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A specific mutation in TBL1XR1 causes Pierpont syndrome

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 an...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853543/
https://www.ncbi.nlm.nih.gov/pubmed/26769062
http://dx.doi.org/10.1136/jmedgenet-2015-103233
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author 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
author_facet 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
author_sort Heinen, Charlotte A
collection PubMed
description 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.
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spelling pubmed-48535432016-05-06 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 J Med Genet Developmental Defects 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. BMJ Publishing Group 2016-05 2016-01-14 /pmc/articles/PMC4853543/ /pubmed/26769062 http://dx.doi.org/10.1136/jmedgenet-2015-103233 Text en Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/
spellingShingle Developmental Defects
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
title A specific mutation in TBL1XR1 causes Pierpont syndrome
title_full A specific mutation in TBL1XR1 causes Pierpont syndrome
title_fullStr A specific mutation in TBL1XR1 causes Pierpont syndrome
title_full_unstemmed A specific mutation in TBL1XR1 causes Pierpont syndrome
title_short A specific mutation in TBL1XR1 causes Pierpont syndrome
title_sort specific mutation in tbl1xr1 causes pierpont syndrome
topic Developmental Defects
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853543/
https://www.ncbi.nlm.nih.gov/pubmed/26769062
http://dx.doi.org/10.1136/jmedgenet-2015-103233
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