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Author Notes:

Correspondence to Dr Donna M Martin, Departments of Pediatrics and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA; donnamm@umich.edu

We thank Drs Susan L Dagenais and Robert H Lyons from the UM DNA Sequencing Core for help with sequencing, members of the Martin laboratory for their technical help, Dr Christopher Vlangos for providing the COS7 cells, Jillian Lee Wiggins for help with the statistical analyses, and Dr Rick Neubig for critically reading this manuscript. pmCIT–C1 and pmCIT–N1 vectors were generously provided by Dr Lois Weisman at the University of Michigan.

Competing interests: None.

Subjects:

Research Funding:

VMS was supported by the Genome Sciences Training Grant.

This work was supported by NIH T32 DC00011 (JAM), NIH K12 HD028820 (JKB), an award from the Elizabeth E Kennedy (Children's Research) Fund through the Department of Pediatrics (JKB), an award from the University of Michigan Center for Genetics in Health and Medicine (DMM and JZL), an award from the Michigan Institute for Clinical and Health Research (DMM), and NIH R01 grants NS054784 and DC009410 (DMM).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • GENETICS & HEREDITY
  • MENTAL-RETARDATION
  • MISSENSE MUTATIONS
  • ACTIVATE RAF-1
  • PROTEIN
  • GTPASE
  • GENOME
  • EVOLUTION
  • GENES
  • TRANSPORT
  • EPILEPSY

Disruption of RAB40AL function leads to Martin-Probst syndrome, a rare X-linked multisystem neurodevelopmental human disorder

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Journal Title:

Journal of Medical Genetics

Volume:

Volume 49, Number 5

Publisher:

, Pages 332-340

Type of Work:

Article | Final Publisher PDF

Abstract:

Background and aim MartineProbst syndrome (MPS) is a rare X-linked disorder characterised by deafness, cognitive impairment, short stature and distinct craniofacial dysmorphisms, among other features. The authors sought to identify the causative mutation for MPS. Methods and results Massively parallel sequencing in two affected, related male subjects with MPS identified a RAB40AL (also called RLGP) missense mutation (chrX:102,079,078-102,079,079AC/GA p.D59G; hg18). RAB40AL encodes a small Ras-like GTPase protein with one suppressor of cytokine signalling box. The p.D59G variant is located in a highly conserved region of the GTPase domain between b-2 and b-3 strands. Using RT-PCR, the authors show that RAB40AL is expressed in human fetal and adult brain and kidney, and adult lung, heart, liver and skeletal muscle. RAB40AL appears to be a primate innovation, with no orthologues found in mouse, Xenopus or zebrafish. Western analysis and fluorescence microscopy of GFP-tagged RAB40AL constructs from transiently transfected COS7 cells show that the D59G missense change renders RAB40AL unstable and disrupts its cytoplasmic localisation. Conclusions This is the first study to show that mutation of RAB40AL is associated with a human disorder. Identification of RAB40AL as the gene mutated in MPS allows for further investigations into the molecular mechanism(s) of RAB40AL and its roles in diverse processes such as cognition, hearing and skeletal development.

Copyright information:

© 2012, Published by the BMJ Publishing Group Limited.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 2.0 Generic License (http://creativecommons.org/licenses/by-nc/2.0/).

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