Abstract
Infantile movement disorders are rare and genetically heterogeneous. We set out to identify the disease-causing mutation in siblings with a novel recessive neurodegenerative movement disorder. Genetic linkage analysis and whole-exome sequencing were performed in the original family. A cohort of six unrelated patients were sequenced for further mutations in the identified candidate gene. Pathogenicity of the mutation was evaluated by in silico analyses and by structural modeling. We identified the first and homozygous mutation (p.Gly114Ala) in the Mediator subunit 20 gene (MED20) in siblings presenting with infantile-onset spasticity and childhood-onset dystonia, progressive basal ganglia degeneration, and brain atrophy. Mediator refers to an evolutionarily conserved multi-subunit RNA polymerase II co-regulatory complex. Pathogenicity of the identified missense mutation is suggested by in silico analyses, by structural modeling, and by previous reporting of mutations in four distinct Mediator subunits causing neurodegenerative phenotypes. No further MED20 mutations were detected in this study.
Conclusion: We delineate a novel infantile-onset neurodegenerative movement disorder and emphasize the Mediator complex as critical for normal neuronal function. Definitive proof of pathogenicity of the identified MED20 mutation will require confirmation in unrelated patients.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- HC:
-
Head circumference
- LOD:
-
Likelihood-of-the-odds
- MED:
-
Mediator complex
- MED20:
-
Mediator subunit 20 gene
- MRI:
-
Magnetic resonance imaging
- NBIA:
-
Neurodegeneration with brain iron accumulation
- NCBI:
-
National Center for Biotechnology Information
- NUP62:
-
Nucleoporin 62 kDa gene
- PCR:
-
Polymerase chain reaction
- PDB:
-
Protein Data Bank
- PolyPhen 2:
-
Polymorphism Phenotyping version 2
- SD:
-
Standard deviations
- SIFT:
-
Sorting Intolerant from Tolerant
- SNP:
-
Single nucleotide polymorphism
References
Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101. doi:10.1038/ng786
Arnold K, Bordoli L, Kopp J, Schwede T (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22:195–201. doi:10.1093/bioinformatics/bti770
Basel-Vanagaite L, Muncher L, Straussberg R, Pasmanik-Chor M, Yahav M, Rainshtein L, Walsh CA, Magal N, Taub E, Drasinover V, Shalev H, Attia R, Rechavi G, Simon AJ, Shohat M (2006) Mutated nup62 causes autosomal recessive infantile bilateral striatal necrosis. Ann Neurol 60:214–222. doi:10.1002/ana.20902
Basel-Vanagaite L, Straussberg R, Ovadia H, Kaplan A, Magal N, Shorer Z, Shalev H, Walsh C, Shohat M (2004) Infantile bilateral striatal necrosis maps to chromosome 19q. Neurology 62:87–90
Dinopoulos A, Cecil KM, Schapiro MB, Papadimitriou A, Hadjigeorgiou GM, Wong B, deGrauw T, Egelhoff JC (2005) Brain MRI and proton MRS findings in infants and children with respiratory chain defects. Neuropediatrics 36:290–301. doi:10.1055/s-2005-872807
Hashimoto S, Boissel S, Zarhrate M, Rio M, Munnich A, Egly JM, Colleaux L (2011) MED23 mutation links intellectual disability to dysregulation of immediate early gene expression. Science 333:1161–1163. doi:10.1126/science.1206638
Hoischen A, Krumm N, Eichler EE (2014) Prioritization of neurodevelopmental disease genes by discovery of new mutations. Nat Neurosci 17:764–772. doi:10.1038/nn.3703
Karijolich JJ, Hampsey M (2012) The Mediator complex. Curr Biol 22:R1030–R1031. doi:10.1016/j.cub.2012.11.011
Kaufmann R, Straussberg R, Mandel H, Fattal-Valevski A, Ben-Zeev B, Naamati A, Shaag A, Zenvirt S, Konen O, Mimouni-Bloch A, Dobyns WB, Edvardson S, Pines O, Elpeleg O (2010) Infantile cerebral and cerebellar atrophy is associated with a mutation in the MED17 subunit of the transcription preinitiation mediator complex. Am J Hum Genet 87:667–670. doi:10.1016/j.ajhg.2010.09.016
Koleske AJ, Buratowski S, Nonet M, Young RA (1992) A novel transcription factor reveals a functional link between the RNA polymerase II CTD and TFIID. Cell 69:883–894
Lariviere L, Plaschka C, Seizl M, Wenzeck L, Kurth F, Cramer P (2012) Structure of the Mediator head module. Nature 492:448–451. doi:10.1038/nature11670
Leal A, Huehne K, Bauer F, Sticht H, Berger P, Suter U, Morera B et al (2009) Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models. Neurogenetics 10:275–287. doi:10.1007/s10048-009-0183-3
Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760. doi:10.1093/bioinformatics/btp324
Piruat JI, Aguilera A (1996) Mutations in the yeast SRB2 general transcription factor suppress hpr1-induced recombination and show defects in DNA repair. Genetics 143:1533–1542
Reetz K, Costa AS, Mirzazade S, Lehmann A, Juzek A, Rakowicz M, Boguslawska R, Schöls L, Linnemann C, Mariotti C, Grisoli M, Dürr A, van de Warrenburg BP, Timmann D, Pandolfo M, Bauer P, Jacobi H, Hauser TK, Klockgether T, Schulz JB, Investigators. aSG (2013) Genotype-specific patterns of atrophy progression are more sensitive than clinical decline in SCA1, SCA3 and SCA6. Brain 136:905–917
Risheg H, Graham JM Jr, Clark RD, Rogers RC, Opitz JM, Moeschler JB, Peiffer AP, May M, Joseph SM, Jones JR, Stevenson RE, Schwartz CE, Friez MJ (2007) A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome. Nat Genet 39:451–453. doi:10.1038/ng1992
Rouault TA (2013) Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat Rev Neurosci 14:551–564. doi:10.1038/nrn3453
Schwartz CE, Tarpey PS, Lubs HA, Verloes A, May MM, Risheg H, Friez MJ, Futreal PA, Edkins S, Teague J, Briault S, Skinner C, Bauer-Carlin A, Simensen RJ, Joseph SM, Jones JR, Gecz J, Stratton MR, Raymond FL, Stevenson RE (2007) The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. J Med Genet 44:472–477. doi:10.1136/jmg.2006.048637
Tabarki B, Al-Shafi S, Al-Shahwan S, Azmat Z, Al-Hashem A, Al-Adwani N, Biary N, Al-Zawahmah M, Khan S, Zuccoli G (2013) Biotin-responsive basal ganglia disease revisited: clinical, radiologic, and genetic findings. Neurology 80:261–267. doi:10.1212/WNL.0b013e31827deb4c
Takagi Y, Calero G, Komori H, Brown JA, Ehrensberger AH, Hudmon A, Asturias F, Kornberg RD (2006) Head module control of mediator interactions. Mol Cell 23:355–364. doi:10.1016/j.molcel.2006.06.007
Vulto-van Silfhout AT, de Vries BB, van Bon BW, Hoischen A, Ruiterkamp-Versteeg M, Gilissen C, Gao F, van Zwam M, Harteveld CL, van Essen AJ, Hamel BC, Kleefstra T, Willemsen MA, Yntema HG, van Bokhoven H, Brunner HG, Boyer TG, de Brouwer AP (2013) Mutations in MED12 cause X-linked Ohdo syndrome. Am J Hum Genet 92:401–406. doi:10.1016/j.ajhg.2013.01.007
Acknowledgments
The authors thank Sabine Möstl (Medical University of Vienna) for video documentation and Dr. Malvina Herceg (Medical University of Vienna) for performing NCV. The study was partially funded by the Austrian Society of Pediatrics (ÖGKJ) and an in-house grant of the Department of Pediatrics and Adolescent Medicine of Medical University Vienna (both to J.V.).
The Austrian Society of Pediatrics had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.
Conflict of interest
The authors declare no competing financial interests.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by Peter de Winter
This study is dedicated to Professor Arnold Pollak for his life work for preterm infants and for infants with inherited diseases.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Video 1
Patient 1 at 16 years of age. Cheerful disposition, no voluntary movements when lying in the prone position. Marked truncal hypotonia upon passive rotation from prone to supine position. Increased muscle tone is evident during rapid passive motion of the upper but less so of lower extremities. Deep tendon reflexes cannot be elicited and pyramidal tracts signs are absent. (WMV 4,294 kb)
Video 2
Patient 1, part 2. The patient is asked to grab a toy which induces generalized dystonia with constant mouth opening and fixed posture of left upper and lower extremities. Inability to grasp objects with her right hand with dystonic posture of fingers. Inability to walk and bradykinesia. (WMV 5,372 kb)
Video 3
Patient 2 at 2 years of age. Mild muscle weakness revealed during active rotation from prone to supine position and when getting into the upright position. Movements are slow and uncoordinated for her age and the right hand is fisted while crawling. There is no dystonia present. (WMV 2,950 kb)
Video 4
Patient 2, part 2. She presents with increased muscle tone of lower and upper limbs and brisk reflexes, Babinski sign is absent. She has no speech development. (WMV 3,169 kb)
Rights and permissions
About this article
Cite this article
Vodopiutz, J., Schmook, M.T., Konstantopoulou, V. et al. MED20 mutation associated with infantile basal ganglia degeneration and brain atrophy. Eur J Pediatr 174, 113–118 (2015). https://doi.org/10.1007/s00431-014-2463-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00431-014-2463-7