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RAB3GAP1, RAB3GAP2 and RAB18: disease genes in
Micro and Martsolf syndromes
Mark T Handley2, Sarah M Carpanini2,
Shin-ichiro Yoshimura3, Stephen Brown1, Danai Bem4,
Deborah Morris-Rosendahl5, Francis A Barr6 and
Irene Aligianis2
1
University of Edinburgh, Edinburgh, United Kingdom
2
MRC Human Genetics Unit, Edinburgh, United Kingdom
3
University of Liverpool, Liverpool, United Kingdom
4
University of Birmingham, Birmingham, United Kingdom
5
Institut für Humangenetik, Freiburg, Germany
6
University of Oxford, Oxford, United Kingdom
Micro and Martsolf syndromes (MIM 60018 and MIM 21270 respectively)
are heterogeneous autosomal recessive disorders. Affected children present
with abnormalities of the eye (congenital cataracts, micropthalmia, optic
atrophy and cortical blindness), brain (microcephaly, developmental delay
and polymicrogyria), genitals (hypothalamic hypogonadism) and peripheral
nervous system (progressive spastic paraplegia). Disease-causing mutations
in RAB3GAP1, RAB3GAP2 and most recently RAB18 have been reported in
cases of Micro syndrome, while mutations in RAB3GAP2 have been reported
in cases of Martsolf syndrome. We investigated a cohort of 116 families by
sequencing these genes and identified pathogenic mutations in ~50% of
cases. Among these, we report the first missense mutations in RAB3GAP1
and RAB3GAP2, and the first Martsolf syndrome-causing mutations in
RAB3GAP1. These data contribute to an emerging paradigm in which Micro
and Martsolf syndromes represent a phenotypic continuum related to the
nature and severity of the mutations present in the disease gene: loss-offunction mutations result in Micro syndrome while mutations causing partial
loss-of-function or incomplete loss of functional protein cause the milder
Martsolf syndrome.
RAB3GAP1 and RAB3GAP2 encode the catalytic and noncatalytic subunits
of RAB3GAP, a novel Rab GTPase-activating protein with specificity towards
RAB3 isoforms. RAB3 is involved in modulating the regulated exocytosis of
hormones and neurotransmitters while RAB18 is thought to regulate lipolysis
and lipogenesis. We are undertaking biochemical studies to determine the
functional relationship between these proteins.