Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency
Open Access
- 21 July 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in European Journal of Human Genetics
- Vol. 18 (12), 1315-1321
- https://doi.org/10.1038/ejhg.2010.105
Abstract
Aortic dilatation/dissection (AD) can occur spontaneously or in association with genetic syndromes, such as Marfan syndrome (MFS; caused by FBN1 mutations), MFS type 2 and Loeys–Dietz syndrome (associated with TGFBR1/TGFBR2 mutations), and Ehlers–Danlos syndrome (EDS) vascular type (caused by COL3A1 mutations). Although mutations in FBN1 and TGFBR1/TGFBR2 account for the majority of AD cases referred to us for molecular genetic testing, we have obtained negative results for these genes in a large cohort of AD patients, suggesting the involvement of additional genes or acquired factors. In this study we assessed the effect of COL3A1 deletions/duplications in this cohort. Multiplex ligation-dependent probe amplification (MLPA) analysis of 100 unrelated patients identified one hemizygous deletion of the entire COL3A1 gene. Subsequent microarray analyses and sequencing of breakpoints revealed the deletion size of 3 408 306 bp at 2q32.1q32.3. This deletion affects not only COL3A1 but also 21 other known genes (GULP1, DIRC1, COL5A2, WDR75, SLC40A1, ASNSD1, ANKAR, OSGEPL1, ORMDL1, LOC100129592, PMS1, MSTN, C2orf88, HIBCH, INPP1, MFSD6, TMEM194B, NAB1, GLS, STAT1, and STAT4), mutations in three of which (COL5A2, SLC40A1, and MSTN) have also been associated with an autosomal dominant disorder (EDS classical type, hemochromatosis type 4, and muscle hypertrophy). Physical and laboratory examinations revealed that true haploinsufficiency of COL3A1, COL5A2, and MSTN, but not that of SLC40A1, leads to a clinical phenotype. Our data not only emphasize the impact/role of COL3A1 in AD patients but also extend the molecular etiology of several disorders by providing hitherto unreported evidence for true haploinsufficiency of the underlying gene.Keywords
This publication has 44 references indexed in Scilit:
- Homozygosity for a null allele of COL3A1 results in recessive Ehlers–Danlos syndromeEuropean Journal of Human Genetics, 2009
- Molecular mechanisms of classical Ehlers-Danlos syndrome (EDS)Human Mutation, 2009
- Mechanisms for human genomic rearrangementsPathoGenetics, 2008
- Ehlers-Danlos syndrome type IVOrphanet Journal of Rare Diseases, 2007
- Large genomic fibrillin-1 (FBN1) gene deletions provide evidence for true haploinsufficiency in Marfan syndromeHuman Genetics, 2007
- Aneurysm Syndromes Caused by Mutations in the TGF-β ReceptorNew England Journal of Medicine, 2006
- Development of a Functional Skin Matrix Requires Deposition of Collagen V HeterotrimersMolecular and Cellular Biology, 2004
- Myostatin Mutation Associated with Gross Muscle Hypertrophy in a ChildNew England Journal of Medicine, 2004
- A translocation interrupts the COL5A1 gene in a patient with Ehlers–Danlos syndrome and hypomelanosis of ItoNature Genetics, 1996
- Targeted mutation in the col5a2 gene reveals a regulatory role for type V collagen during matrix assemblyNature Genetics, 1995