HV, Cornelia Kraus, Ekici AB, Reis A, Rauch A (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 31:722–733 - PubMed
12. Vrecar I, Innes J, Jones EA et al (2017) Further clinical delineation of the MEF2C haploinsufficiency syndrome: report on new cases and literature review of severe neurodevelopmental disorders presenting with seizures, absent speech and involuntary movements. J Pediatr Genet 6:129–141 - PubMed
13. Borlot F, Whitney R, Cohn RD, Weiss SK (2019) MEF2C-related epilepsy: Delineating the phenotypic spectrum from a novel mutation and literature review. Seizure 67:86–90 - PubMed
14. Beecham GW, Hamilton K, Naj AC, Martin ER, Huentelman M, Myers AJ, Corneveaux JJ, Hardy J, Vonsattel JP, Younkin SG, Bennett DA, de Jager PL, Larson EB, Crane PK, Kamboh MI, Kofler JK, Mash DC, Duque L, Gilbert JR, Gwirtsman H, Buxbaum JD, Kramer P, Dickson DW, Farrer LA, Frosch MP, Ghetti B, Haines JL, Hyman BT, Kukull WA, Mayeux RP, Pericak-Vance MA, Schneider JA, Trojanowski JQ, Reiman EM, the Alzheimer's Disease Genetics Consortium (ADGC), Schellenberg GD, Montine TJ (2014) Genome-wide association meta-analysis of neuropathologic features of Alzheimer’s disease and related dementias. PLoS Genet 10:e1004606 - PubMed
15. Lambert JC, Ibrahim-Verbaas CA, Harold D et al (2014) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45:1452–1458 - PubMed
16. Ruiz A, Heilmann S, Becker T et al (2014) Follow-up of loci from the International Genomics of Alzheimer’s Disease Project identifies TRIP4 as a novel susceptibility gene. Transl Psychiatry 4:e358 - PubMed
17. Wang X, Lopez OL, Sweet RA et al (2015) Genetic determinants of disease progression in Alzheimer’s disease. J Alzheimers Dis 43:649–655 - PubMed
18. Sao T, Yoshino Y, Yamazaki K, Ozaki Y, Mori Y, Ochi S, Yoshida T, Mori T, Iga JI, Ueno SI (2018) MEF2C mRNA expression and cognitive function in Japanese patients with Alzheimer’s disease. Psychiatry Clin Neurosci 72:160–167 - PubMed
19. Cho E-G, Zaremba JD, McKercher SR et al (2011) MEF2C enhances dopaminergic neuron differentiation of human embryonic stem cells in a Parkinsonian rat Model. PLoS One 6:e24027 - PubMed
20. Ryan SD, Dolatabadi N, Chan SF, Zhang X, Akhtar MW, Parker J, Soldner F, Sunico CR, Nagar S, Talantova M, Lee B, Lopez K, Nutter A, Shan B, Molokanova E, Zhang Y, Han X, Nakamura T, Masliah E, Yates JR III, Nakanishi N, Andreyev AY, Okamoto SI, Jaenisch R, Ambasudhan R, Lipton SA (2013) Isogenic human iPSC Parkinson’s model shows nitrosative stress-induced dysfunction in MEF2-PGC1α transcription. Cell 155:1351–1364 - PubMed
21. Calvo AC, Manzano R, Atencia-Cibreiro G et al (2012) Genetic biomarkers for ALS disease in transgenic SOD1 G93A mice. PLoS One 7:1–10 - PubMed
22. Jellinger KA (2008) Neuropathological aspects of Alzheimer disease, Parkinson disease and frontotemporal dementia. Neurodegener Dis 5:118–121 - PubMed
23. Lattante S, Ciura S, Rouleau GA, Kabashi E (2015) Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD). Trends Genet 1:1–11 - PubMed
24. Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, Ogar JM, Rohrer JD, Black S, Boeve BF, Manes F, Dronkers NF, Vandenberghe R, Rascovsky K, Patterson K, Miller BL, Knopman DS, Hodges JR, Mesulam MM, Grossman M (2011) Classification of primary progressive aphasia and its variants. Neurology 76:1006–1014 - PubMed
25. Mesulam MM (1982) Slowly progressive aphasia without generalized dementia. Ann Neurol 11:592–598 - PubMed
26. Moore D (2003) Preparation and analysis of DNA. In: Ausubel FM, Brent R, Kingston RE, et al eds. Current protocols in molecular biology. UK: John Willey & Sons 2.01-2.1.9f - PubMed
27. Den Dunnen JT, Antonarakis SE (2003) Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 15:7–12 - PubMed
28. Hofacker IL (2003) Vienna RNA secondary structure server. Nucleic Acids Res 31:3429–3431 - PubMed
29. Warde-Farley D, Donaldson SL, Comes O et al (2010) The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res 38:214–220 - PubMed
30. Baldeiras I, Santana I, Garrucho MH et al (2012) CSF biomarkers for the early diagnosis of Alzheimer’s disease in a routine clinical setting - the first Portuguese study. Sinapse 12:14–22 - PubMed
31. Frietze S, Lan X, Jin VX, Farnham PJ (2010) Genomic targets of the KRAB and SCAN domain-containing zinc finger protein 263. J Biol Chem 285:1393–1403 - PubMed
32. Sementchenko VI, Watson DK (2000) Ets target genes: past, present and future. Oncogene 19:6533–6548 - PubMed
33. Arnold MA, Kim Y, Czubryt MP, Phan D, McAnally J, Qi X, Shelton JM, Richardson JA, Bassel-Duby R, Olson EN (2007) MEF2C transcription factor controls chondrocyte hypertrophy and bone development. Dev Cell 12:377–389 - PubMed
34. Edmondson DG, Lyons GE, Martin JF, Olson EN (1994) Mef2 gene expression marks the cardiac and skeletal muscle lineages during mouse embryogenesis. Development 120:1251–1263 - PubMed
35. Harrington AJ, Bridges CM, Berto S, Blankenship K, Cho JY, Assali A, Siemsen BM, Moore HW, Tsvetkov E, Thielking A, Konopka G, Everman DB, Scofield MD, Skinner SA, Cowan CW (2020) MEF2C hypofunction in neuronal and neuroimmune populations produce MEF2C haploinsufficiency syndrome-like behaviors in mice. Biol Psychiatry 88:488–499 - PubMed
36. Alonso-Montes C, Naves-Diaz M, Fernandez-Martin JL, Rodriguez-Reguero J, Moris C, Coto E, Cannata-Andia JB, Rodriguez I (2012) New polymorphisms in human MEF2C gene as potential modifier of hypertrophic cardiomyopathy. Mol Biol Rep 39:8777–8785 - PubMed
37. Hughes TA (2006) Regulation of gene expression by alternative untranslated regions. Trends Genet 22:119–122 - PubMed
38. Dahlqvist J, Klar J, Tiwari N, Schuster J, Törmä H, Badhai J, Pujol R, van Steensel MAM, Brinkhuizen T, Gijezen L, Chaves A, Tadini G, Vahlquist A, Dahl N (2010) A single-nucleotide deletion in the POMP 5′ UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis. Am J Hum Genet 86:596–603 - PubMed
39. Badhai J, Schuster J, Gidlöf O, Dahl N (2011) 5′UTR variants of ribosomal protein S19 transcript determine translational efficiency: implications for Diamond-Blackfan anemia and tissue variability. PLoS One 6:1–7 - PubMed
40. Kozak M (1991) Structural features in eukaryotic mRNA that modulate the initiation of translation. J Biol Chem 266:19867–19870 - PubMed
41. Gingras A, Raught B, Sonenberg N (1999) eIF4 Initiation factors: effectors of mRNA recruitment of translation. Annu Rev Biochem 68:913–963 - PubMed
42. Kozak M, Lane H (1994) Features in the 5′ non-coding sequences of rabbit alpha and beta-globin mRNAs that affect translational efficiency. J Mol Biol 235:95–110 - PubMed
43. Glass D, Viñuela A, Davies MN, Ramasamy A, Parts L, Knowles D, Brown AA, Hedman ÅK, Small KS, Buil A, Grundberg E, Nica AC, Meglio PD, Nestle FO, Ryten M, the UK Brain Expression consortium, the MuTHER consortium, Durbin R, McCarthy MI, Deloukas P, Dermitzakis ET, Weale ME, Bataille V, Spector TD (2013) Gene expression changes with age in skin, adipose tissue, blood and brain. Genome Biol 14:R75 - PubMed
44. Ferrari R, Forabosco P, Vandrovcova J et al (2016) Frontotemporal dementia: insights into the biological underpinnings of disease through gene co-expression network analysis. Mol Neurodegener 11:21 - PubMed
45. Giunta M, Solje E, Gardoni F, Borroni B, Benussi A (2021) Experimental disease-modifying agents for frontotemporal lobar degeneration. J Exp Pharmacol 13:359–376 - PubMed

Publication Types

• Journal Article

Grant support

• UIDB/04326/2020 (CCMAR)/Fundação para a Ciência e a Tecnologia
• PEst-C/SAU/LA0001/2013-2014/Fundação para a Ciência e a Tecnologia
• PTDC/SAU-EPI/121811/2010/Fundação para a Ciência e a Tecnologia