Deborah J. Morris-Rosendahl's present address is National Heart and Lung Institute, Imperial College, London, UK.
Mutation Spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and Genotype–Phenotype Correlations in Warburg Micro Syndrome and Martsolf Syndrome
Article first published online: 11 APR 2013
© 2013 Wiley Periodicals, Inc.
Volume 34, Issue 5, pages 686–696, May 2013
How to Cite
Handley, M. T., Morris-Rosendahl, D. J., Brown, S., Macdonald, F., Hardy, C., Bem, D., Carpanini, S. M., Borck, G., Martorell, L., Izzi, C., Faravelli, F., Accorsi, P., Pinelli, L., Basel-Vanagaite, L., Peretz, G., Abdel-Salam, G. M.H., Zaki, M. S., Jansen, A., Mowat, D., Glass, I., Stewart, H., Mancini, G., Lederer, D., Roscioli, T., Giuliano, F., Plomp, A. S., Rolfs, A., Graham, J. M., Seemanova, E., Poo, P., García-Cazorla, À., Edery, P., Jackson, I. J., Maher, E. R. and Aligianis, I. A. (2013), Mutation Spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and Genotype–Phenotype Correlations in Warburg Micro Syndrome and Martsolf Syndrome. Hum. Mutat., 34: 686–696. doi: 10.1002/humu.22296
Present address: National Heart and Lung Institute, Imperial College, London, UK
Communicated by Graham R. Taylor
Additional Supporting Information may be found in the online version of this article.
Contract grant sponsors: Newlife: Molecular Investigations of Micro and Martsolf Syndromes (07-08/12); MRC Human Genetics Unit Program leader Track Fellowship (RA1631 and RA1905).
- Issue published online: 11 APR 2013
- Article first published online: 11 APR 2013
- Accepted manuscript online: 19 FEB 2013 07:20AM EST
- Manuscript Accepted: 7 FEB 2013
- Manuscript Received: 6 DEC 2012
- Newlife: Molecular Investigations of Micro and Martsolf Syndromes. Grant Number: 07-08/12
- MRC Human Genetics Unit Program leader Track Fellowship. Grant Numbers: RA1631, RA1905
Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB3GAP1, RAB3GAP2, or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published families and 52 new families. One-hundred and forty-four Micro and nine Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, mutations in RAB3GAP2 in 7% of cases, and mutations in RAB18 in 5% of cases. These are listed in Leiden Open source Variation Databases, which was created by us for all three genes. Genotype–phenotype correlations for these genes have now established that the clinical phenotypes in Micro syndrome and MS represent a phenotypic continuum related to the nature and severity of the mutations present in the disease genes, with more deleterious mutations causing Micro syndrome and milder mutations causing MS. RAB18 has not yet been linked to the RAB3 pathways, but mutations in all three genes cause an indistinguishable phenotype, making it likely that there is some overlap. There is considerable genetic heterogeneity for these disorders and further gene identification will help delineate these pathways.