Osteogenesis imperfecta due to recurrent point mutations at CpG dinucleotides in the COL1A1 gene of type I collagen.
Most individuals with osteogenesis imperfecta (OI) are heterozygous for dominant mutations in one of the genes that encode the chains of type I collagen. Each of the more than 30 mutations characterized to date has been unique to the affected member(s) of the family. We have determined that two individuals with a progressive deforming variety of OI, OI type III, have the same new dominant mutation [alpha 1(I)gly154 to arg] and that two unrelated infants with perinatal lethal OI, OI type II, share a second new dominant mutation [alpha 1(I)gly1003 to ser]. These mutations occurred at CpG dinucleotides, in a manner consistent with deamination of a methylated cytosine residue, and raise the possibility that CpG dinucleotides are common sites of recurrent mutations in collagen genes. Further, these findings confirm that the OI type-III phenotype, previously thought to be inherited in an autosomal recessive manner, can result from new dominant mutations in the COL1A1 gene of type-I collagen.
Pruchno
C J
CJ
Department of Medicine, University of Washington, Seattle 98195.
Cohn
D H
DH
Wallis
G A
GA
Willing
M C
MC
Starman
B J
BJ
Zhang
X M
XM
Byers
P H
PH
D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D003094:Collagen / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D015226:Dinucleoside Phosphates / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D005804:Genes, Lethal; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics*
D003094:Collagen; D004247:DNA; D015226:Dinucleoside Phosphates; C015772:CpG dinucleotide