A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome.
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A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome. / Borck, Guntram; Wunram, Heidrun; Steiert, Angela; Volk, Alexander; Körber, Friederike; Roters, Sigrid; Herkenrath, Peter; Wollnik, Bernd; Morris-Rosendahl, Deborah J; Kubisch, Christian.
In: HUM GENET, Vol. 129, No. 1, 1, 2011, p. 45-50.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome.
AU - Borck, Guntram
AU - Wunram, Heidrun
AU - Steiert, Angela
AU - Volk, Alexander
AU - Körber, Friederike
AU - Roters, Sigrid
AU - Herkenrath, Peter
AU - Wollnik, Bernd
AU - Morris-Rosendahl, Deborah J
AU - Kubisch, Christian
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Humans
KW - Female
KW - Infant
KW - Genetic Predisposition to Disease
KW - Molecular Sequence Data
KW - Base Sequence
KW - Consanguinity
KW - Sequence Deletion
KW - Intellectual Disability/genetics
KW - Microcephaly/genetics
KW - Exons/genetics
KW - Homozygote
KW - Abnormalities, Multiple/genetics
KW - Agenesis of Corpus Callosum
KW - Cataract/congenital/genetics
KW - Cornea/abnormalities
KW - Hypogonadism/genetics
KW - Optic Atrophy/genetics
KW - RNA Splicing/genetics
KW - rab3 GTP-Binding Proteins/genetics
KW - Humans
KW - Female
KW - Infant
KW - Genetic Predisposition to Disease
KW - Molecular Sequence Data
KW - Base Sequence
KW - Consanguinity
KW - Sequence Deletion
KW - Intellectual Disability/genetics
KW - Microcephaly/genetics
KW - Exons/genetics
KW - Homozygote
KW - Abnormalities, Multiple/genetics
KW - Agenesis of Corpus Callosum
KW - Cataract/congenital/genetics
KW - Cornea/abnormalities
KW - Hypogonadism/genetics
KW - Optic Atrophy/genetics
KW - RNA Splicing/genetics
KW - rab3 GTP-Binding Proteins/genetics
M3 - SCORING: Journal article
VL - 129
SP - 45
EP - 50
JO - HUM GENET
JF - HUM GENET
SN - 0340-6717
IS - 1
M1 - 1
ER -
