Abstract
Genetic syndromes involving both brain and eye abnormalities are numerous and include syndromes such as Warburg micro syndrome, Kaufman oculocerebrofacial syndrome, Cerebro-oculo-facio-skeletal syndrome, Kahrizi syndrome and others. Using exome sequencing, we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families, all originating from the same village. The protein encoded by MED25 belongs to Mediator complex or MED complex, which is an evolutionary conserved multi-subunit RNA polymerase II transcriptional regulator complex. The MED25 point mutation is located in the von Willebrand factor type A (MED25 VWA) domain which is responsible for MED25 recruitment into the Mediator complex; co-immunoprecipitation experiment demonstrated that this mutation dramatically impairs MED25 interaction with the Mediator complex in mammalian cells.
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References
Adzhubei IA, Schmidt S, Peshkin L et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249. doi:10.1038/nmeth0410-248
Basel-Vanagaite L, Attia R, Yahav M et al (2006a) The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation. J Med Genet 43:203–210. doi:10.1136/jmg.2005.035709
Basel-Vanagaite L, Taub E, Halpern GJ et al (2006b) Genetic screening for autosomal recessive nonsyndromic mental retardation in an isolated population in Israel. Eur J Hum Genet 15:250–253. doi:10.1038/sj.ejhg.5201750
Benkert P, Tosatto SCE, Schomburg D (2008) QMEAN: a comprehensive scoring function for model quality assessment. Proteins Struct Funct Bioinform 71:261–277. doi:10.1002/prot.21715
Benkert P, Kunzli M, Schwede T (2009) QMEAN server for protein model quality estimation. Nucleic Acids Res 37:W510–W514. doi:10.1093/nar/gkp322
Esnault C, Ghavi-Helm Y, Brun S et al (2008) Mediator-dependent recruitment of TFIIH modules in preinitiation complex. Mol Cell 31:337–346. doi:10.1016/j.molcel.2008.06.021
Figueiredo T, Melo US, Pessoa ALS et al (2015) Homozygous missense mutation in MED25 segregates with syndromic intellectual disability in a large consanguineous family. J Med Genet 52:123–127. doi:10.1136/jmedgenet-2014-102793
Finn RD, Clements J, Eddy SR (2011) HMMER web server: interactive sequence similarity searching. Nucleic Acids Res 39:W29–W37. doi:10.1093/nar/gkr367
Finn RD, Bateman A, Clements J et al (2014) Pfam: the protein families database. Nucleic Acids Res 42:D222–D230. doi:10.1093/nar/gkt1223
Hunter S, Jones P, Mitchell A et al (2012) InterPro in 2011: new developments in the family and domain prediction database. Nucleic Acids Res 40:D306–D312. doi:10.1093/nar/gkr948
Jaber L, Bailey-Wilson JE, Haj-Yehia M et al (1994) Consanguineous matings in an Israeli-Arab community. Arch Pediatr Adolesc Med 148:412–415
Jaber L, Halpern GJ, Shohat T (2000) Trends in the frequencies of consanguineous marriages in the Israeli Arab community. Clin Genet 58:106–110. doi:10.1034/j.1399-0004.2000.580203.x
Jaroszewski L, Rychlewski L, Li Z et al (2005) FFAS03: a server for profile-profile sequence alignments. Nucleic Acids Res 33:W284–W288. doi:10.1093/nar/gki418
Katoh K, Standley DM (2013) MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol Biol Evol 30:772–780. doi:10.1093/molbev/mst010
Kornberg RD (2005) Mediator and the mechanism of transcriptional activation. Trends Biochem Sci 30:235–239. doi:10.1016/j.tibs.2005.03.011
Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081. doi:10.1038/nprot.2009.86
Kyte J, Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157:105–132. doi:10.1016/0022-2836(82)90515-0
Landau M, Mayrose I, Rosenberg Y et al (2005) ConSurf 2005: the projection of evolutionary conservation scores of residues on protein structures. Nucleic Acids Res 33:W299–W302. doi:10.1093/nar/gki370
Leal A, Huehne K, Bauer F 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
Lee H-K, Park U-H, Kim E-J, Um S-J (2007) MED25 is distinct from TRAP220/MED1 in cooperating with CBP for retinoid receptor activation. EMBO J 26:3545–3557. doi:10.1038/sj.emboj.7601797
Malik S, Roeder RG (2010) The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation. Nat Rev Genet 11:761–772. doi:10.1038/nrg2901
McGuffin LJ, Roche DB (2010) Rapid model quality assessment for protein structure predictions using the comparison of multiple models without structural alignments. Bioinformatics 26:182–188. doi:10.1093/bioinformatics/btp629
Mittler G, Stühler T, Santolin L et al (2003) A novel docking site on Mediator is critical for activation by VP16 in mammalian cells. EMBO J 22:6494–6504. doi:10.1093/emboj/cdg619
Nakamura Y, Yamamoto K, He X et al (2011) Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25. Nat Commun 2:251. doi:10.1038/ncomms1242
Rana R, Surapureddi S, Kam W et al (2011) Med25 is required for rna polymerase II recruitment to specific promoters, thus regulating xenobiotic and lipid metabolism in human liver. Mol Cell Biol 31:466–481. doi:10.1128/MCB.00847-10
Šali A, Potterton L, Yuan F et al (1995) Evaluation of comparative protein modeling by MODELLER. Proteins Struct Funct Bioinform 23:318–326. doi:10.1002/prot.340230306
UniProt (2014) Activities at the universal protein resource (UniProt). Nucleic Acids Res 42:D191–D198. doi:10.1093/nar/gkt1140
Verger A, Baert J-L, Verreman K et al (2013) The Mediator complex subunit MED25 is targeted by the N-terminal transactivation domain of the PEA3 group members. Nucleic Acids Res 41:4847–4859. doi:10.1093/nar/gkt199
Vorup-Jensen T, Ostermeier C, Shimaoka M et al (2003) Structure and allosteric regulation of the alpha X beta2 integrin I domain. Proc Natl Acad Sci 100:1873–1878. doi:10.1073/pnas.0237387100
Vriend G (1990) WHAT IF: a molecular modeling and drug design program. J Mol Graph 8:52–56. doi:10.1016/0263-7855(90)80070-V
Wiederstein M, Sippl MJ (2007) ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res 35:W407–W410. doi:10.1093/nar/gkm290
Wilson D, Pethica R, Zhou Y et al (2009) SUPERFAMILY–sophisticated comparative genomics, data mining, visualization and phylogeny. Nucleic Acids Res 37:D380–D386. doi:10.1093/nar/gkn762
Yang F, DeBeaumont R, Zhou S, Naar AM (2004) The activator-recruited cofactor/Mediator coactivator subunit ARC92 is a functionally important target of the VP16 transcriptional activator. Proc Natl Acad Sci 101:2339–2344. doi:10.1073/pnas.0308676100
Acknowledgments
The authors thank the families for their cooperation. This study was supported by Israeli Ministry of Health Chief Scientist foundation [No 3-4963] and Israeli Science Foundation [No 558/09]. Additionally, we would like to thank the Humanitarian Genetic Counselling Fund and Rambam Medical Center for partial support of this study. We thank the Nord-Pas de Calais Regional Council (Project Emergent) for supporting this study. The authors declare that they have no conflict of interest.
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L. Basel-Vanagaite and P. Smirin-Yosef are equally contributed and shares first joint authorship.
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Basel-Vanagaite, L., Smirin-Yosef, P., Essakow, J.L. et al. Homozygous MED25 mutation implicated in eye–intellectual disability syndrome. Hum Genet 134, 577–587 (2015). https://doi.org/10.1007/s00439-015-1541-x
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DOI: https://doi.org/10.1007/s00439-015-1541-x