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Original article
A specific mutation in TBL1XR1 causes Pierpont syndrome
  1. Charlotte A Heinen1,2,
  2. Aldo Jongejan3,
  3. Peter J Watson4,
  4. Bert Redeker5,
  5. Anita Boelen1,
  6. Olga Boudzovitch-Surovtseva1,
  7. Francesca Forzano6,
  8. Roel Hordijk7,
  9. Richard Kelley8,
  10. Ann H Olney9,
  11. Mary Ella Pierpont10,
  12. G Bradley Schaefer11,
  13. Fiona Stewart12,
  14. A S Paul van Trotsenburg2,
  15. Eric Fliers1,
  16. John W R Schwabe4,
  17. Raoul C Hennekam13
  1. 1Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
  2. 2Department of Paediatric Endocrinology, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
  3. 3Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
  4. 4Department of Biochemistry, Henry Wellcome Laboratories of Structural Biology, University of Leicester, Leicester, UK
  5. 5Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
  6. 6Medical Genetics Unit, Ospedali Galliera, Genova, Italy
  7. 7Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
  8. 8Division of Metabolism, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, Maryland, USA
  9. 9Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Centre, Omaha, Nebraska, USA
  10. 10Division of Genetics, Children's Hospitals and Clinics of Minnesota, University of Minnesota, Minneapolis, Minnesota, USA
  11. 11Division of Medical Genetics, Arkansas Children's Hospital, Little Rock, Arkansas, USA
  12. 12Division of Medical Genetics, Belfast City Hospital, Belfast, Ireland
  13. 13Department of Paediatrics, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
  1. Correspondence to Dr Raoul C Hennekam, Department of Paediatrics, H7-236, Academic Medical Centre, P.O. Box 22660, Amsterdam 1100 DD, The Netherlands; r.c.hennekam{at}


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>C (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.

  • Genetics
  • Molecular genetics
  • Psychiatry

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