Mutation in Rab3 GTPase-activating protein (RAB3GAP) noncatalytic subunit in a kindred with martsolf syndrome

Irene A. Aligianis, Neil V. Morgan, Marina Mione, Colin A. Johnson, Elisabeth Rosser, Raoul C. Hennekam, Gill Adams, Richard C. Trembath, Daniela T. Pilz, Neil Stoodley, Anthony T. Moore, Steve Wilson, Eamonn R. Maher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

75 Citations (Scopus)


We identified a homozygous missense mutation in the noncatalytic subunit (RAB3GAP2) of RAB3GAP that results in abnormal splicing in a family with congenital cataracts, hypogonadism, and mild mental retardation (Martsolf syndrome). Recently, mutations in the catalytic subunit of RAB3GAP (RAB3GAP1), a key regulator of calcium-mediated hormone and neurotransmitter exocytosis, were reported in Warburg micro syndrome, a severe neurodevelopmental condition with overlapping clinical features. RAB3GAP is a heterodimeric protein that consists of a catalytic subunit and a noncatalytic subunit encoded by RAB3GAP1 and RAB3GAP2, respectively. We performed messenger RNA-expression studies of RAB3GAP1 and RAB3GAP2 orthologues in Danio rerio embryos and demonstrated that, whereas developmental expression of rab3gap1 was generalized (similar to that reported elsewhere in mice), rab3gap2 expression was restricted to the central nervous system. These findings are consistent with RAB3GAP2 having a key role in neurodevelopment and may indicate that Warburg micro and Martsolf syndromes represent a spectrum of disorders. However, we did not detect RAB3GAP2 mutations in patients with Warburg micro syndrome. These findings suggest that RAB3GAP dysregulation may result in a spectrum of phenotypes that range from Warburg micro syndrome to Martsolf syndrome.

Original languageEnglish
Pages (from-to)702-707
Number of pages6
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - Apr 2006
Externally publishedYes

Bibliographical note

Funding Information:
We thank the U.K. Birth Defects Foundation, the Medical Research Council, and the Wellcome Trust for funding. We are most grateful to the families who helped with this research. All participants gave informed consent, and the research was approved by the South Birmingham Research Ethics Committee.


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