A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features

Abstract Childhood onset clinical syndromes involving intellectual disability and dysmorphic features, such as polydactyly, suggest common developmental pathways link seemingly unrelated phenotypes. We identified a consanguineous family of Saudi origin with varying complex features including intelle...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Hussein Sheikh Mohamoud, Saleem Ahmed, Musharraf Jelani, Nuha Alrayes, Kay Childs, Nirmal Vadgama, Mona Mohammad Almramhi, Jumana Yousuf Al-Aama, Steve Goodbourn, Jamal Nasir
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/18faae44fa1d4821af5795128001f81b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:18faae44fa1d4821af5795128001f81b
record_format	dspace
spelling	oai:doaj.org-article:18faae44fa1d4821af5795128001f81b2021-12-02T15:08:43ZA missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features10.1038/s41598-018-20658-w2045-2322https://doaj.org/article/18faae44fa1d4821af5795128001f81b2018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-20658-whttps://doaj.org/toc/2045-2322Abstract Childhood onset clinical syndromes involving intellectual disability and dysmorphic features, such as polydactyly, suggest common developmental pathways link seemingly unrelated phenotypes. We identified a consanguineous family of Saudi origin with varying complex features including intellectual disability, speech delay, facial dysmorphism and polydactyly. Combining, microarray based comparative genomic hybridisation (CGH) to identify regions of homozygosity, with exome sequencing, led to the identification of homozygous mutations in five candidate genes (RSPH6A, ANKK1, AMOTL1, ALKBH8, TRAPPC6A), all of which appear to be pathogenic as predicted by Proven, SIFT and PolyPhen2 and segregate perfectly with the disease phenotype. We therefore looked for differences in expression levels of each protein in HEK293 cells, expressing either the wild-type or mutant full-length cDNA construct. Unexpectedly, wild-type TRAPPC6A appeared to be unstable, but addition of the proteasome inhibitor MG132 stabilised its expression. Mutations have previously been reported in several members of the TRAPP complex of proteins, including TRAPPC2, TRAPPC9 and TRAPPC11, resulting in disorders involving skeletal abnormalities, intellectual disability, speech impairment and developmental delay. TRAPPC6A joins a growing list of proteins belonging to the TRAPP complex, implicated in clinical syndromes with neurodevelopmental abnormalities.Hussein Sheikh MohamoudSaleem AhmedMusharraf JelaniNuha AlrayesKay ChildsNirmal VadgamaMona Mohammad AlmramhiJumana Yousuf Al-AamaSteve GoodbournJamal NasirNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-9 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hussein Sheikh Mohamoud Saleem Ahmed Musharraf Jelani Nuha Alrayes Kay Childs Nirmal Vadgama Mona Mohammad Almramhi Jumana Yousuf Al-Aama Steve Goodbourn Jamal Nasir A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features
description	Abstract Childhood onset clinical syndromes involving intellectual disability and dysmorphic features, such as polydactyly, suggest common developmental pathways link seemingly unrelated phenotypes. We identified a consanguineous family of Saudi origin with varying complex features including intellectual disability, speech delay, facial dysmorphism and polydactyly. Combining, microarray based comparative genomic hybridisation (CGH) to identify regions of homozygosity, with exome sequencing, led to the identification of homozygous mutations in five candidate genes (RSPH6A, ANKK1, AMOTL1, ALKBH8, TRAPPC6A), all of which appear to be pathogenic as predicted by Proven, SIFT and PolyPhen2 and segregate perfectly with the disease phenotype. We therefore looked for differences in expression levels of each protein in HEK293 cells, expressing either the wild-type or mutant full-length cDNA construct. Unexpectedly, wild-type TRAPPC6A appeared to be unstable, but addition of the proteasome inhibitor MG132 stabilised its expression. Mutations have previously been reported in several members of the TRAPP complex of proteins, including TRAPPC2, TRAPPC9 and TRAPPC11, resulting in disorders involving skeletal abnormalities, intellectual disability, speech impairment and developmental delay. TRAPPC6A joins a growing list of proteins belonging to the TRAPP complex, implicated in clinical syndromes with neurodevelopmental abnormalities.
format	article
author	Hussein Sheikh Mohamoud Saleem Ahmed Musharraf Jelani Nuha Alrayes Kay Childs Nirmal Vadgama Mona Mohammad Almramhi Jumana Yousuf Al-Aama Steve Goodbourn Jamal Nasir
author_facet	Hussein Sheikh Mohamoud Saleem Ahmed Musharraf Jelani Nuha Alrayes Kay Childs Nirmal Vadgama Mona Mohammad Almramhi Jumana Yousuf Al-Aama Steve Goodbourn Jamal Nasir
author_sort	Hussein Sheikh Mohamoud
title	A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features
title_short	A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features
title_full	A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features
title_fullStr	A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features
title_full_unstemmed	A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features
title_sort	missense mutation in trappc6a leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/18faae44fa1d4821af5795128001f81b
work_keys_str_mv	AT husseinsheikhmohamoud amissensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT saleemahmed amissensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT musharrafjelani amissensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT nuhaalrayes amissensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT kaychilds amissensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT nirmalvadgama amissensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT monamohammadalmramhi amissensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT jumanayousufalaama amissensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT stevegoodbourn amissensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT jamalnasir amissensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT husseinsheikhmohamoud missensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT saleemahmed missensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT musharrafjelani missensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT nuhaalrayes missensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT kaychilds missensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT nirmalvadgama missensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT monamohammadalmramhi missensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT jumanayousufalaama missensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT stevegoodbourn missensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures AT jamalnasir missensemutationintrappc6aleadstobuildupoftheproteininpatientswithaneurodevelopmentalsyndromeanddysmorphicfeatures
_version_	1718387985494310912

A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features

Ejemplares similares