Abstract
Background:
Mutations in the X-linked gene MED12 cause at least three different, but closely related, entities of syndromic intellectual disability. Recently, a new syndrome caused by MED13L deleterious variants has been described, which shows similar clinical manifestations including intellectual disability, hypotonia, and other congenital anomalies.
Methods:
Genotyping of 1,256 genes related with neurodevelopment was performed by next-generation sequencing in three unrelated patients and their healthy parents. Clinically relevant findings were confirmed by conventional sequencing.
Results:
Each patient showed one de novo variant not previously reported in the literature or databases. Two different missense variants were found in the MED12 or MED13L genes and one nonsense mutation was found in the MED13L gene.
Conclusion:
The phenotypic consequences of these mutations are closely related and/or have been previously reported in one or other gene. Additionally, MED12 and MED13L code for two closely related partners of the mediator kinase module. Consequently, we propose the concept of a common MED12/MED13L clinical spectrum, encompassing Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, Ohdo syndrome, MED13L haploinsufficiency syndrome, and others.
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References
Liu X, Bushnell DA, Kornberg RD. RNA polymerase II transcription: structure and mechanism. Biochim Biophys Acta 2013;1829:2–8.
Lee TI, Young RA. Transcriptional regulation and its misregulation in disease. Cell 2013;152:1237–51.
Dotson MR, Yuan CX, Roeder RG, et al. Structural organization of yeast and mammalian mediator complexes. Proc Natl Acad Sci USA 2000;97:14307–10.
Taatjes DJ, Näär AM, Andel F 3rd, Nogales E, Tjian R. Structure, function, and activator-induced conformations of the CRSP coactivator. Science 2002;295:1058–62.
Taatjes DJ. The human Mediator complex: a versatile, genome-wide regulator of transcription. Trends Biochem Sci 2010;35:315–22.
Conaway RC, Conaway JW. Origins and activity of the Mediator complex. Semin Cell Dev Biol 2011;22:729–34.
Borggrefe T, Davis R, Erdjument-Bromage H, Tempst P, Kornberg RD. A complex of the Srb8, -9, -10, and -11 transcriptional regulatory proteins from yeast. J Biol Chem 2002;277:44202–7.
Malumbres M, Harlow E, Hunt T, et al. Cyclin-dependent kinases: a family portrait. Nat Cell Biol 2009;11:1275–6.
Knuesel MT, Meyer KD, Bernecky C, Taatjes DJ. The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function. Genes Dev 2009;23:439–51.
Conaway RC, Conaway JW. Function and regulation of the Mediator complex. Curr Opin Genet Dev 2011;21:225–30.
Graham JM Jr, Schwartz CE. MED12 related disorders. Am J Med Genet A 2013;161A:2734–40.
Lei L, Lin H, Zhong S, et al. Analysis of mutations in 7 candidate genes for dextro-Transposition of the great arteries in Chinese population. J Thorac Dis 2014;6:491–6.
van Haelst MM, Monroe GR, Duran K, et al. Further confirmation of the MED13L haploinsufficiency syndrome. Eur J Hum Genet 2015;23:135–8.
Redin C, Gérard B, Lauer J, et al. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. J Med Genet 2014;51:724–36.
Gilissen C, Hehir-Kwa JY, Thung DT, et al. Genome sequencing identifies major causes of severe intellectual disability. Nature 2014;511:344–7.
Cafiero C, Marangi G, Orteschi D, et al. Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome. Eur J Hum Genet 2015;23:1499–504.
Adegbola A, Musante L, Callewaert B, et al. Redefining the MED13L syndrome. European Journal of Hum Genet 2015; 00: 1–9.
Schwartz CE, Tarpey PS, Lubs HA, et al. The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. J Med Genet 2007;44:472–7.
Vulto-van Silfhout AT, de Vries BB, van Bon BW, et al. Mutations in MED12 cause X-linked Ohdo syndrome. Am J Hum Genet 2013;92:401–6.
Yamamoto T, Shimojima K. A novel MED12 mutation associated with non-specific X-linked intellectual disability. Hum Genome Var 2015;2:15018.
Utami KH, Winata CL, Hillmer AM, et al. Impaired development of neural-crest cell-derived organs and intellectual disability caused by MED13L haploinsufficiency. Hum Mutat 2014;35:1311–20.
Daniels DL, Ford M, Schwinn MK, et al. Mutual exclusivity of MED12/MED12L, MED13/13L, and CDK8/19 paralogs revealed within the CDK-mediator kinase module. J Proteomics Bioinform S2: 004. doi:10.4172/jpb.S2-004
Mukhopadhyay A, Kramer JM, Merkx G, et al. CDK19 is disrupted in a female patient with bilateral congenital retinal folds, microcephaly and mild mental retardation. Hum Genet 2010;128:281–91.
Kaufmann R, Straussberg R, Mandel H, et al. Infantile cerebral and cerebellar atrophy is associated with a mutation in the MED17 subunit of the transcription preinitiation mediator complex. Am J Hum Genet 2010;87:667–70.
Hashimoto S, Boissel S, Zarhrate M, et al. MED23 mutation links intellectual disability to dysregulation of immediate early gene expression. Science 2011;333:1161–3.
Leal A, Huehne K, Bauer F, et al. 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 2009;10:275–87.
Ito M, Yuan CX, Okano HJ, Darnell RB, Roeder RG. Involvement of the TRAP220 component of the TRAP/SMCC coactivator complex in embryonic development and thyroid hormone action. Mol Cell 2000;5:683–93.
Vodopiutz J, Schmook MT, Konstantopoulou V, et al. MED20 mutation associated with infantile basal ganglia degeneration and brain atrophy. Eur J Pediatr 2015;174:113–8.
Takahashi H, Parmely TJ, Sato S, et al. Human mediator subunit MED26 functions as a docking site for transcription elongation factors. Cell 2011;146:92–104.
Papai G, Weil PA, Schultz P. New insights into the function of transcription factor TFIID from recent structural studies. Curr Opin Genet Dev 2011;21:219–24.
Rooms L, Reyniers E, Scheers S, et al. TBP as a candidate gene for mental retardation in patients with subtelomeric 6q deletions. Eur J Hum Genet 2006;14:1090–6.
Hellman-Aharony S, Smirin-Yosef P, Halevy A, et al. Microcephaly thin corpus callosum intellectual disability syndrome caused by mutated TAF2. Pediatr Neurol 2013;49:411–416.e1.
Abu-Amero KK, Hellani A, Salih MA, et al. Ophthalmologic abnormalities in a de novo terminal 6q deletion. Ophthalmic Genet 2010;31:1–11.
O’Rawe JA, Wu Y, Dörfel MJ, et al. TAF1 Variants Are Associated with Dysmorphic Features, Intellectual Disability, and Neurological Manifestations. Am J Hum Genet 2015;97:922–32.
Makino S, Kaji R, Ando S, et al. Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism. Am J Hum Genet 2007;80:393–406.
Herzfeld T, Nolte D, Grznarova M, Hofmann A, Schultze JL, Müller U. X-linked dystonia parkinsonism syndrome (XDP, lubag): disease-specific sequence change DSC3 in TAF1/DYT3 affects genes in vesicular transport and dopamine metabolism. Hum Mol Genet 2013;22:941–51.
Kagey MH, Newman JJ, Bilodeau S, et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 2010;467:430–5.
Deardorff MA, Kaur M, Yaeger D, et al. Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation. Am J Hum Genet 2007;80:485–94.
Ho HH, Eaves LC. Kabuki make-up (Niikawa-Kuroki) syndrome: cognitive abilities and autistic features. Dev Med Child Neurol 1997;39:487–90.
Yuan B, Pehlivan D, Karaca E, et al. Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes. J Clin Invest 2015;125:636–51.
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The authors sincerely thank all the participants in the present study.
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Caro-Llopis, A., Rosello, M., Orellana, C. et al. De novo mutations in genes of mediator complex causing syndromic intellectual disability: mediatorpathy or transcriptomopathy?. Pediatr Res 80, 809–815 (2016). https://doi.org/10.1038/pr.2016.162
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DOI: https://doi.org/10.1038/pr.2016.162
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