PUBLICATION

Loss-of-Function Mutations in RAB18 Cause Warburg Micro Syndrome

Authors

Bem, D., Yoshimura, S., Nunes-Bastos, R., Bond, F.F., Kurian, M.A., Rahman, F., Handley, M.T., Hadzhiev, Y., Masood, I., Straatman-Iwanowska, A.A., Cullinane, A.R., McNeill, A., Pasha, S.S., Kirby, G.A., Foster, K., Ahmed, Z., Morton, J.E., Williams, D., Graham, J.M., Dobyns, W.B., Burglen, L., Ainsworth, J.R., Gissen, P., Muller, F., Maher, E.R., Barr, F.A., and Aligianis, I.A.

ID

ZDB-PUB-110512-8

Date

2011

Source

American journal of human genetics 88(4): 499-507 (Journal)

Registered Authors

Hadzhiev, Yavor, Müller, Ferenc

Keywords

none

MeSH Terms

Abnormalities, Multiple/genetics
Abnormalities, Multiple/metabolism
Amino Acid Sequence
Amino Acid Substitution
Base Sequence
Cataract/congenital
Cataract/genetics
Cataract/metabolism
Codon, Terminator
Consanguinity
Cornea/abnormalities
Cornea/metabolism
DNA Mutational Analysis
Female
Founder Effect
Haplotypes
Humans
Hypogonadism/genetics
Hypogonadism/metabolism
Intellectual Disability/genetics
Intellectual Disability/metabolism
Male
Microcephaly/genetics
Microcephaly/metabolism
Models, Molecular
Molecular Sequence Data
Mutant Proteins/genetics
Mutant Proteins/metabolism
Mutation*
Mutation, Missense
Optic Atrophy/genetics
Optic Atrophy/metabolism
Pedigree
Phenotype
Protein Binding
Sequence Deletion
Sequence Homology, Amino Acid
rab GTP-Binding Proteins/chemistry
rab GTP-Binding Proteins/genetics*
rab GTP-Binding Proteins/metabolism
rab3 GTP-Binding Proteins/genetics

PubMed

21473985 Full text @ Am. J. Hum. Genet.

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.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Mutations / Transgenics

Human Disease / Model

Sequence Targeting Reagents

Fish

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Bem et al., 2011 ZDB-PUB-110512-8 PMID:21473985

Loss-of-Function Mutations in RAB18 Cause Warburg Micro Syndrome

Bem et al., 2011

ZDB-PUB-110512-8
PMID:21473985