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Disruption of RAB40AL Function Leads To Developmental defects J Med Genet: first published as 10.1136/jmedgenet-2011-100575 on 11 May 2012. Downloaded from ORIGINAL ARTICLE Disruption of RAB40AL function leads to MartineProbst syndrome, a rare X-linked multisystem neurodevelopmental human disorder Jirair Krikor Bedoyan,1 Valerie M Schaibley,2 Weiping Peng,2 Yongsheng Bai,3 Kajari Mondal,4 Amol C Shetty,4 Mark Durham,1 Joseph A Micucci,5 Arti Dhiraaj,1 Jennifer M Skidmore,1 Julie B Kaplan,1 Cindy Skinner,6 Charles E Schwartz,6 Anthony Antonellis,2 Michael E Zwick,4 James D Cavalcoli,3 Jun Z Li,2,3 Donna M Martin1,2 < Additional materials are ABSTRACT diphosphate (GDP)-bound conformations (Ras- published online only. To view Background and aim MartineProbst syndrome (MPS) GTP and Ras-GDP).3 Ras proteins generate distinct these files please visit the is a rare X-linked disorder characterised by deafness, signal outputs in cells, despite interacting with journal online (http://jmg.bmj. com/content/49/5.toc). cognitive impairment, short stature and distinct a common set of competing activators (GTPase craniofacial dysmorphisms, among other features. The activating proteins) and exchange factors (guanine 1Department of Pediatrics, The University of Michigan Medical authors sought to identify the causative mutation for nucleotide exchange factors) which regulate Ras- 45 School, Ann Arbor, Michigan, MPS. GTP levels. Ras proteins contain a hypervariable USA Methods and results Massively parallel sequencing in (HVR) domain within the C-terminal 25e50 2 Department of Human two affected, related male subjects with MPS identified amino acids. The HVR contains sites for post- Genetics, The University of a RAB40AL (also called RLGP) missense mutation translational lipid and other modifications and is Michigan Medical School, Ann / fi Arbor, Michigan, USA (chrX:102,079,078-102,079,079AC GA p.D59G; the only region that differs signi cantly in sequence 3Center for Computational hg18). RAB40AL encodes a small Ras-like GTPase among the otherwise highly homologous Ras genes. Medicine and Bioinformatics, protein with one suppressor of cytokine signalling box. HVR domains confer distinct biochemical proper- The University of Michigan, Ann The p.D59G variant is located in a highly conserved ties of the Ras proteins and are involved in subcel- Arbor, Michigan, USA b b 4Department of Human region of the GTPase domain between -2 and -3 lular localisation and signal transduction. Cell- and Genetics, Emory University strands. Using RT-PCR, the authors show that RAB40AL tissue-specific expression may also contribute to the School of Medicine, Atlanta, is expressed in human fetal and adult brain and kidney, unique biological and developmental effects of Ras Georgia, USA and adult lung, heart, liver and skeletal muscle. RAB40AL proteins.6 5Department of Biological appears to be a primate innovation, with no orthologues Rab GTPases belong to the Ras superfamily of http://jmg.bmj.com/ Chemistry, The University of 7 Michigan Medical School, Ann found in mouse, Xenopus or zebrafish. Western analysis small GTPases. More than 50 Rab proteins have Arbor, Michigan, USA and fluorescence microscopy of GFP-tagged RAB40AL been described in mammalian cells, each with 6Greenwood Genetic Center, constructs from transiently transfected COS7 cells show a specific subcellular localisation and many with Greenwood, South Carolina, that the D59G missense change renders RAB40AL specific patterns of tissue distribution.89Rab USA unstable and disrupts its cytoplasmic localisation. proteins are involved in regulating intracellular Correspondence to Conclusions This is the first study to show that vesicle transport and trafficking of proteins Dr Donna M Martin, mutation of RAB40AL is associated with a human between organelles, behaving as membrane-associ- on September 24, 2021 by guest. Protected copyright. Departments of Pediatrics and disorder. Identification of RAB40AL as the gene mutated ated molecular switches.89The suppressor of Human Genetics, University of in MPS allows for further investigations into the cytokine signalling (SOCS) box distinguishes the Michigan, Ann Arbor, MI 48109, USA; [email protected] molecular mechanism(s) of RAB40AL and its roles in four Rab40 proteins (Rab40a, Rab40al, Rab40b and diverse processes such as cognition, hearing and skeletal Rab40c) from other Rab GTPases. SOCS box- Received 18 October 2011 development. containing proteins interact with an E3 ubiquitin Revised 22 March 2012 ligase complex (with elongins B and C) that poly- Accepted 23 March 2012 ubiquitinates target proteins for subsequent degra- dation.10 The target specificity of the complex is determined by a proteineprotein interaction INTRODUCTION domain located N-terminal of the SOCS box- Mutations in genes encoding Ras proteins are containing protein.10 RAB40AL is a 278-amino acid responsible for a number of human genetic disor- Ras-like GTPase protein with a single SOCS box ders, including Costello (HRAS), Noonan immediately proximal to the C-terminal HVR (KRAS and NRAS), cardiofaciocutaneous (KRAS) domain. and autoimmune lymphoproliferative (NRAS) RAB40AL (RLGP) was previously implicated in syndromes.1 2 Ras proteins are components of the a male person with an inversion (46,X,inv(X) Ras/mitogen-activated protein kinase pathway and (p21.2q22.2)) disrupting the RAB40AL promoter This paper is freely available are important for proper cellular growth, differen- region.11 This individual was diagnosed with online under the BMJ Journals unlocked scheme, see http:// tiation and proliferation. Ras proteins canonically congenital muscular dystrophy accompanied by jmg.bmj.com/site/about/ cycle (or switch) between active guanosine severe intellectual disability, congenital nystagmus unlocked.xhtml triphosphate (GTP)-bound and inactive guanosine and athetosis. He never developed meaningful 332 J Med Genet 2012;49:332e340. doi:10.1136/jmedgenet-2011-100575 Developmental defects J Med Genet: first published as 10.1136/jmedgenet-2011-100575 on 11 May 2012. Downloaded from speech nor sat without support, and died at 18 years of age from genes between DXS1003 and DXS1220 (chrX:46,419,359- suffocation due to tracheal obstruction. He was also diagnosed 114,514,483; hg18; Xp11.3-Xq23).12 13 Deletions >1kb were with congenital Duchenne-type muscular dystrophy and excluded by PCR.12 13 Candidate genes COL4A5, DIAPH2, harboured a deletion of DMD exons 43e60, but his severe POU3F4, ATRX, TIMM8A, XNP, ALEX2, KCNE1L and UBE1, intellectual disability was ascribed to the disruption of RAB40AL located within the 68 megabase target region, were previously function.11 The authors hypothesised that RAB40AL may play excluded by direct sequencing or dHPLC.12 13 Female carriers in a critical role in the development or function of the central the pedigree have been found to exhibit non-random (or skewed) nervous system (CNS) by transducing signals or transporting X-inactivation.13 Here we provide evidence that a germline molecules across mitochondrial membranes.11 missense mutation in RAB40AL leads to MPS. MartineProbst syndrome (MPS; MIM 300519) is a rare multi- organ system neurodevelopmental disorder initially charac- terised in three related male subjects with sensorineural hearing MATERIALS AND METHODS loss, cognitive impairment, short stature and craniofacial DNA samples from individuals were obtained with informed dysmorphisms.12 MPS shares some characteristics with Costello consent as approved by the Institutional Review Board for syndrome (CS) and Noonan syndrome (NS) such as short Human Subject Research at the University of Michigan Medical stature, cognitive impairment and craniofacial dysmorphisms. Center. However, unlike CS and NS, individuals with MPS also exhibit sensorineural hearing loss, renal insufficiency and impaired Variant discovery and analysis via massively parallel sequencing haematopoiesis.12 13 Additional clinical features seen in one We performed whole genome sequencing (WGS), whole exome individual with MPS (patient 1 in Martin et al,12 same as indi- sequencing (WES) and X chromosome-specific exome14 15 vidual II-1 in figure 1A) include chronic dyspnoea, pulmonary sequencing to identify the causative mutation in MPS (see hypertension, septal cirrhosis and abnormal branching patterns Supplemental Methods for detailed methods). It should be of large hepatic vessels (unpublished data). The causative acknowledged that the word ‘whole’, used here in the context of mutation for MPS was previously localised to a 68 megabase massively parallel sequencing, does not imply absolute and common haplotype region on X chromosome containing 683 complete coverage of all human genomic or exonic sequences. Figure 1 RAB40AL p.D59G variant analysis and segregation. (A) The p.D59G variant identified in the sequenced individuals (III-5 and IV-1) segregates with the phenotype in the family. For individuals with a red dot, p.D59G was identified by Sanger sequencing. Affected individuals are shown in blue. For individuals with a green dot, p.D59G status was not http://jmg.bmj.com/ determined. (B) Sequence chromatograms showing the two consecutive nucleotide changes (AC/GA) in a male subject (hemizygous) affected with MPS and an unaffected obligate female carrier (heterozygous). This change results in on September 24, 2021 by guest. Protected copyright. an Asp to Gly change at codon 59. Sanger sequencing readouts are shown. (C) The p.D59G variant (red) lies within a highly conserved 37 amino acid region of the GTPase domain and is conserved from humans to mosquitoes.
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    Journal of Human Genetics (2014) 59, 300–306 & 2014 The Japan Society of Human Genetics All rights reserved 1434-5161/14 www.nature.com/jhg ORIGINAL ARTICLE An emerging phenotype of Xq22 microdeletions in females with severe intellectual disability, hypotonia and behavioral abnormalities Toshiyuki Yamamoto1, Anna Wilsdon2, Shelagh Joss3, Bertrand Isidor4,5, Anna Erlandsson6, Mohnish Suri2, Noriko Sangu1, Shino Shimada1, Keiko Shimojima1,Ce´dric Le Caignec4,5, Lena Samuelsson6 and Margarita Stefanova6,7,8 The majority of Xq22 duplications seen in patients with Pelizaeus–Merzbacher disease (PMD) include proteolipid protein 1 (PLP1), the gene responsible for PMD, and neighboring genes. Some cases result from larger duplications up to 7 Mb in size. In comparison, the deletions including PLP1 seen in PMD patients are small. In this study, we present the genetic and clinical information for five female patients with deletions involving the Xq22 region, and review the correlation between the genotype and phenotype. Three of the five patients show similar large deletions (43 Mb) ranging from Xq22.1 to Xq22.3 and all manifest severe intellectual disability, hypotonia and behavioral abnormalities. The most striking similarity among them are the behavioral problems, including poor eye contact and sleep disturbance. We propose that this represents an emerging distinctive microdeletion syndrome encompassing PLP1 in female patients. The possible candidate region responsible for such distinctive features has been narrowed down to the neighboring region for PLP1, including the interleukin 1 receptor accessory protein-like 2 (IL1RAPL2) gene and the clustered brain expressed X-linked (BEX) genes. The gene(s) responsible for severe neurological features in the patients in this study would be located in the regions proximate to PLP1; thus, males with the deletions involving the gene(s) would be lethal, and finally, the sizes of the deletions in PMD patients would be smaller than those of the duplications.
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