Pregnancy in carriers of high-affinity hemoglobins

Pregnancy in female carriers of abnormal hemoglobins with great avidity for oxygen provides a unique opportunity to assess the importance of the usual difference in oxygen affinity between fetal and maternal blood. Outcome of pregnancy was recorded for carriers of hemoglobins Bethesda, Osler, and Yakima, whose p50s (9.5, 9.1, and 12 mm Hg at pH 7.4) were far lower than that of a normal fetus (23 mm Hg at pH 7.3). Neither spontaneous abortions nor intrauterine growth retardation could be attributed to the presence of high oxygen affinity in the mothers. In vitro simulations suggested that neither maternal or fetal polycythemia alone was sufficient to adjust for perturbation of the normal situation, and increased uterine and/or fetal blood flow probably provided additional compensation.     

Long-segment femoropopliteal stenoses: is angioplasty a boon or a bust?

Analysis of 193 femoropopliteal angioplasties demonstrated patency rates in the stenotic group of 75.5% at 6 months and 54.4% at 54 months. The patency rates for the occlusive group were 93.7% at 6 months and 72.9% at 54 months; these rates were significantly better than those in patients with stenoses. A group of 14 patients with long-segment (greater than 7 cm) stenosis had the highest risk of early failure, with a 6-month patency of 23.1%. After removal of the long-segment stenosis group from the results, there were no significant differences between the long-term patencies for stenotic and occlusive lesions. If angioplasty of long stenoses is attempted, a high initial success rate but early failure should be anticipated.     

Functional analysis of Gscl in the pathogenesis of the DiGeorge and velocardiofacial syndromes

Gscl encodes a Goosecoid-related homeodomain protein that is expressed during mouse embryogenesis. In situ hybridization and immunohistochemistry studies show that Gscl is expressed in the pons region of the developing central nervous system and primordial germ cells. Gscl expression is also detected in a subset of adult tissues, including brain, eye, thymus, thyroid region, stomach, bladder and testis. Gscl is located within a region of the mouse genome that is syntenic with the region commonly deleted in DiGeorge and velocardiofacial syndrome (DGS/VCFS) patients. DGS/VCFS patients have craniofacial abnormalities, cardiac outflow defects and hypoplasia of the parathyroid gland and thymus due to haploinsufficiency of a gene or genes located within the deleted region. Thus, the genomic location of Gscl and its expression in a subset of the tissues affected in DGS/VCFS patients suggest that Gscl may contribute to the pathogenesis of DGS/VCFS. To determine the role of Gscl during mouse embryogenesis and in DGS/VCFS, we have deleted Gscl by gene targeting in mouse embryonic stem cells. Both Gscl heterozygous and Gscl null mice were normal and fertile, suggesting that Gscl is not a major factor in DGS/VCFS. Interestingly, expression of the adjacent Es2 gene in the pons region of Gscl null fetuses was absent, suggesting that mutations within the DGS/VCFS region can influence expression of adjacent genes. In addition, embryos that lacked both Gscl and the related Gsc gene appeared normal. These studies represent the first functional analysis of a DGS/VCFS candidate gene in vivo. These Gscl null mice will be an important genetic resource for crosses with other mouse models of the DGS/VCFS.      

Molecular characterization of breakpoints in patients with holoprosencephaly and definition of the HPE2 critical region 2p21

Holoprosencephaly (HPE) is a common developmental defect involving the brain and face in humans. Cytogenetic deletions in patients with HPE have localized one of the HPE genes (HPE2) to the chromosomal region 2p21. Here we report the molecular genetic characterization of nine HPE patients with cytogenetic deletions or translocations involving 2p21. We have determined the parental origin of the deleted chromosomes and defined the HPE2 critical region between D2S119 and D2S88/D2S391. As a first step towards cloning the HPE2 gene which is crucial for normal brain development we have constructed a YAC contig which spans the smallest region of deletion overlap. Several of these YACs could be identified which span three different 2p21 breakpoints in HPE patients. These YACs narrow the HPE2 critical region to less than 1 Mb and are now being further analyzed to identify the gene causing holoprosencephaly on chromosome 2.