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What is the new Cardiac Valvular Form of EDS? |
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Splice site mutations in the COL1A2 gene of type I
collagen can give rise to forms of Ehlers-Danlos syndrome (EDS) because
of partial or complete skipping of exon 6, as well as to mild, moderate, or lethal forms of osteogenesis imperfecta
as a consequence of skipping of other exons. We identified three
unrelated individuals with a rare recessively inherited form of EDS
(characterized by joint hypermobility, skin hyperextensibility, and
cardiac valvular defects); in two of them, COL1A2 messenger RNA (mRNA)
instability results from compound heterozygosity for splice site
mutations in the COL1A2 gene, and, in the third, it results from
homozygosity for a nonsense codon. The splice site mutations led to use
of cryptic splice donor sites, creation of a downstream premature
termination codon, and extremely unstable mRNA. In the wild-type
allele, the two introns (IVS11 and IVS24) in which these mutations
occurred were usually spliced slowly in relation to their respective
immediate upstream introns. In the mutant alleles, the upstream intron
was removed, so that exon skipping could not occur. In the context of
the mutation in IVS24, computer-generated folding of a short stretch of
mRNA surrounding the mutation site demonstrated realignment of the
relationships between the donor and acceptor sites that could
facilitate use of a cryptic donor site. These findings suggest that the
order of intron removal is an important variable in prediction of
mutation outcome at splice sites and that folding of the nascent mRNA
could be one element that contributes to determination of order of
splicing. The complete absence of pro alpha 2(I)chains has the
surprising effect of producing cardiac valvular disease without bone
involvement. (Schwarze U, et.al "Rare autosomal recessive cardiac
valvular form of Ehlers-Danlos syndrome results from mutations in the
COL1A2 gene that activate the nonsense-mediated RNA decay pathway"Am J
Hum Genet. 2004 May;74(5):917-30. Epub 2004 Apr 09).
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