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

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.

Structural abnormalities of the craniofacial complex and congenital malformations.

This article was meant to be a very cursory survey of the multiple defects that abnormal development can produce in all areas of the craniofacial complex. Careful examination for these abnormalities should lead the clinician to earlier referral of patients for additional examination by a genetics team. This often enables more focused care for the individual and better counseling concerning future pregnancies. Aase points out that "funny looking face" or "syndromic facies" is no longer helpful. Accurate assessment of the face with measurement leads to better diagnosis and ultimately better patient care. All children with facial defects deserve early intervention by a multidisciplined craniofacial team including geneticists, surgeons, dentists, speech pathologists, and other specialists. Part of the process of early referral to this team involves early detection and recognition in the neonatal period. It is hoped that this article stimulates the pediatrician to be aware of these abnormalities, recognize their importance, and seek additional help for patients, no matter what their age.