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

Hussein Sheikh Mohamoud, Saleem Ahmed, Musharraf Jelani, Nuha Alrayes, Kay Childs, Nirmal Vadgama, Mona Mohammad Almramhi, Jumana Yousuf Al-Aama, Steve Goodbourn, Jamal Nasir

Research output: Contribution to JournalArticle

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.
Original languageEnglish
Article number2053
JournalScientific Reports
Volume8
Issue number1
Early online date1 Feb 2018
DOIs
Publication statusPublished - 1 Dec 2018

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Missense Mutation
Intellectual Disability
Polydactyly
Exome
Language Development Disorders
Phenotype
Mutation
Proteins
Proteasome Inhibitors
Comparative Genomic Hybridization
HEK293 Cells
Complementary DNA
Genes

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Mohamoud, Hussein Sheikh ; Ahmed, Saleem ; Jelani, Musharraf ; Alrayes, Nuha ; Childs, Kay ; Vadgama, Nirmal ; Almramhi, Mona Mohammad ; Al-Aama, Jumana Yousuf ; Goodbourn, Steve ; Nasir, Jamal. / A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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Mohamoud, HS, Ahmed, S, Jelani, M, Alrayes, N, Childs, K, Vadgama, N, Almramhi, MM, Al-Aama, JY, Goodbourn, S & Nasir, J 2018, 'A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features', Scientific Reports, vol. 8, no. 1, 2053. https://doi.org/10.1038/s41598-018-20658-w

A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features. / Mohamoud, Hussein Sheikh; Ahmed, Saleem; Jelani, Musharraf; Alrayes, Nuha; Childs, Kay; Vadgama, Nirmal; Almramhi, Mona Mohammad; Al-Aama, Jumana Yousuf; Goodbourn, Steve; Nasir, Jamal.

In: Scientific Reports, Vol. 8, No. 1, 2053, 01.12.2018.

Research output: Contribution to JournalArticle

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T1 - A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features

AU - Mohamoud, Hussein Sheikh

AU - Ahmed, Saleem

AU - Jelani, Musharraf

AU - Alrayes, Nuha

AU - Childs, Kay

AU - Vadgama, Nirmal

AU - Almramhi, Mona Mohammad

AU - Al-Aama, Jumana Yousuf

AU - Goodbourn, Steve

AU - Nasir, Jamal

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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