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
Centre for Physical Activity and Life Sciences
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.
https://doi.org/10.1038/s41598-018-20658-w
E-pub ahead of print - 1 Feb 2018
TRAPPC6A
Neurodevelopmental syndrome
Dysmorphic features
10.1038/s41598-018-20658-wLicence: CC BY
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Missense Mutation Medicine & Life Sciences 100%
Intellectual Disability Medicine & Life Sciences 91%
Polydactyly Medicine & Life Sciences 90%
benzyloxycarbonylleucyl-leucyl-leucine aldehyde Medicine & Life Sciences 43%
Language Development Disorders Medicine & Life Sciences 43%
Exome Medicine & Life Sciences 38%
Proteasome Inhibitors Medicine & Life Sciences 38%
Dr Jamal Nasir
jamal.nasirnorthampton.acuk
University of Northampton, Science - Senior Lecturer in Human Genetics & Genomics
Mohamoud, H. S., Ahmed, S., Jelani, M., Alrayes, N., Childs, K., Vadgama, N., Almramhi, M. M., Al-Aama, J. Y., 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, 8(1), 1-9. [ 2053 (2018) ]. https://doi.org/10.1038/s41598-018-20658-w
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. pp. 1-9.
@article{d14d6cc37e1b4fc4ac7521c60b876513,
title = "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 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.",
keywords = "TRAPPC6A, Protein, Neurodevelopmental syndrome, Dysmorphic features",
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",
doi = "10.1038/s41598-018-20658-w",
publisher = "Nature Research",
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 (2018) , pp. 1-9. 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 (2018) , 01.02.2018, p. 1-9.
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
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.
KW - TRAPPC6A
KW - Protein
KW - Neurodevelopmental syndrome
KW - Dysmorphic features
UR - http://www.mendeley.com/research/missense-mutation-trappc6a-leads-buildup-protein-patients-neurodevelopmental-syndrome-dysmorphic-fea-1
U2 - 10.1038/s41598-018-20658-w
DO - 10.1038/s41598-018-20658-w
M1 - 2053 (2018)
Mohamoud HS, Ahmed S, Jelani M, Alrayes N, Childs K, Vadgama N et al. A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features. Scientific Reports. 2018 Feb 1;8(1):1-9. 2053 (2018) . https://doi.org/10.1038/s41598-018-20658-w