Cystic fibrosis mutation analysis: report from 22 U.K. regional genetics laboratories.

We have collated the results of cystic fibrosis (CF) mutation analysis conducted in 22 laboratories in the United Kingdom. A total of 9,807 CF chromosomes have been analysed, demonstrating 56 different mutations so far observed and accounting for 86% of CF genes in the native Caucasian population of the United Kingdom. delta F508 is the most common at 75.3% of CF mutations (range 56.5-83.7%), followed by G551D (3.08%; range 0.71-7.60%), G542X (1.68%; range 0.85-3.66%), 621 + 1 (G > T) (0.93%; range 0.41-3.16%), 1717-1(G > A) (0.57%; range 0.17-1.14%), 1898 + 1)(G > A) (0.46%), R117H (0.46%), N1303K (0.46%), and R553X (0.46%). The data show a clear geographical variation in the distribution of some of the mutations, most notably a marked regional variation in the distribution of 621 + 1 (G > T) and 1989 + 1(G > A), which are both apparently more frequent in Wales. R560T and R117H appear to be more frequent in Ireland and Scotland, and G551D more frequent in Scotland. In summary, these data illustrate that the mutations present within a particular population need to be defined in order to provide meaningful carrier screening and testing for rare mutations in affected individuals. Furthermore, it is apparent that the ethnic origin of a patient, even within a small country such as the United Kingdom, should be taken into account.

An immunohistologic study of endothelialization of uteroplacental vessels in human pregnancy--evidence that endothelium is focally disrupted by trophoblast in preeclampsia.

OBJECTIVE: Our objective was to study the endothelial status of the luminal lining of uteroplacental vessels in the human placental bed in normal and abnormal pregnancy in the third trimester. STUDY DESIGN: Six placental basal plates from uncomplicated pregnancies and five from pregnancies complicated by preeclampsia (n = 3), preeclampsia and a small-for-gestational-age infant (n = 1), and diabetes mellitus (n = 1) were accessioned from the archives because of documentation of their containing uteroplacental vessels. Five placental bed biopsy specimens with intraluminal endovascular trophoblast in the third trimester were also studied. Sections were subjected to immunohistochemical analysis with monoclonal and polyclonal antibodies labeling endothelium and trophoblast. RESULTS: In third-trimester normal uncomplicated pregnancies the uteroplacental arteries and veins were completely endothelialized with no disruption of the endothelium. In third-trimester abnormal pregnancies the uteroplacental veins were also completely endothelialized. However, intraluminal endovascular trophoblast was seen within the uteroplacental arteries in eight of the 10 complicated pregnancies; this finding was associated with disruption of the endothelium. CONCLUSION: In preeclampsia there is an aberrant wave of endovascular trophoblast migration in the third trimester, resulting in focal disruption of the endothelium. This may be responsible for the endothelial cell dysfunction thought to be of pathogenetic importance in preeclampsia.

The human placental bed in health and disease.

The morphology of the human placental bed is reviewed. The pathological features seen in spontaneous abortion, pregnancy-induced hypertension, intrauterine growth retardation, placenta accreta and postpartum haemorrhage suggest that abnormal placentation may be a common feature. A defect in the normal materno-trophoblastic interaction is implicated in the pathogenesis of abnormal placentation.

Preferential expression of the complement regulatory protein decay accelerating factor at the fetomaternal interface during human pregnancy.

The expression of decay accelerating factor (DAF) was investigated in human fetal and extra-fetal tissues using a panel of mAb directed against different epitopes on the DAF molecule. By immunostaining, extensive reactivity was observed on the placental trophoblast epithelium and this was confined exclusively to sites of direct contact with maternal blood and tissues at the fetomaternal interface. Within the fetus, by contrast, very little staining was observed especially on hemopoietic cell populations in the developing liver. The antibodies identified a component of 70,000 m.w., comigrating on SDS-PAGE with red cell DAF, on isolated trophoblast membranes and an apparently quantitative increase in the expression of DAF was observed during placental development. Northern analysis using a DAF cDNA clone revealed 1.5-, 1.6-, and 2.2-kb mRNA transcripts typical of DAF in mRNA prepared from whole term placentae and from purified trophoblast cells. DAF appears to be preferentially expressed at the fetomaternal interface during development and may function specifically to inhibit amplification convertases formed at this site either directly or indirectly as a result of maternal complement activation. This molecule may play an important role in protecting the semiallogeneic human conceptus from maternal C-mediated attack.