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

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    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

    Cite this

    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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    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.",
    author = "Mohamoud, {Hussein Sheikh} and Saleem Ahmed and Musharraf Jelani and Nuha Alrayes and Kay Childs and Nirmal Vadgama and Almramhi, {Mona Mohammad} and Al-Aama, {Jumana Yousuf} and Steve Goodbourn and Jamal Nasir",
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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 journalArticleResearchpeer-review

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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

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    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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