Disruption of one intra-chain disulphide bond in the carboxyl-terminal propeptide of the proalpha1(I) chain of type I procollagen permits slow assembly and secretion of overmodified, but stable procollagen trimers and results in mild osteogenesis imperfecta.

Type I procollagen is a heterotrimer comprised of two proalpha1(I) chains and one proalpha2(I) chain. Chain recognition, association, and alignment of proalpha chains into correct registration are thought to occur through interactions between the C-terminal propeptide domains of the three chains. The C-propeptide of each chain contains a series of cysteine residues (eight in proalpha1(I) and seven in proalpha2(I)), the last four of which form intra-chain disulphide bonds. The remaining cysteine residues participate in inter-chain stabilisation. Because these residues are conserved, they are thought to be important for folding and assembly of procollagen. We identified a mutation (3897C-->G) that substituted tryptophan for the cysteine at position 1299 in proalpha1(I) (C1299W, the first cysteine that participates in intra-chain bonds) and resulted in mild osteogenesis imperfecta. The patient was born with a fractured clavicle and four rib fractures. By 18 months of age he had had no other fractures and was on the 50th centile for length and weight. The proband's mother, maternal aunt, and grandfather had the same mutation and had few fractures, white sclerae, and discoloured teeth, but their heights were within the normal range. In the patient's cells the defective chains remained as monomers for over 80 minutes (about four times normal) and were overmodified. Some secreted procollagens were also overmodified but had normal thermal stability, consistent with delayed, but normal helix formation. This intra-chain bond may stabilise the C-propeptide and promote rapid chain association. Other regions of the C-propeptide thus play more prominent roles in chain registration and triple helix nucleation.

Prader-Willi syndrome is caused by disruption of the SNRPN gene.

A Prader-Willi syndrome patient is described who has a de novo balanced translocation, (4;15)(q27;q11.2)pat, with breakpoints lying between SNRPN exons 2 and 3. Parental-origin studies indicate that there is no uniparental disomy and no apparent deletion. This patient expresses ZNF127, SNRPN exons 1 and 2, IPW, and D15S227E (PAR1) but does not express either SNRPN exons 3 and 4 or D15S226E (PAR5), as assayed by reverse transcription-PCR, of peripheral blood cells. Methylation studies showed normal biparental patterns of inheritance of loci DN34/ZNF127, D15S63, and SNRPN exon 1. Results for this patient and that reported by Sun et al. support the contention that an intact genomic region and/or transcription of SNRPN exons 2 and 3 play a pivotal role in the manifestations of the major clinical phenotype in Prader-Willi syndrome.

Non-mosaic trisomy 16 in a third-trimester fetus.

BACKGROUND: Trisomy 16 in the most common trisomy first-trimester spontaneous abortions, suggesting a high rate of non-disjunction of this chromosome. Deoxyribonucleic acid studies in aborted conceptuses with trisomy 16 have demonstrated a maternal origin in all cases. There have been cases of confined placental mosaicism, fetal mosaicism, and partial trisomy involving chromosome 16 reported in term fetuses. However, to our knowledge, there have been no previous reports of a near-term fetus with full trisomy 16 since the advent of modern chromosomal banding techniques. CASE: A 25-year-old Filipino woman underwent obstetric sonographic evaluation at 32 weeks' gestation; results were remarkable for oligohydramnios, severe growth restriction, and multiple dysmorphic features. Percutaneous umbilical blood sampling was performed for rapid karyotyping, viral serology, and blood profiles. The fetal karyotype was 47, XY+16; the remainder of the laboratory analysis was unremarkable. The patient went into spontaneous labor at 35 weeks' gestation and delivered a stillborn female fetus (birth weight 783 g). Chromosomes from skin, brain, and chorionic villi were examined and all demonstrated trisomy 16 (47, XX,+16). Deoxyribonucleic acid primers for known polymorphic regions of chromosome 16 were used and determined the origin of the extra chromosome to be non-disjunction during paternal meiosis. CONCLUSION: Previously, full trisomy 16 has been thought to be incompatible with fetal survival past the early second trimester. This case also contrasts with previously reported experience with trisomy 16 in that parental origin studies determined that the extra chromosome 16 originated from the father, suggesting that paternal derivation of the additional chromosome may play a role in the ultimate phenotypic expression.