Cargando…

Missense Mutation R338W in ARHGEF9 in a Family with X-linked Intellectual Disability with Variable Macrocephaly and Macro-Orchidism

Non-syndromal X-linked intellectual disability (NS-XLID) represents a broad group of clinical disorders in which ID is the only clinically consistent manifestation. Although in many cases either chromosomal linkage data or knowledge of the >100 existing XLID genes has assisted mutation discovery,...

Descripción completa

Detalles Bibliográficos
Autores principales: Long, Philip, May, Melanie M., James, Victoria M., Grannò, Simone, Johnson, John P., Tarpey, Patrick, Stevenson, Roger E., Harvey, Kirsten, Schwartz, Charles E., Harvey, Robert J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719118/
https://www.ncbi.nlm.nih.gov/pubmed/26834553
http://dx.doi.org/10.3389/fnmol.2015.00083
_version_ 1782410883793682432
author Long, Philip
May, Melanie M.
James, Victoria M.
Grannò, Simone
Johnson, John P.
Tarpey, Patrick
Stevenson, Roger E.
Harvey, Kirsten
Schwartz, Charles E.
Harvey, Robert J.
author_facet Long, Philip
May, Melanie M.
James, Victoria M.
Grannò, Simone
Johnson, John P.
Tarpey, Patrick
Stevenson, Roger E.
Harvey, Kirsten
Schwartz, Charles E.
Harvey, Robert J.
author_sort Long, Philip
collection PubMed
description Non-syndromal X-linked intellectual disability (NS-XLID) represents a broad group of clinical disorders in which ID is the only clinically consistent manifestation. Although in many cases either chromosomal linkage data or knowledge of the >100 existing XLID genes has assisted mutation discovery, the underlying cause of disease remains unresolved in many families. We report the resolution of a large family (K8010) with NS-XLID, with variable macrocephaly and macro-orchidism. Although a previous linkage study had mapped the locus to Xq12-q21, this region contained too many candidate genes to be analyzed using conventional approaches. However, X-chromosome exome sequencing, bioinformatics analysis and segregation analysis revealed a novel missense mutation (c.1012C>T; p.R338W) in ARHGEF9. This gene encodes collybistin (CB), a neuronal GDP-GTP exchange factor previously implicated in several cases of XLID, as well as clustering of gephyrin and GABA(A) receptors at inhibitory synapses. Molecular modeling of the CB R338W substitution revealed that this change results in the substitution of a long electropositive side-chain with a large non-charged hydrophobic side-chain. The R338W change is predicted to result in clashes with adjacent amino acids (K363 and N335) and disruption of electrostatic potential and local folding of the PH domain, which is known to bind phosphatidylinositol-3-phosphate (PI(3)P/PtdIns-3-P). Consistent with this finding, functional assays revealed that recombinant CB CB2(SH3−)(R338W) was deficient in PI(3)P binding and was not able to translocate EGFP-gephyrin to submembrane microaggregates in an in vitro clustering assay. Taken together, these results suggest that the R338W mutation in ARHGEF9 is the underlying cause of NS-XLID in this family.
format Online
Article
Text
id pubmed-4719118
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-47191182016-01-29 Missense Mutation R338W in ARHGEF9 in a Family with X-linked Intellectual Disability with Variable Macrocephaly and Macro-Orchidism Long, Philip May, Melanie M. James, Victoria M. Grannò, Simone Johnson, John P. Tarpey, Patrick Stevenson, Roger E. Harvey, Kirsten Schwartz, Charles E. Harvey, Robert J. Front Mol Neurosci Neuroscience Non-syndromal X-linked intellectual disability (NS-XLID) represents a broad group of clinical disorders in which ID is the only clinically consistent manifestation. Although in many cases either chromosomal linkage data or knowledge of the >100 existing XLID genes has assisted mutation discovery, the underlying cause of disease remains unresolved in many families. We report the resolution of a large family (K8010) with NS-XLID, with variable macrocephaly and macro-orchidism. Although a previous linkage study had mapped the locus to Xq12-q21, this region contained too many candidate genes to be analyzed using conventional approaches. However, X-chromosome exome sequencing, bioinformatics analysis and segregation analysis revealed a novel missense mutation (c.1012C>T; p.R338W) in ARHGEF9. This gene encodes collybistin (CB), a neuronal GDP-GTP exchange factor previously implicated in several cases of XLID, as well as clustering of gephyrin and GABA(A) receptors at inhibitory synapses. Molecular modeling of the CB R338W substitution revealed that this change results in the substitution of a long electropositive side-chain with a large non-charged hydrophobic side-chain. The R338W change is predicted to result in clashes with adjacent amino acids (K363 and N335) and disruption of electrostatic potential and local folding of the PH domain, which is known to bind phosphatidylinositol-3-phosphate (PI(3)P/PtdIns-3-P). Consistent with this finding, functional assays revealed that recombinant CB CB2(SH3−)(R338W) was deficient in PI(3)P binding and was not able to translocate EGFP-gephyrin to submembrane microaggregates in an in vitro clustering assay. Taken together, these results suggest that the R338W mutation in ARHGEF9 is the underlying cause of NS-XLID in this family. Frontiers Media S.A. 2016-01-20 /pmc/articles/PMC4719118/ /pubmed/26834553 http://dx.doi.org/10.3389/fnmol.2015.00083 Text en Copyright © 2016 Long, May, James, Grannò, Johnson, Tarpey, Stevenson, Harvey, Schwartz and Harvey. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Long, Philip
May, Melanie M.
James, Victoria M.
Grannò, Simone
Johnson, John P.
Tarpey, Patrick
Stevenson, Roger E.
Harvey, Kirsten
Schwartz, Charles E.
Harvey, Robert J.
Missense Mutation R338W in ARHGEF9 in a Family with X-linked Intellectual Disability with Variable Macrocephaly and Macro-Orchidism
title Missense Mutation R338W in ARHGEF9 in a Family with X-linked Intellectual Disability with Variable Macrocephaly and Macro-Orchidism
title_full Missense Mutation R338W in ARHGEF9 in a Family with X-linked Intellectual Disability with Variable Macrocephaly and Macro-Orchidism
title_fullStr Missense Mutation R338W in ARHGEF9 in a Family with X-linked Intellectual Disability with Variable Macrocephaly and Macro-Orchidism
title_full_unstemmed Missense Mutation R338W in ARHGEF9 in a Family with X-linked Intellectual Disability with Variable Macrocephaly and Macro-Orchidism
title_short Missense Mutation R338W in ARHGEF9 in a Family with X-linked Intellectual Disability with Variable Macrocephaly and Macro-Orchidism
title_sort missense mutation r338w in arhgef9 in a family with x-linked intellectual disability with variable macrocephaly and macro-orchidism
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719118/
https://www.ncbi.nlm.nih.gov/pubmed/26834553
http://dx.doi.org/10.3389/fnmol.2015.00083
work_keys_str_mv AT longphilip missensemutationr338winarhgef9inafamilywithxlinkedintellectualdisabilitywithvariablemacrocephalyandmacroorchidism
AT maymelaniem missensemutationr338winarhgef9inafamilywithxlinkedintellectualdisabilitywithvariablemacrocephalyandmacroorchidism
AT jamesvictoriam missensemutationr338winarhgef9inafamilywithxlinkedintellectualdisabilitywithvariablemacrocephalyandmacroorchidism
AT grannosimone missensemutationr338winarhgef9inafamilywithxlinkedintellectualdisabilitywithvariablemacrocephalyandmacroorchidism
AT johnsonjohnp missensemutationr338winarhgef9inafamilywithxlinkedintellectualdisabilitywithvariablemacrocephalyandmacroorchidism
AT tarpeypatrick missensemutationr338winarhgef9inafamilywithxlinkedintellectualdisabilitywithvariablemacrocephalyandmacroorchidism
AT stevensonrogere missensemutationr338winarhgef9inafamilywithxlinkedintellectualdisabilitywithvariablemacrocephalyandmacroorchidism
AT harveykirsten missensemutationr338winarhgef9inafamilywithxlinkedintellectualdisabilitywithvariablemacrocephalyandmacroorchidism
AT schwartzcharlese missensemutationr338winarhgef9inafamilywithxlinkedintellectualdisabilitywithvariablemacrocephalyandmacroorchidism
AT harveyrobertj missensemutationr338winarhgef9inafamilywithxlinkedintellectualdisabilitywithvariablemacrocephalyandmacroorchidism