Nuclear retention of COL1A1 messenger RNA identifies null alleles causing mild osteogenesis imperfecta

被引:43
|
作者
RedfordBadwal, DA
Stover, ML
Valli, M
McKinstry, MB
Rowe, DW
机构
[1] UNIV CONNECTICUT, SCH MED, DEPT PEDIAT, FARMINGTON, CT 06030 USA
[2] UNIV PAVIA, DEPT BIOCHEM, I-27100 PAVIA, ITALY
来源
JOURNAL OF CLINICAL INVESTIGATION | 1996年 / 97卷 / 04期
关键词
collagen diseases; bone; RNA splicing; polymerase chain reaction; polymorphism; single strand conformational;
D O I
10.1172/JCI118495
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Osteogenesis imperfecta (OI) is a heritable connective tissue disorder characterized by bone fragility. Most cases of severe OI result from mutations in the coding region of the COL1A1 or COL1A2 genes yielding an abnormal collagen alpha. chain. In contrast, many patients with mild OI show evidence of a null allele due to a premature stop mutation in the mutant RNA transcript. We have previously described a null allele arising from a splice donor mutation where the transcript containing the included intron was sequestered in the nucleus. Here we demonstrate that transcripts from null alleles arising from premature stop mutations are also present in the nucleus and absent in the cytoplasm. Using reverse transcriptase-PCR and single-strand conformational polymorphism of COL1A1 mRNA from patients with mild OI, we describe three patients with distinct null producing mutations identified from the mutant transcript within the nuclear compartment. A fourth patient with a Gly-->Arg expressed point mutation exhibits the mutant transcript in both compartments. Defining the distribution of allelic variants of COL1A1 mRNA in the nuclear and cytoplasmic compartments gives further insight into cell biology of OI and provides a strategy for investigating potential causes of a null allele.
引用
收藏
页码:1035 / 1040
页数:6
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