Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family
Disease gene discovery in neurodevelopmental disorders, including X-linked intellectual disability (XLID) has recently been accelerated by next-generation DNA sequencing approaches. To date, more than 100 human X chromosome genes involved in neuronal signaling pathways and networks implicated in cog...
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Frontiers Media S.A.
2016-01-01
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| Schriftenreihe: | Frontiers in Molecular Neuroscience |
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| Online Zugang: | https://www.frontiersin.org/article/10.3389/fnmol.2015.00085/full |
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| author | Vera M. Kalscheuer Vera M. Kalscheuer Victoria M. James Miranda L. Himelright Philip Long Renske Oegema Corinna Jensen Melanie Bienek Hao Hu Stefan A. Haas Maya Topf A. Jeannette M. Hoogeboom Kirsten Harvey Randall Walikonis Robert J. Harvey |
| author_facet | Vera M. Kalscheuer Vera M. Kalscheuer Victoria M. James Miranda L. Himelright Philip Long Renske Oegema Corinna Jensen Melanie Bienek Hao Hu Stefan A. Haas Maya Topf A. Jeannette M. Hoogeboom Kirsten Harvey Randall Walikonis Robert J. Harvey |
| author_sort | Vera M. Kalscheuer |
| collection | DOAJ |
| description | Disease gene discovery in neurodevelopmental disorders, including X-linked intellectual disability (XLID) has recently been accelerated by next-generation DNA sequencing approaches. To date, more than 100 human X chromosome genes involved in neuronal signaling pathways and networks implicated in cognitive function have been identified. Despite these advances, the mutations underlying disease in a large number of XLID families remained unresolved. We report the resolution of MRX78, a large family with six affected males and seven affected females, showing X-linked inheritance. Although a previous linkage study had mapped the locus to the short arm of chromosome X (Xp11.4-p11.23), this region contained too many candidate genes to be analyzed using conventional approaches. However, our X-chromosome exome resequencing, bioinformatics analysis and inheritance testing revealed a missense mutation (c.C2366T, p.A789V) in IQSEC2, encoding a neuronal GDP-GTP exchange factor for Arf family GTPases (ArfGEF) previously implicated in XLID. Molecular modeling of IQSEC2 revealed that the A789V substitution results in the insertion of a larger side-chain into a hydrophobic pocket in the catalytic Sec7 domain of IQSEC2. The A789V change is predicted to result in numerous clashes with adjacent amino acids and disruption of local folding of the Sec7 domain. Consistent with this finding, functional assays revealed that recombinant IQSEC2A789V was not able to catalyze GDP-GTP exchange on Arf6 as efficiently as wild-type IQSEC2. Taken together, these results strongly suggest that the A789V mutation in IQSEC2 is the underlying cause of XLID in the MRX78 family. |
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| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-22T07:05:07Z |
| publishDate | 2016-01-01 |
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| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-a2e475b4a1c74c8fbd64a1e3a70b30b02022-12-21T18:34:41ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992016-01-01810.3389/fnmol.2015.00085172894Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 FamilyVera M. Kalscheuer0Vera M. Kalscheuer1Victoria M. James2Miranda L. Himelright3Philip Long4Renske Oegema5Corinna Jensen6Melanie Bienek7Hao Hu8Stefan A. Haas9Maya Topf10A. Jeannette M. Hoogeboom11Kirsten Harvey12Randall Walikonis13Robert J. Harvey14Department of Human Molecular Genetics, Max Planck Institute for Molecular GeneticsBerlin, GermanyResearch Group Development and Disease, Max Planck Institute for Molecular GeneticsBerlin, GermanyDepartment of Pharmacology, UCL School of PharmacyLondon, UKDepartment of Physiology and Neurobiology, University of ConnecticutStorrs, CT, USADepartment of Pharmacology, UCL School of PharmacyLondon, UKDepartment of Clinical Genetics, Erasmus MC University Medical Center RotterdamRotterdam, NetherlandsDepartment of Human Molecular Genetics, Max Planck Institute for Molecular GeneticsBerlin, GermanyDepartment of Human Molecular Genetics, Max Planck Institute for Molecular GeneticsBerlin, GermanyDepartment of Human Molecular Genetics, Max Planck Institute for Molecular GeneticsBerlin, GermanyDepartment of Computational Molecular Biology, Max Planck Institute for Molecular GeneticsBerlin, GermanyDepartment of Biological Sciences, Institute for Structural and Molecular Biology, Birkbeck CollegeLondon, UKDepartment of Clinical Genetics, Erasmus MC University Medical Center RotterdamRotterdam, NetherlandsDepartment of Pharmacology, UCL School of PharmacyLondon, UKDepartment of Physiology and Neurobiology, University of ConnecticutStorrs, CT, USADepartment of Pharmacology, UCL School of PharmacyLondon, UKDisease gene discovery in neurodevelopmental disorders, including X-linked intellectual disability (XLID) has recently been accelerated by next-generation DNA sequencing approaches. To date, more than 100 human X chromosome genes involved in neuronal signaling pathways and networks implicated in cognitive function have been identified. Despite these advances, the mutations underlying disease in a large number of XLID families remained unresolved. We report the resolution of MRX78, a large family with six affected males and seven affected females, showing X-linked inheritance. Although a previous linkage study had mapped the locus to the short arm of chromosome X (Xp11.4-p11.23), this region contained too many candidate genes to be analyzed using conventional approaches. However, our X-chromosome exome resequencing, bioinformatics analysis and inheritance testing revealed a missense mutation (c.C2366T, p.A789V) in IQSEC2, encoding a neuronal GDP-GTP exchange factor for Arf family GTPases (ArfGEF) previously implicated in XLID. Molecular modeling of IQSEC2 revealed that the A789V substitution results in the insertion of a larger side-chain into a hydrophobic pocket in the catalytic Sec7 domain of IQSEC2. The A789V change is predicted to result in numerous clashes with adjacent amino acids and disruption of local folding of the Sec7 domain. Consistent with this finding, functional assays revealed that recombinant IQSEC2A789V was not able to catalyze GDP-GTP exchange on Arf6 as efficiently as wild-type IQSEC2. Taken together, these results strongly suggest that the A789V mutation in IQSEC2 is the underlying cause of XLID in the MRX78 family.https://www.frontiersin.org/article/10.3389/fnmol.2015.00085/fullArfGEFBRAG1IQ-ArfGEFIQSEC2MRX78XLID |
| spellingShingle | Vera M. Kalscheuer Vera M. Kalscheuer Victoria M. James Miranda L. Himelright Philip Long Renske Oegema Corinna Jensen Melanie Bienek Hao Hu Stefan A. Haas Maya Topf A. Jeannette M. Hoogeboom Kirsten Harvey Randall Walikonis Robert J. Harvey Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family Frontiers in Molecular Neuroscience ArfGEF BRAG1 IQ-ArfGEF IQSEC2 MRX78 XLID |
| title | Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family |
| title_full | Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family |
| title_fullStr | Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family |
| title_full_unstemmed | Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family |
| title_short | Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family |
| title_sort | novel missense mutation a789v in iqsec2 underlies x linked intellectual disability in the mrx78 family |
| topic | ArfGEF BRAG1 IQ-ArfGEF IQSEC2 MRX78 XLID |
| url | https://www.frontiersin.org/article/10.3389/fnmol.2015.00085/full |
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