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

Journal of Medical Genetics
Jirair Krikor BedoyanDonna M Martin

Abstract

Martin--Probst 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. 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 β-2 and β-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. This is the first study to show that mutation of RAB40AL is associated with a human disorder. Identification of RAB40AL as the gene mutat...Continue Reading

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Citations

Jul 23, 2013·American Journal of Human Genetics·Amélie PitonJean-Louis Mandel
Dec 15, 2017·Small GTPases·Marcellus J Banworth, Guangpu Li
Apr 27, 2018·American Journal of Medical Genetics. Part a·Giovanni NeriRoger E Stevenson

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Methods Mentioned

BETA
nucleotide exchange
GTPases
GTPase
PCR
exome
Exome Sequencing
electrophoresis
transfection
Protein Assay
transfections

Software Mentioned

CLUSTAL W
PhyloP
MitoPred
UCSC Genome Browser
BWA
AlignGVGD
PolyPhen
SAMTools
SeattleSeq
SPSS Statistics

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