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

• Published in: American journal of human genetics Vol. 88; no. 4; pp. 499 - 507
• Main Authors: Bem, Danai, Yoshimura, Shin-Ichiro, Nunes-Bastos, Ricardo, Bond, Frances F., Kurian, Manju A., Rahman, Fatima, Handley, Mark T.W., Hadzhiev, Yavor, Masood, Imran, Straatman-Iwanowska, Ania A., Cullinane, Andrew R., McNeill, Alisdair, Pasha, Shanaz S., Kirby, Gail A., Foster, Katharine, Ahmed, Zubair, Morton, Jenny E., Williams, Denise, Graham, John M., Dobyns, William B., Burglen, Lydie, Ainsworth, John R., Gissen, Paul, Müller, Ferenc, Maher, Eamonn R., Barr, Francis A., Aligianis, Irene A.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 08.04.2011; Cell Press; Elsevier
• Subjects: Abnormalities, Multiple - genetics; Abnormalities, Multiple - metabolism; Amino Acid Sequence; Amino Acid Substitution; Base Sequence; Biological and medical sciences; Cataract - congenital; Cataract - genetics; Cataract - metabolism; Codon, Terminator; Consanguinity; Cornea - abnormalities; Cornea - metabolism; Danio rerio; DNA Mutational Analysis; Female; Founder Effect; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetics of eukaryotes. Biological and molecular evolution; Haplotypes; Hormones; Humans; Hypogonadism - genetics; Hypogonadism - metabolism; Intellectual Disability - genetics; Intellectual Disability - metabolism; Male; Medical genetics; Medical sciences; Microcephaly - genetics; Microcephaly - metabolism; Models, Molecular; Molecular and cellular biology; Molecular Sequence Data; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutation; Mutation, Missense; Neurodegeneration; Neurological disorders; Neurotransmitters; Optic Atrophy - genetics; Optic Atrophy - metabolism; Pathogenesis; Pedigree; Phenotype; Protein Binding; Proteins; rab GTP-Binding Proteins - chemistry; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism; rab3 GTP-Binding Proteins - genetics; Sequence Deletion; Sequence Homology, Amino Acid; Human; Loss function; Genetics; Mutation
• DOI: 10.1016/j.ajhg.2011.03.012
• ISSN: 0002-9297

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.