A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome
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Warburg Micro syndrome and Martsolf syndrome are clinically overlapping autosomal recessive conditions characterized by congenital cataracts, microphthalmia, postnatal microcephaly, and developmental delay. The neurodevelopmental and ophthalmological phenotype is more severe in Warburg Micro syndrome in which cerebral malformations and severe motor and mental retardation are common. While biallelic loss-of-function mutations in RAB3GAP1 are present in the majority of patients with Warburg Micro syndrome; a hypomorphic homozygous splicing mutation of RAB3GAP2 has been reported in a single family with Martsolf syndrome. Here, we report a novel homozygous RAB3GAP2 small in-frame deletion, c.499_507delTTCTACACT (p.Phe167_Thr169del) that causes Warburg Micro syndrome in a girl from a consanguineous Turkish family presenting with congenital cataracts, microphthalmia, absent visually evoked potentials, microcephaly, polymicrogyria, hypoplasia of the corpus callosum, and severe developmental delay. No RAB3GAP2 mutations were detected in ten additional unrelated patients with RAB3GAP1-negative Warburg Micro syndrome, consistent with further genetic heterogeneity. In conclusion, we provide evidence that RAB3GAP2 mutations are not specific to Martsolf syndrome. Rather, our findings suggest that loss-of-function mutations of RAB3GAP1 as well as functionally severe RAB3GAP2 mutations cause Warburg Micro syndrome while hypomorphic RAB3GAP2 mutations can result in the milder Martsolf phenotype. Thus, a phenotypic severity gradient may exist in the RAB3GAP-associated disease continuum (the “Warburg–Martsolf syndrome”) which is presumably determined by the mutant gene and the nature of the mutation.
KeywordsCongenital Cataract Autosomal Recessive Disease Microphthalmia Muscular Hypotonia Syndrome Phenotype
G.B. was supported by the Deutsche Forschungsgemeinschaft (DFG; BO2985/3-1).
Conflict of interest
The authors declare that they have no conflict of interest.
- Aligianis IA, Johnson CA, Gissen P, Chen D, Hampshire D, Hoffmann K, Maina EN, Morgan NV, Tee L, Morton J, Ainsworth JR, Horn D, Rosser E, Cole TR, Stolte-Dijkstra I, Fieggen K, Clayton-Smith J, Mégarbané A, Shield JP, Newbury-Ecob R, Dobyns WB, Graham JM Jr, Kjaer KW, Warburg M, Bond J, Trembath RC, Harris LW, Takai Y, Mundlos S, Tannahill D, Woods CG, Maher ER (2005) Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome. Nat Genet 37:221–223CrossRefPubMedGoogle Scholar
- Aligianis IA, Morgan NV, Mione M, Johnson CA, Rosser E, Hennekam RC, Adams G, Trembath RC, Pilz DT, Stoodley N, Moore AT, Wilson S, Maher ER (2006) Mutation in Rab3 GTPase-activating protein (RAB3GAP) noncatalytic subunit in a kindred with Martsolf syndrome. Am J Hum Genet 78:702–707CrossRefPubMedGoogle Scholar
- Morris-Rosendahl DJ, Segel R, Born AP, Conrad C, Loeys B, Brooks SS, Müller L, Zeschnigk C, Botti C, Rabinowitz R, Uyanik G, Crocq MA, Kraus U, Degen I, Faes F (2010) New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish. Eur J Hum Genet. 2010 May 26. doi: 10.1038/ejhg.2010.79 [Epub ahead of print]
- Sakane A, Manabe S, Ishizaki H, Tanaka-Okamoto M, Kiyokage E, Toida K, Yoshida T, Miyoshi J, Kamiya H, Takai Y, Sasaki T (2006) Rab3 GTPase-activating protein regulates synaptic transmission and plasticity through the inactivation of Rab3. Proc Natl Acad Sci USA 103:10029–10034CrossRefPubMedGoogle Scholar