A specific mutation in TBL1XR1 causes Pierpont syndrome
Open accessAbstract
BACKGROUND: The combination of developmental delay, facial characteristics, hearing loss and abnormal fat distribution in the distal limbs is known as Pierpont syndrome. The aim of the present study was to detect and study the cause of Pierpont syndrome. METHODS: We used whole-exome sequencing to analyse four unrelated individuals with Pierpont syndrome, and Sanger sequencing in two other unrelated affected individuals. Expression of mRNA of the wild-type candidate gene was analysed in human postmortem brain specimens, adipose tissue, muscle and liver. Expression of RNA in lymphocytes in patients and controls was additionally analysed. The variant protein was expressed in, and purified from, HEK293 cells to assess its effect on protein folding and function. RESULTS: We identified a single heterozygous missense variant, c.1337A>G (p.Tyr446Cys), in transducin β-like 1 X-linked receptor 1 (TBL1XR1) as disease-causing in all patients. TBL1XR1 mRNA expression was demonstrated in pituitary, hypothalamus, white and brown adipose tissue, muscle and liver. mRNA expression is lower in lymphocytes of two patients compared with the four controls. The mutant TBL1XR1 protein assembled correctly into the nuclear receptor corepressor (NCoR)/ silencing mediator for retinoid and thyroid receptors (SMRT) complex, suggesting a dominant-negative mechanism. This contrasts with loss-of-function germline TBL1XR1 deletions and other TBL1XR1 mutations that have been implicated in autism. However, autism is not present in individuals with Pierpont syndrome. CONCLUSIONS: This study identifies a specific TBL1XR1 mutation as the cause of Pierpont syndrome. Deletions and other mutations in TBL1XR1 can cause autism. The marked differences between Pierpont patients with the p.Tyr446Cys mutation and individuals with other mutations and whole gene deletions indicate a specific, but as yet unknown, disease mechanism of the TBL1XR1 p.Tyr446Cys mutation.
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Mutations in TBLR1 and TBL1 have been associated with autism, intellectual disability, Pierpont syndrome, and West syndrome.
“Already, mutations in other components of the complex, TBLR1 and TBL1, have been associated with autism, intellectual disability, Pierpont syndrome, a disorder characterized by developmental delay and abnormal fat distribution in the distal limbs, and West syndrome, a disorder with RTT-like features [216–219].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [218]
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Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations
O’Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., Levy, R., Ko, A., Lee, C., Smith, J. D., et al. (2012) · Nature · doi:10.1038/nature10989 · Cited by 2,165 · see citing works
Structure of Hdac3 Bound to Co-Repressor and Inositol Tetraphosphate
Watson, P. J., Fairall, L., Santos, G. M., & Schwabe, J. W. R. (2012) · Nature · doi:10.1038/nature10728 · Cited by 505 · see citing works
Self-citationSMRT Derepression by the IκB Kinase α
Hoberg, J. E., Yeung, F., & Mayo, M. W. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.10.010 · Cited by 220 · see citing works
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Research works printed but not linked: 28
- [1]Pierpont M, Stewart F, Gorlin R Plantar lipomatosis, unusual facial phenotype and developmental delay: a new MCA/MR syndrome. Am J Med Genet 1998; 75: 18– 21. 10.1002/(SICI)1096-8628(19980106)75:1<18::AID-AJMG5>3.0.CO;2-M 9450851 · DOI
- [2]Oudesluijs GG, Hordijk R, Boon M, Sijens PE, Hennekam RC Plantar lipomatosis, unusual facies, and developmental delay: confirmation of Pierpont syndrome. Am J Med Genet 2005; 137A: 77– 80. 10.1002/ajmg.a.30863 16007632 · DOI
- [3]Vadivelu S, Edelman M, Schneider SJ, Mittler MA Choroid plexus papilloma and Pierpont syndrome. J Neurosurg Pediatr 2013; 11: 115– 8. 10.3171/2012.10.PEDS12219 23176139 · DOI
- [4]Wright EM, Suri M, White SM, de Leeuw N, Vulto-van Silfhout AT, Stewart F, McKee S, Mansour S, Connell FC, Chopra M, Kirk EP, Devriendt K, Reardon W, Brunner H, Donnai D Pierpont syndrome: a collaborative study. Am J Med Genet 2011; 155A: 2203– 11. 10.1002/ajmg.a.34147 21834056 PMC4495254 · DOI
- [5]Sim JC, White SM, Fitzpatrick E, Wilson GR, Gillies G, Pope K, Mountford HS, Torring PM, McKee S, Vulto-van Silfhout AT, Jhangiani SN, Muzny DM, Leventer RJ, Delatycki MB, Amor DJ, Lockhart PJ Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency. Orphanet J Rare Dis 2014; 9: 43 10.1186/1750-1172-9-43 24674232 PMC4022252 · DOI
- [6]McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010; 20: 1297– 303. 10.1101/gr.107524.110 20644199 PMC2928508 · DOI · Paper page
- [7]DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, Philippakis AA, del Angel G, Rivas MA, Hanna M, McKenna A, Fennell TJ, Kernytsky AM, Sivachenko AY, Cibulskis K, Gabriel SB, Altshuler D, Daly MJ A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 2011; 43: 491– 8. 10.1038/ng.806 21478889 PMC3083463 · DOI
- [8]Li MX, Gui HS, Kwan JS, Bao SY, Sham PC A comprehensive framework for prioritizing variants in exome sequencing studies of Mendelian diseases. Nucleic Acids Res 2012; 40: e53 10.1093/nar/gkr1257 22241780 PMC3326332 · DOI
- [10]Bisschop PH, Dekker MJ, Osterthun W, Kwakkel J, Anink JJ, Boelen A, Unmehopa UA, Koper JW, Lamberts SW, Stewart PM, Swaab DF, Fliers E Expression of 11beta-hydroxysteroid dehydrogenase type 1 in the human hypothalamus. J Neuroendocrinol 2013; 25: 425– 32. 10.1111/jne.12017 23286317 · DOI
- [11]Ramakers C, Ruijter JM, Deprez RH, Moorman AF Assumption-free analysis of quantitative real-time polymerase chain reaction (PCR) data. Neurosci Lett 2003; 339: 62– 6. 10.1016/S0304-3940(02)01423-4 12618301 · DOI
- [12]Cerna D, Wilson DK The structure of Sif2p, a WD repeat protein functioning in the SET3 corepressor complex. J Mol Biol 2005; 351: 923– 35. 10.1016/j.jmb.2005.06.025 16051270 · DOI
- [13]Zhang XM, Chang Q, Zeng L, Gu J, Brown S, Basch RS TBLR1 regulates the expression of nuclear hormone receptor co-repressors. BMC Cell Biol 2006; 7: 31 10.1186/1471-2121-7-31 16893456 PMC1555579 · DOI
- [14]Oberoi J, Fairall L, Watson PJ, Yang JC, Czimmerer Z, Kampmann T, Goult BT, Greenwood JA, Gooch JT, Kallenberger BC, Nagy L, Neuhaus D, Schwabe JW Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery. Nat Struct Mol Biol 2011; 18: 177– 84. 10.1038/nsmb.1983 21240272 PMC3232451 · DOI · Paper page
- [15]Hu X, Lazar MA Transcriptional repression by nuclear hormone receptors. Trends Endocrinol Metab 2000; 11: 6– 10. 10.1016/S1043-2760(99)00215-5 10652499 · DOI
- [16]Tagami T, Madison LD, Nagaya T, Jameson JL Nuclear receptor corepressors activate rather than suppress basal transcription of genes that are negatively regulated by thyroid hormone. Mol Cell Biol 1997; 17: 2642– 8. 10.1128/MCB.17.5.2642 9111334 PMC232114 · DOI
- [17]Perissi V, Aggarwal A, Glass CK, Rose DW, Rosenfeld MG A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors. Cell 2004; 116: 511– 26. 10.1016/S0092-8674(04)00133-3 14980219 · DOI
- [19]Li J, Wang CY TBL1-TBLR1 and beta-catenin recruit each other to Wnt target-gene promoter for transcription activation and oncogenesis. Nat Cell Biol 2008; 10: 160– 9. 10.1038/ncb1684 18193033 · DOI
- [20]Braggio E, McPhail ER, Macon W, Lopes MB, Schiff D, Law M, Fink S, Sprau D, Giannini C, Dogan A, Fonseca R, O'Neill BP Primary central nervous system lymphomas: a validation study of array-based comparative genomic hybridization in formalin-fixed paraffin-embedded tumor specimens. Clin Cancer Res 2011; 17: 4245– 53. 10.1158/1078-0432.CCR-11-0395 21562036 PMC3131452 · DOI
- [21]Gonzalez-Aguilar A, Idbaih A, Boisselier B, Habbita N, Rossetto M, Laurenge A, Bruno A, Jouvet A, Polivka M, Adam C, Figarella-Branger D, Miquel C, Vital A, Ghesquières H, Gressin R, Delwail V, Taillandier L, Chinot O, Soubeyran P, Gyan E, Choquet S, Houillier C, Soussain C, Tanguy ML, Marie Y, Mokhtari K, Hoang-Xuan K Recurrent mutations of MYD88 and TBL1XR1 in primary central nervous system lymphomas. Clin Cancer Res 2012; 18: 5203– 11. 10.1158/1078-0432.CCR-12-0845 22837180 · DOI
- [22]Parker H, An Q, Barber K, Case M, Davies T, Konn Z, Stewart A, Wright S, Griffiths M, Ross FM, Moorman AV, Hall AG, Irving JA, Harrison CJ, Strefford JC The complex genomic profile of ETV6-RUNX1 positive acute lymphoblastic leukemia highlights a recurrent deletion of TBL1XR1. Genes Chromosomes Cancer 2008; 47: 1118– 25. 10.1002/gcc.20613 18767146 · DOI
- [23]Andersson E, Eldfors S, Edgren H, Ellonen P, Väkevä L, Ranki A, Mustjoki S Novel TBL1XR1, EPHA7 and SLFN12 mutations in a Sezary syndrome patient discovered by whole exome sequencing. Exp Dermatol 2014; 23: 366– 8. 10.1111/exd.12405 24689486 · DOI
- [24]Liu L, Lin C, Liang W, Wu S, Liu A, Wu J, Zhang X, Ren P, Li M, Song L TBL1XR1 promotes lymphangiogenesis and lymphatic metastasis in esophageal squamous cell carcinoma. Gut 2015; 64: 26– 36. 10.1136/gutjnl-2013-306388 24667177 · DOI
- [25]Kadota M, Sato M, Duncan B, Ooshima A, Yang HH, Diaz-Meyer N, Gere S, Kageyama S, Fukuoka J, Nagata T, Tsukada K, Dunn BK, Wakefield LM, Lee MP Identification of novel gene amplifications in breast cancer and coexistence of gene amplification with an activating mutation of PIK3CA. Cancer Res 2009; 69: 7357– 65. 10.1158/0008-5472.CAN-09-0064 19706770 PMC2745517 · DOI
- [27]O'Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, Carvill G, Kumar A, Lee C, Ankenman K, Munson J, Hiatt JB, Turner EH, Levy R, O'Day DR, Krumm N, Coe BP, Martin BK, Borenstein E, Nickerson DA, Mefford HC, Doherty D, Akey JM, Bernier R, Eichler EE, Shendure J Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 2012; 338: 1619– 22. 10.1126/science.1227764 23160955 PMC3528801 · DOI · Paper page
- [28]Saitsu H, Tohyama J, Walsh T, Kato M, Kobayashi Y, Lee M, Tsurusaki Y, Miyake N, Goto Y, Nishino I, Ohtake A, King MC, Matsumoto N A girl with West syndrome and autistic features harboring a de novo TBL1XR1 mutation. J Hum Genet 2014; 59: 581– 3. 10.1038/jhg.2014.71 25102098 · DOI · Paper page
- [29]Tabet AC, Leroy C, Dupont C, Serrano E, Hernandez K, Gallard J, Pouvreau N, Gadisseux JF, Benzacken B, Verloes A De novo deletion of TBL1XR1 in a child with non-specific developmental delay supports its implication in intellectual disability. Am J Med Genet 2014; 164A: 2335– 7. 10.1002/ajmg.a.36619 24891185 · DOI
- [30]Pons L, Cordier MP, Labalme A, Till M, Louvrier C, Schluth-Bolard C, Lesca G, Edery P, Sanlaville D A new syndrome of intellectual disability with dysmorphism due to TBL1XR1 deletion. Am J Med Genet A 2015; 167A: 164– 8. 10.1002/ajmg.a.36759 25425123 · DOI · Paper page
- [31]Millson A, Lagrave D, Willis MJ, Rowe LR, Lyon E, South ST Chromosomal loss of 3q26.3–3q26.32, involving a partial neuroligin 1 deletion, identified by genomic microarray in a child with microcephaly, seizure disorder, and severe intellectual disability. Am J Med Genet 2012; 158A: 159– 65. 10.1002/ajmg.a.34349 22106001 · DOI
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- Authors
- Heinen, C. A., Jongejan, A., Watson, P. J., Redeker, B., Boelen, A., Boudzovitch-Surovtseva, O., Forzano, F., Hordijk, R., Kelley, R., Olney, A. H., Pierpont, M. E., Schaefer, G. B., Stewart, F., van Trotsenburg, A. S. P., Fliers, E., Schwabe, J. W. R., & Hennekam, R. C.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- University of Leicester (GB)
- Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
- Ente Ospedaliero Ospedali Galliera (IT)
- University Medical Center Groningen (NL)
- Kennedy Krieger Institute (US)
- Nebraska Medical Center (US)
- University of Minnesota (US)
- Arkansas Children's Hospital (US)
- Belfast City Hospital (GB)
- Department of Paediatric Endocrinology, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
- Corresponding author
- Hennekam, Raoul C
- ORCID
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2016-01-14
- Volume
- 53
- Issue
- 5
- Pages
- 330-337
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- PMC
- PMC4853543
- OpenAlex
- W2288403868
- Cited by
- 73
- References
- 3
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 9 · 2023: 7 · 2022: 4 · 2021: 7 · 2020: 6 · 2019: 6 · 2018: 9 · 2017: 7 · 2016: 5
- FWCI
- 7.27
- Type
- journal article
- Language
- en
- Update notices
- correction (2016-05-24)
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Journal of Medical Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Leicester Research Archive (University of Leicester) (acceptedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- HighWire Press Open Archive (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (100237/Z/12/Z, 100237, 085408, WT100237)
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council (BB/J009598/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
- Keywords
- TBL1XR1, missense mutations, dominant-negative mechanism, nuclear receptor corepressor, developmental delay, hearing loss, autism spectrum disorder, genotype-phenotype correlation
- MeSH terms
- Adult, Child, Developmental Disabilities, DNA Mutational Analysis, Female, Humans, Lipomatosis, Male, Models, Molecular, Nuclear Proteins, Organ Specificity, Repressor Proteins, Gene Expression, Protein Structure, Tertiary, Receptors, Cytoplasmic and Nuclear, Facies, Mutation, Missense, Young Adult, Nuclear Receptor Co-Repressor 1
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