Tissue-specific mosaicism for a lethal osteogenesis imperfecta COL1A1 mutation causes mild OI/EDS overlap syndrome.

Am J Med Genet A 2017 Apr 6;173(4):1047-1050. Epub 2017 Mar 6.

Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.

Type I collagen is the predominant protein of connective tissues such as skin and bone. Mutations in the type I collagen genes (COL1A1 and COL1A2) mainly cause osteogenesis imperfecta (OI). We describe a patient with clinical signs of Ehlers-Danlos syndrome (EDS), including fragile skin, easy bruising, recurrent luxations, and fractures resembling mild OI. Biochemical collagen analysis of the patients' dermal fibroblasts showed faint overmodification of the type I collagen bands, a finding specific for structural defects in type I collagen. Bidirectional Sanger sequencing detected an in-frame deletion in exon 44 of COL1A1 (c.3150_3158del), resulting in the deletion of three amino acids (p.Ala1053_Gly1055del) in the collagen triple helix. This COL1A1 mutation was hitherto identified in four probands with lethal OI, and never in EDS patients. As the peaks on the electropherogram corresponding to the mutant allele were decreased in intensity, we performed next generation sequencing of COL1A1 to study mosaicism in skin and blood. While approximately 9% of the reads originating from fibroblast gDNA harbored the COL1A1 deletion, the deletion was not detected in gDNA from blood. Most likely, the mild clinical symptoms observed in our patient can be explained by the mosaic state of the mutation.

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.38135DOI Listing
April 2017
13 Reads

Publication Analysis

Top Keywords

type collagen
16
col1a1 mutation
8
osteogenesis imperfecta
8
col1a1
6
collagen
6
finding specific
4
specific structural
4
bands finding
4
blood reads
4
collagen bands
4
skin blood
4
structural defects
4
bidirectional sanger
4
sanger sequencing
4
sequencing detected
4
collagen bidirectional
4
study mosaicism
4
overmodification type
4
defects type
4
mosaicism skin
4

References

(Supplied by CrossRef)
The human type I collagen mutation database
Dalgleish et al.
Nucleic Acids Research 1997
The human collagen mutation database 1998
Dalgleish et al.
Nucleic Acids Research 1998
New perspectives on osteogenesis imperfecta
Forlino et al.
Nature Reviews Endocrinology 2011
A 9-base pair deletion in COL1A1 in a lethal variant of osteogenesis imperfecta
Hawkins et al.
Journal of Biological Chemistry 1991

Similar Publications