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.
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Univ Glasgow, Royal Hosp Children, Sch Med, Dev Endocrinol Res Grp,Child Hlth, Glasgow, Lanark, ScotlandUniv Glasgow, Royal Hosp Children, Sch Med, Dev Endocrinol Res Grp,Child Hlth, Glasgow, Lanark, Scotland
McVey, Lindsey C.
Mason, Avril
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Univ Glasgow, Royal Hosp Children, Sch Med, Dev Endocrinol Res Grp,Child Hlth, Glasgow, Lanark, ScotlandUniv Glasgow, Royal Hosp Children, Sch Med, Dev Endocrinol Res Grp,Child Hlth, Glasgow, Lanark, Scotland
Mason, Avril
Pollitt, Rebecca
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Sheffield Childrens NHS Fdn Trust, Western Bank, Sheffield Diagnost Genet Serv, Sheffield, S Yorkshire, EnglandUniv Glasgow, Royal Hosp Children, Sch Med, Dev Endocrinol Res Grp,Child Hlth, Glasgow, Lanark, Scotland
Pollitt, Rebecca
Ahmed, Syed Faisal
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Univ Glasgow, Royal Hosp Children, Sch Med, Dev Endocrinol Res Grp,Child Hlth, Glasgow, Lanark, ScotlandUniv Glasgow, Royal Hosp Children, Sch Med, Dev Endocrinol Res Grp,Child Hlth, Glasgow, Lanark, Scotland
Ahmed, Syed Faisal
Kinning, Esther
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Queen Elizabeth Hosp, West Scotland Genet Serv, Lab Med Bldg, 1345 Govan Rd, Glasgow G51 4TF, Lanark, ScotlandUniv Glasgow, Royal Hosp Children, Sch Med, Dev Endocrinol Res Grp,Child Hlth, Glasgow, Lanark, Scotland