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Human Genetics

, Volume 129, Issue 1, pp 45–50 | Cite as

A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome

  • Guntram BorckEmail author
  • Heidrun Wunram
  • Angela Steiert
  • Alexander E. Volk
  • Friederike Körber
  • Sigrid Roters
  • Peter Herkenrath
  • Bernd Wollnik
  • Deborah J. Morris-Rosendahl
  • Christian Kubisch
Original Investigation

Abstract

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.

Keywords

Congenital Cataract Autosomal Recessive Disease Microphthalmia Muscular Hypotonia Syndrome Phenotype 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

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.

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Guntram Borck
    • 1
    • 2
    • 3
    Email author
  • Heidrun Wunram
    • 4
  • Angela Steiert
    • 5
  • Alexander E. Volk
    • 1
    • 2
    • 3
  • Friederike Körber
    • 6
  • Sigrid Roters
    • 7
  • Peter Herkenrath
    • 4
  • Bernd Wollnik
    • 1
    • 2
  • Deborah J. Morris-Rosendahl
    • 5
  • Christian Kubisch
    • 1
    • 2
    • 3
    • 8
  1. 1.Institute of Human GeneticsUniversity of CologneCologneGermany
  2. 2.Center for Molecular Medicine Cologne (CMMC)University of CologneCologneGermany
  3. 3.Institute for GeneticsUniversity of CologneCologneGermany
  4. 4.Department of PediatricsUniversity of CologneCologneGermany
  5. 5.Institute for Human GeneticsUniversity Clinic FreiburgFreiburgGermany
  6. 6.Department of Pediatric RadiologyUniversity of CologneCologneGermany
  7. 7.Department of OphthalmologyUniversity of CologneCologneGermany
  8. 8.Institute of Human GeneticsUniversity of UlmUlmGermany

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