title: A specific mutation in TBL1XR1 causes Pierpont syndrome.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands Department of Paediatric Endocrinology, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Heinen
authors.affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Aldo
authors.initials: A
authors.lastname: Jongejan
authors.affiliation: Department of Biochemistry, Henry Wellcome Laboratories of Structural Biology, University of Leicester, Leicester, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Watson
authors.affiliation: Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: Redeker
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Anita
authors.initials: A
authors.lastname: Boelen
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Olga
authors.initials: O
authors.lastname: Boudzovitch-Surovtseva
authors.affiliation: Medical Genetics Unit, Ospedali Galliera, Genova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Forzano
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Hordijk
authors.affiliation: Division of Metabolism, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Kelley
authors.affiliation: Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Centre, Omaha, Nebraska, USA.
authors.forename: Ann H
authors.initials: AH
authors.lastname: Olney
authors.affiliation: Division of Genetics, Children's Hospitals and Clinics of Minnesota, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Mary Ella
authors.initials: ME
authors.lastname: Pierpont
authors.affiliation: Division of Medical Genetics, Arkansas Children's Hospital, Little Rock, Arkansas, USA.
authors.forename: G Bradley
authors.initials: GB
authors.lastname: Schaefer
authors.affiliation: Division of Medical Genetics, Belfast City Hospital, Belfast, Ireland.
authors.forename: Fiona
authors.initials: F
authors.lastname: Stewart
authors.affiliation: Department of Paediatric Endocrinology, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: A S Paul
authors.initials: AS
authors.lastname: van Trotsenburg
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Fliers
authors.affiliation: Department of Biochemistry, Henry Wellcome Laboratories of Structural Biology, University of Leicester, Leicester, UK.
authors.forename: John W R
authors.initials: JW
authors.lastname: Schwabe
authors.affiliation: Department of Paediatrics, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Raoul C
authors.initials: RC
authors.lastname: Hennekam
mesh_terms: D000328:Adult; D002648:Child; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019066:Facies; D005260:Female; D015870:Gene Expression; D006801:Humans; D008068:Lipomatosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism; D009928:Organ Specificity; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C473691:TBL1XR1 protein, human
keywords: Genetics; Molecular genetics; Psychiatry