Mutations in GRIP1 cause Fraser syndrome
- Maartje J Vogel1,
- Patrick van Zon1,
- Louise Brueton2,
- Marleen Gijzen1,
- Marc C van Tuil1,
- Phillip Cox3,
- Denny Schanze4,
- Ariana Kariminejad5,
- Siavash Ghaderi-Sohi5,
- Edward Blair6,
- Martin Zenker4,
- Peter J Scambler7,
- Hans Kristian Ploos van Amstel1,
- Mieke M van Haelst1,8
- 1Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
- 2Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham, UK
- 3Department of Pathology, Birmingham Women's Hospital, Birmingham, UK
- 4Institute of Human Genetics, University Hospital, Magdeburg, Germany
- 5Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran
- 6Department of Clinical Genetics, Oxford Radcliffe Hospitals NHS Trust, Oxford, UK
- 7Molecular Medicine Unit, Institute of Child Health, London, UK
- 8Section of Genomic Medicine, Imperial College London, London, UK
- Correspondence to Dr Maartje J Vogel, Department of Medical Genetics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands;
Contributors LB, PC, AK, SG-S, EB, MZ, PJS and MMvH provided all clinical findings and patient samples; MJV designed the study; PZ, MG, MCvT and DS performed experiments; MJV interpreted the molecular data; MJV and MMvH wrote the manuscript; MZ, PJS and HKPvA critically revised the manuscript for important intellectual content; and all authors approved the final version.
- Received 25 October 2011
- Accepted 17 February 2012
- Published Online First 17 April 2012
Background Fraser syndrome (FS) is a autosomal recessive malformation syndrome characterised by cryptophthalmos, syndactyly and urogenital defects. FS is a genetically heterogeneous condition. Thus far, mutations in FRAS1 and FREM2 have been identified as cause of FS. Both FRAS1 and FREM2 encode extracellular matrix proteins that are essential for the adhesion between epidermal basement membrane and the underlying dermal connective tissues during embryonic development. Mutations in murine Grip1, which encodes a scaffolding protein that interacts with Fras1/Frem proteins, result in FS-like defects in mice.
Objective To test GRIP1 for genetic variants in FS families that do not have mutations in FRAS1 and FREM2.
Methods and results In three unrelated families with parental consanguinity, GRIP1 mutations were found to segregate with the disease in an autosomal recessive manner (donor splice site mutation NM_021150.3:c.2113+1G→C in two families and a 4-bp deletion, NM_021150.3:c.1181_1184del in the third). RT-PCR analysis of the GRIP1 mRNA showed that the c.2113+1G→C splice mutation causes skipping of exon 17, leading to a frame shift and a premature stop of translation.
Conclusion Mutations in GRIP1 cause classic FS in humans.
- Fraser syndrome
- Fras/Frem pathway
- Bleb mutant
- eye blebs
- cancer: breast
- clinical genetics
- congenital heart disease
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.