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

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Missense Mutation R338W in ARHGEF9 in a Family with X-Linked Intellectual Disability with Variable Macrocephaly and Macro-Orchidism View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by UCL Discovery ORIGINAL RESEARCH published: 20 January 2016 doi: 10.3389/fnmol.2015.00083 Missense Mutation R338W in ARHGEF9 in a Family with X-linked Intellectual Disability with Variable Macrocephaly and Macro-Orchidism Philip Long 1, Melanie M. May 2, Victoria M. James 1†, Simone Grannò 1, John P. Johnson 3, Patrick Tarpey 4, Roger E. Stevenson 2, Kirsten Harvey 1, Charles E. Schwartz 2* and Robert J. Harvey 1* 1 Department of Pharmacology, UCL School of Pharmacy, London, UK, 2 JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC, USA, 3 Department of Medical Genetics, Shodair Children’s Hospital, Helena, MT, USA, 4 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK Edited by: Jean-Marc Taymans, Non-syndromal X-linked intellectual disability (NS-XLID) represents a broad group of UMR1172, Jean-Pierre Aubert clinical disorders in which ID is the only clinically consistent manifestation. Although Research Center, France in many cases either chromosomal linkage data or knowledge of the >100 existing Reviewed by: Angel L. De Blas, XLID genes has assisted mutation discovery, the underlying cause of disease remains University of Connecticut, USA unresolved in many families. We report the resolution of a large family (K8010) with NS- Silvia Bassani, CNR Institute of Neuroscience, Italy XLID, with variable macrocephaly and macro-orchidism. Although a previous linkage *Correspondence: study had mapped the locus to Xq12-q21, this region contained too many candidate Charles E. Schwartz genes to be analyzed using conventional approaches. However, X-chromosome exome [email protected]; Robert J. Harvey sequencing, bioinformatics analysis and segregation analysis revealed a novel missense [email protected] mutation (c.1012C>T; p.R338W) in ARHGEF9. This gene encodes collybistin (CB), a †Present address: neuronal GDP-GTP exchange factor previously implicated in several cases of XLID, as Victoria M. James, well as clustering of gephyrin and GABA receptors at inhibitory synapses. Molecular Wellcome Trust, London, UK A modeling of the CB R338W substitution revealed that this change results in the Received: 16 October 2015 substitution of a long electropositive side-chain with a large non-charged hydrophobic Accepted: 14 December 2015 side-chain. The R338W change is predicted to result in clashes with adjacent amino Published: 20 January 2016 acids (K363 and N335) and disruption of electrostatic potential and local folding of the Citation: Long P, May MM, James VM, PH domain, which is known to bind phosphatidylinositol-3-phosphate (PI3P/PtdIns- Grannò S, Johnson JP, Tarpey P, 3-P). Consistent with this finding, functional assays revealed that recombinant CB Stevenson RE, Harvey K, Schwartz R338W CB2SH3 was deficient in PI3P binding and was not able to translocate EGFP- CE and Harvey RJ (2016) Missense − Mutation R338W in ARHGEF9 in a gephyrin to submembrane microaggregates in an in vitro clustering assay. Taken Family with X-linked Intellectual together, these results suggest that the R338W mutation in ARHGEF9 is the underlying Disability with Variable Macrocephaly and Macro-Orchidism. cause of NS-XLID in this family. Front. Mol. Neurosci. 8:83. doi: 10.3389/fnmol.2015.00083 Keywords: ARHGEF9, collybistin, gephyrin, PH domain, XLID Frontiers in Molecular Neuroscience | www.frontiersin.org 1 January 2016 | Volume 8 | Article 83 Long et al. ARHGEF9 Mutation in XLID INTRODUCTION also exhibited macro-orchidism and macrocephaly. Linkage analysis suggested that the causative gene was located on Intellectual disability (ID) is characterized by significantly Xp11-q21 (Johnson et al., 1998). We present compelling impaired intellectual and adaptive function, and is often evidence that the likely cause of XLID in this family is defined by an IQ score below 70 in addition to deficits in a missense mutation in ARHGEF9, encoding a neuronal two or more adaptive behaviors (e.g., social skills, problem RhoGEF known as collybistin (CB) involved in both inhibitory solving) that affect everyday life. ID is also subdivided into synaptic organization and mammalian target of rapamycin syndromal ID, where ID is associated with other clinical, complex 1 (mTORC1) signaling pathways (Machado et al., morphological, or behavioral symptoms or non-syndromal 2015). ID, where intellectual deficits appear without other associated defects (Stevenson et al., 2012). X-linked intellectual disability MATERIALS AND METHODS (XLID) refers to forms of ID typically associated with X- linked recessive inheritance. Mutations in monogenic XLID Subjects have been reported in >100 genes, many of which are now Family K8010 was previously reported by Johnson et al.( 1998). used in routine diagnostic screening panels (Basehore et al., Briefly, the males resembled those with fragile X syndrome in 2015). Despite screening for mutations in selected known that they had macrocephaly (abnormally large head, typically XLID genes by conventional linkage/candidate gene analysis 2.5 standard deviations above normal for weight and gender), or array CGH for examining copy number variants (CNVs), macro-orchidism (abnormally large testes), blue eyes, prominent large number of families mapping to the X-chromosome jaw and long facies. Additionally, one carrier female was remained unresolved (Lubs et al., 2012). These cases either described as being ‘‘slow’’. However, using linkage analysis, the represent undiscovered disease-relevant mutations in known locus was mapped to Xq12-q21 rather than Xq27.3. Additionally, genes, or causal mutations in novel XLID loci that remain to be FMR1 gene analysis was negative (Johnson et al., 1998). identified. Mutation and gene discovery in XLID has recently been transformed by large-scale DNA sequencing approaches coupled Exon Capture and DNA Sequencing with stringent variant filtering (Tarpey et al., 2009; Rauch Next generation sequencing was conducted as a partial follow- et al., 2012; Gilissen et al., 2014; Redin et al., 2014; Hu up of 15 probands from a large scale sequencing of 718 et al., 2015; Niranjan et al., 2015; Tzschach et al., 2015). X-chromosome genes in 208 XLID probands (Tarpey et al., For example, a recent study in a large cohort of unresolved 2009). The deep sequencing was conducted using the Agilent families with XLID revealed that 20% of families carried SureSelect Human X chromosome kit (Takano et al., 2012). > pathogenic variants in established XLID genes (Hu et al., A novel and unique mutation in ARHGEF9, c.1012C T, was 2015), as well as revealing seven novel XLID genes (CLCN4, noted in K8010. Segregation analysis was conducted using Sanger CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM, and USP27X) sequencing. and two candidates (CDK16 and TAF1). Another strategy, known as Affected Kindred/Cross-Cohort Analysis (Niranjan Polymorphism Analysis et al., 2015) has also identified variants in known and novel Screening of 566 normal individuals (420 males, 146 females) XLID genes including PLXNA3, GRIPAP1, EphrinB1 and for the ARHGEF9 c.1012C>T variant was carried out using OGT. However, analysis of next-generation data sets has also allele-specific amplification. Primers used were: ARHGEF9- 0 0 highlighted a number of XLID genes where truncating variants ASOF 5 -TACGGCCGCAACCAGCtGt 3 and ARHGEF9- 0 0 or previously published ‘‘mutations’’ are observed at a relatively ASOR 5 -CCCATCAGTATTTGCCCACT-3 . The ASOF primer high frequency in normal controls, calling into question whether recognized the mutation, which is indicated by the ‘‘t’’ at the 0 0 certain single nucleotide variants (SNVs) are indeed causal 3 end of the primer. The third base from the 3 end was also (Tarpey et al., 2009; Piton et al., 2013). This highlights the changed from an ‘‘a’’ to a ‘‘t’’ to increase the specificity of need for integrating structure-function based approaches into the PCR. The ASOR primer was designed so that the Tm of the analysis pipeline for validating potentially disease-causing both primers were similar and to generate a PCR product of variants. above 500 bp. Gradient duplex PCR analysis was conducted In this study, we have combined next-generation sequencing, using mutation and normal samples to choose the optimum variant filtering and structure-function assays to resolve the annealing temperature. High-throughput duplex PCR analysis cause of XLID in a large family (K8010) with NS-XLID, with with a mutation and normal sample as positive and negative variable macrocephaly and macro-orchidism (Johnson et al., controls. 1998). The previous clinical study in this family revealed ten affected males and two affected females in two generations, as Molecular Modeling of the Collybistin well as four obligatory carriers. Most affected males exhibited R338W Mutation macrocephaly and macro-orchidism, which are typical signs The non-synonymous R338W substitution was modeled into of the fragile X syndrome. However, cytogenetic testing and the structure of rat CB (PDB 2DFK; Xiang et al., 2006) analysis of FMR1 indicated they did not have this syndrome. using the swapaa command in Chimera (Pettersen et al., It was also notable that some normal males in the family 2004) using the Dunbrack backbone-dependent rotamer library Frontiers in Molecular Neuroscience| www.frontiersin.org 2 January 2016 | Volume 8 | Article 83 Long et al. ARHGEF9 Mutation in XLID (Dunbrack, 2002). This took into account the lowest clash RESULTS score, highest number of H-bonds and highest
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