title: Loss-of-function mutations in RAB18 cause Warburg micro syndrome.
abstract: Warburg Micro syndrome and Martsolf syndrome are heterogenous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Previously, identification of mutations in RAB3GAP1 and RAB3GAP2 in both these syndromes implicated dysregulation of the RAB3 cycle (which controls calcium-mediated exocytosis of neurotransmitters and hormones) in disease pathogenesis. RAB3GAP1 and RAB3GAP2 encode the catalytic and noncatalytic subunits of the hetrodimeric enzyme RAB3GAP (RAB3GTPase-activating protein), a key regulator of the RAB3 cycle. We performed autozygosity mapping in five consanguineous families without RAB3GAP1/2 mutations and identified loss-of-function mutations in RAB18. A c.71T > A (p.Leu24Gln) founder mutation was identified in four Pakistani families, and a homozygous exon 2 deletion (predicted to result in a frameshift) was found in the fifth family. A single family whose members were compound heterozygotes for an anti-termination mutation of the stop codon c.619T > C (p.X207QextX20) and an inframe arginine deletion c.277_279 del (p.Arg93 del) were identified after direct gene sequencing and multiplex ligation-dependent probe amplification (MLPA) of a further 58 families. Nucleotide binding assays for RAB18(Leu24Gln) and RAB18(Arg93del) showed that these mutant proteins were functionally null in that they were unable to bind guanine. The clinical features of Warburg Micro syndrome patients with RAB3GAP1 or RAB3GAP2 mutations and RAB18 mutations are indistinguishable, although the role of RAB18 in trafficking is still emerging, and it has not been linked previously to the RAB3 pathway. Knockdown of rab18 in zebrafish suggests that it might have a conserved developmental role. Our findings imply that RAB18 has a critical role in human brain and eye development and neurodegeneration.
authors.affiliation: Medical and Molecular Genetics, School of Clinical and Experimental Medicine and Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Danai
authors.initials: D
authors.lastname: Bem
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Yoshimura
authors.forename: Ricardo
authors.initials: R
authors.lastname: Nunes-Bastos
authors.forename: Frances C
authors.initials: FC
authors.lastname: Bond
authors.forename: Frances F
authors.initials: FF
authors.lastname: Bond
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
authors.forename: Fatima
authors.initials: F
authors.lastname: Rahman
authors.forename: Mark T W
authors.initials: MT
authors.lastname: Handley
authors.forename: Yavor
authors.initials: Y
authors.lastname: Hadzhiev
authors.forename: Imran
authors.initials: I
authors.lastname: Masood
authors.forename: Ania A
authors.initials: AA
authors.lastname: Straatman-Iwanowska
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Cullinane
authors.forename: Alisdair
authors.initials: A
authors.lastname: McNeill
authors.forename: Shanaz S
authors.initials: SS
authors.lastname: Pasha
authors.forename: Gail A
authors.initials: GA
authors.lastname: Kirby
authors.forename: Katharine
authors.initials: K
authors.lastname: Foster
authors.forename: Zubair
authors.initials: Z
authors.lastname: Ahmed
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Morton
authors.forename: Denise
authors.initials: D
authors.lastname: Williams
authors.forename: John M
authors.initials: JM
authors.lastname: Graham
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Lydie
authors.initials: L
authors.lastname: Burglen
authors.forename: John R
authors.initials: JR
authors.lastname: Ainsworth
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.forename: Ferenc
authors.initials: F
authors.lastname: Müller
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: Francis A
authors.initials: FA
authors.lastname: Barr
authors.forename: Irene A
authors.initials: IA
authors.lastname: Aligianis
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D002386:Cataract / Q000151:congenital / Q000235:genetics / Q000378:metabolism; D018388:Codon, Terminator; D003241:Consanguinity; D003315:Cornea / Q000002:abnormalities / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D006239:Haplotypes; D006801:Humans; D007006:Hypogonadism / Q000235:genetics / Q000378:metabolism; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism; D008297:Male; D008831:Microcephaly / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D020125:Mutation, Missense; D009896:Optic Atrophy / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D011485:Protein Binding; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D020691:rab GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020692:rab3 GTP-Binding Proteins / Q000235:genetics
chemical_list: D018388:Codon, Terminator; D050505:Mutant Proteins; C484168:RAB18 protein, human; C555465:RAB3GAP2 protein, human; D020691:rab GTP-Binding Proteins; D020692:rab3 GTP-Binding Proteins