Fine mapping and genetic heterogeneity in the pure form of autosomal dominant familial spastic paraplegia

We evaluated seven families segregating pure, autosomal dominant familial spastic paraplegia (SPG) for linkage to four recently identified SPG loci on chromosomes 2q (1), 8q (2), 12q (3), and 19q (4). These families were previously shown to be unlinked to SPG loci on chromosomes 2p, 14q, and 15q. Two families demonstrated linkage to the new loci. One family (family 3) showed significant evidence for linkage to chromosome 12q, peaking at D12S1691 (maximum lod=3.22). Haplotype analysis of family 3 did not identify any recombinants among affected individuals in the 12q candidate region. Family 5 yielded a peak lod score of 2.02 at marker D19S868 and excluded linkage to other known SPG loci. Haplotype analysis of family 5 revealed several crossovers in affected individuals, thereby potentially narrowing the SPG12 candidate region to a 5-cM region between markers D19S868 and D19S220. Three of the families definitively excluded all four loci examined, providing evidence for further genetic heterogeneity of pure, autosomal dominant SPG. In conclusion, these data confirm the presence of SPG10 (chromosome 12), potentially reduce the minimum candidate region for SPG12 (chromosome 19q), and suggest there is at least one additional autosomal dominant SPG locus. Electronic Publication     

Murine hematopoietic stem and progenitor cells: I. Enrichment and biologic characterization

Murine bone marrow cells were fractionated by fluorescence-activated cell sorting into Rh123lo Lin- c-kit+ Ly6A+, Rh123hi Lin-c-kit+ Ly6A+, and Lin- c-kit+ Ly6A- populations within which most, if not all, of the hematopoietic activities of the marrow resided. The Rh123lo Lin- c- kit+Ly6A+ cells, which consist exclusively of small- or medium-sized lymphocyte-like cells, are highly enriched for long-term hematopoietic in vivo repopulating cells. The enrichment factor for these cells from the marrow was estimated as 2,000-fold. The Rh123hi Lin- c-kit+ Ly6A+ cells, although also highly enriched for day-12 spleen colony-forming units, were relatively depleted of long-term in vivo repopulation capacity. Most, if not all Lin- c-kit+ Ly6A- cells were Rb123hi. In contrast to both Rh123lo and Rh123hi Lin- c-kit+ Ly6A+ stem cell populations, the Lin- c-kit+ Ly6A- cells can be stimulated to proliferate in vitro in the presence of single cytokines, which is a characteristic of committed progenitor cells. No marked synergistic interactions between individual cytokines were observed with this cell population. Both Rh123hi Lin- c-kit+ Ly6A+ mature stem cell and Lin- c- kit+ Ly6A- progenitor cell populations displayed in vivo repopulation kinetics resembling those of the putative short-term hematopoietic repopulating cells.     

Effect of active site-modified thrombin on the hydrolysis of platelet- associated glycoprotein V by native thrombin

To determine the relationship between equilibrium binding of thrombin to sites on the platelet surface and the cleavage of membrane glycoprotein V (GPV) by thrombin, we examined the effect of active site- modified thrombin (1-chloro-3-tosylamido-7-amino-L-2-heptanone thrombin toslysCH2-thrombin) on the binding of native thrombin to platelets and on the hydrolysis of GPV by native thrombin. ToslysCH2-thrombin inhibited binding of native thrombin to high affinity sites on the platelet surface. In contrast, hydrolysis of GPV by native thrombin, even at threshold thrombin concentrations, was not inhibited by pretreatment with toslysCH2-thrombin at concentrations up to 210 nmol/L. ToslysCH2-thrombin also had no appreciable effect on platelet aggregation or release of 14C-serotonin induced by native thrombin. Because toslysCH2-thrombin does not inhibit platelet release, aggregation, or GPV hydrolysis by native thrombin but does inhibit high affinity surface binding by native thrombin, these results indicate that thrombin binding and hydrolysis of GPV are separate and unrelated events.     

Genetic analysis of anthropometric measures in 11-year-old twins: the Medical College of Virginia Twin Study

We have conducted a cross-sectional analysis of the genetic and environmental contributions to the variance of anthropometric measurements in children during early adolescence. Univariate path analysis was used to estimate the relative contributions of genes, individual environment, and family environment to measures of childhood obesity in 259 11-y-old Caucasian twin pairs. Triceps, subcapular, and suprailiac skinfold thicknesses, as well as waist circumferences, ht, and wt were measured in a standardized protocol. In this sample, a parsimonious model that included only additive genetic effects and environmental factors unique to the individual provided an adequate explanation for the variation in ht, wt, quetelet index, and subscapular and triceps skinfolds. In this largely preadolescent population, different magnitudes of genetic effects were seen in males and females for waist circumference, biiliac diameter, and suprailiac skinfold.     

High-density lipoprotein-cholesterol subfractions in adolescent twins

Data on the levels of high-density lipoprotein-cholesterol (HDL-C) and subfractions in 102 adolescent twin pairs and their parents are presented. Children with a family history of premature cardiovascular death had lower levels of HDL2-C than did those without such a history. White girls reporting a high level of physical activity had higher levels of HDL-C and HDL2-C than did their more sedentary peers. In general, children of mothers who smoked had lower HDL2-C than did children of nonsmoking mothers. These findings suggest that low levels of HDL2-C in children may identify families in which there is an increased risk of coronary heart disease and that parental smoking may contribute to changes in this risk factor in the children of smokers as well as in the smokers themselves.     

Social support in improving perinatal outcome: the Resource Mothers Program

This report studies the Resource Mothers Program, an organization that improves perinatal outcome through social support. Resource Mothers are nonprofessional women who combine warmth, parenting experience, and knowledge of their local community services to reduce the hazards associated with rural adolescent pregnancy. Each Resource Mother is assigned to a pregnant teenage primigravida and serves as part of her support system throughout pregnancy and until the infant's first birthday. We studied 565 matched pairs (case/control) of rural teenage primigravidas with single pregnancies with and without the social support of the Resource Mother. There were significantly more patients with adequate prenatal care in the program group (P less than .000001). The frequency of low birth weight infants was significantly less (P = .006), as was the small-for-gestational-age rate (P = .002).     

Autoimmunity in congenital rubella syndrome

Two hundred one deaf adolescents with congenital rubella syndrome and 83 age-matched deaf control subjects were evaluated for the presence of organ-specific antibodies directed against thyroid microsomes, thyroglobulin, pancreatic islets, adrenal cortex, and gastric parietal cells. Positive thyroid microsomal or thyroglobulin antibodies were found in 23.3% (47/201) of the rubella group and in 12.0% (10/83) of control subjects. Nine of 46 (19.6%) in the rubella group and two of nine (22.2%) control subjects with thyroid autoimmunity had thyroid gland dysfunction as indicated by elevated serum TSH concentrations. Neither islet cell nor adrenal cortical antibodies were detected in any subject tested; parietal cell antibodies were detected in 5.5% (8/146) of those in the rubella group and 8.8% (6/68) of control subjects tested, but occurred most frequently in subjects with thyroid autoimmunity (6/36, 16.7% vs 8/178, 4.5%; P less than 0.05). It is recommended that all patients with congenital rubella syndrome be screened for thyroid autoimmunity and that those with positive antibody titers be evaluated for the presence of thyroid dysfunction.