A specific mutation in TBL1XR1 causes Pierpont syndrome

Charlotte A. Heinen, Aldo Jongejan, Peter J. Watson, Bert Redeker, Anita Boelen, Olga Boudzovitch-Surovtseva, Francesca Forzano, Roel Hordijk, Richard Kelley, Ann H. Olney, Mary Ella Pierpont, G. Bradley Schaefer, Fiona Stewart, A. S Paul van Trotsenburg, Eric Fliers, John W R Schwabe, Raoul C. Hennekam

Research output: Contribution to journalArticle

Abstract

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 ß-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.

Original languageEnglish (US)
JournalJournal of Medical Genetics
DOIs
StateAccepted/In press - Jan 14 2016

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Autistic Disorder
Mutation
Messenger RNA
Lymphocytes
Transducin
Exome
Co-Repressor Proteins
Muscles
White Adipose Tissue
Brown Adipose Tissue
Sequence Deletion
HEK293 Cells
Liver
Protein Folding
Retinoids
Gene Deletion
Mutant Proteins
Hearing Loss
Hypothalamus
Adipose Tissue

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Heinen, C. A., Jongejan, A., Watson, P. J., Redeker, B., Boelen, A., Boudzovitch-Surovtseva, O., ... Hennekam, R. C. (Accepted/In press). A specific mutation in TBL1XR1 causes Pierpont syndrome. Journal of Medical Genetics. https://doi.org/10.1136/jmedgenet-2015-103233

A specific mutation in TBL1XR1 causes Pierpont syndrome. / Heinen, Charlotte A.; Jongejan, Aldo; Watson, Peter J.; Redeker, Bert; Boelen, Anita; Boudzovitch-Surovtseva, Olga; Forzano, Francesca; Hordijk, Roel; Kelley, Richard; Olney, Ann H.; Pierpont, Mary Ella; Schaefer, G. Bradley; Stewart, Fiona; van Trotsenburg, A. S Paul; Fliers, Eric; Schwabe, John W R; Hennekam, Raoul C.

In: Journal of Medical Genetics, 14.01.2016.

Research output: Contribution to journalArticle

Heinen, CA, Jongejan, A, Watson, PJ, Redeker, B, Boelen, A, Boudzovitch-Surovtseva, O, Forzano, F, Hordijk, R, Kelley, R, Olney, AH, Pierpont, ME, Schaefer, GB, Stewart, F, van Trotsenburg, ASP, Fliers, E, Schwabe, JWR & Hennekam, RC 2016, 'A specific mutation in TBL1XR1 causes Pierpont syndrome', Journal of Medical Genetics. https://doi.org/10.1136/jmedgenet-2015-103233
Heinen CA, Jongejan A, Watson PJ, Redeker B, Boelen A, Boudzovitch-Surovtseva O et al. A specific mutation in TBL1XR1 causes Pierpont syndrome. Journal of Medical Genetics. 2016 Jan 14. https://doi.org/10.1136/jmedgenet-2015-103233
Heinen, Charlotte A. ; Jongejan, Aldo ; Watson, Peter J. ; Redeker, Bert ; Boelen, Anita ; Boudzovitch-Surovtseva, Olga ; Forzano, Francesca ; Hordijk, Roel ; Kelley, Richard ; Olney, Ann H. ; Pierpont, Mary Ella ; Schaefer, G. Bradley ; Stewart, Fiona ; van Trotsenburg, A. S Paul ; Fliers, Eric ; Schwabe, John W R ; Hennekam, Raoul C. / A specific mutation in TBL1XR1 causes Pierpont syndrome. In: Journal of Medical Genetics. 2016.
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abstract = "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 {\ss}-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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T1 - A specific mutation in TBL1XR1 causes Pierpont syndrome

AU - Heinen, Charlotte A.

AU - Jongejan, Aldo

AU - Watson, Peter J.

AU - Redeker, Bert

AU - Boelen, Anita

AU - Boudzovitch-Surovtseva, Olga

AU - Forzano, Francesca

AU - Hordijk, Roel

AU - Kelley, Richard

AU - Olney, Ann H.

AU - Pierpont, Mary Ella

AU - Schaefer, G. Bradley

AU - Stewart, Fiona

AU - van Trotsenburg, A. S Paul

AU - Fliers, Eric

AU - Schwabe, John W R

AU - Hennekam, Raoul C.

PY - 2016/1/14

Y1 - 2016/1/14

N2 - 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 ß-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.

AB - 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 ß-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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