Biomedical subjects
Publications and source records attributed to F S Collins.
An adult female with Turner syndrome presented with severe lymphedema and chylous ascites. In addition, the patient was found to have a right-sided aortic arch and a left-sided inferior vena cava. Although lymphedema is common in infants with Turner syndrome is previously unreported. In this patient, a peritoneo-venous shunt appeared to be beneficial.
Linkage relationships of the gene for peripheral neurofibromatosis (NF) were assessed in a large American Caucasian pedigree using two DNA markers located on chromosome 8. Linkage to the thyroglobulin locus, located at 8q24, was excluded (lod less than or equal to -2.0) to 21 cM. Data obtained for the tissue plasminogen activator locus, located at 8p12, excluded linkage to 4 cM. These results exclude between 20 to 30% of chromosome 8 as a possible map location for the NF gene in this family. Comparison of the two DNA markers excluded their linkage to 0.5 cM.
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The most common forms of hereditary persistence of fetal hemoglobin (HPFH) involve large deletions that remove the adult delta and beta genes but leave the paired fetal genes (G gamma and A gamma) intact. The size of these deletions has previously eluded exact definition. Using pulsed-field gel electrophoresis and the enzyme SfiI, which cuts only rarely in genomic DNA, we have constructed a large-scale restriction map of the beta-globin cluster in normal and HPFH DNA. The deletions in HPFH-1, which occurs in American blacks, and in HPFH-2, which occurs in Ghanaian blacks, are found to be approximately 105 kilobases (kb) in length, though the endpoints are staggered by approximately 5 kb. The fact that two previously reported gamma delta beta-thalassemia deletions to the 5' side of the beta-globin cluster are also about 100 kb suggests a common mechanism, possibly involving the loss of a complete chromatin loop.
Fifty-seven cases of apple peel jejunal atresia have been reported in the English literature. Patients with this anomaly have a high incidence of prematurity (70%), malrotation (54%), short gut syndrome (74%), multiple atresias (15%), complications (63%), and mortality (54%). Mortality has decreased from 63% to 47% since 1970. We report three new cases of apple peel jejunal atresia, including two from one family. Radiographic evidence of high small bowel obstruction and a malrotated microcolon on preoperative roentgenogram with barium enema should suggest this diagnosis. Five families, including ours, have been reported in which more than one child was affected, and it has been suggested that this disorder is transmitted by an autosomal recessive gene. However, the occurrence of conventional intestinal atresia in other siblings, the association with multiple atresias, and discordance in a set of apparently monozygotic twins indicate that there may be a more complex spectrum of genetic transmission. Subsequent siblings are at increased risk for apple peel atresia or related malformations. Prenatal ultrasound can facilitate early diagnosis and treatment.
A thalassemic beta-globin gene cloned from a haplotype I chromosome contains a T to G transversion at position 116 of IVS1 which results in the generation of an abnormal alternative acceptor splice site. Transient expression studies revealed a 4-fold decrease in the amount of RNA produced with greater than 99% of it being abnormally spliced despite preservation of the normal acceptor splice site at position 130. These results suggest that the mutation at IVS1 position 116 results in beta zero thalassemia. A closely related mutation at position 110 of IVS1 also generates a novel acceptor site and results in a similar decrease in total mRNA produced, but approximately 20% of the mRNA produced is normally spliced and thus the phenotype is that of beta + thalassemia. These observations suggest that short range position effects may play a dramatic role in the choice of potential splice acceptor sites. We demonstrate the presence of abnormally spliced mRNA in reticulocytes of affected individuals and show the mutation at IVS1 position 116 segregating from the mutation at IVS1 position 110 in a three generation pedigree. The mutation results in the creation of a MaeI restriction site, as do a number of other thalassemic mutations, and we demonstrate some difficulties that may arise in the differential diagnosis of these mutations.
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In the Greek A gamma beta + type of hereditary persistence of fetal hemoglobin (HPFH), adult heterozygotes produce about 20% fetal hemoglobin (HbF), which is predominantly of the A gamma chain variety. The affected beta-globin gene cluster produces near normal amounts of beta-like globin, but in a A gamma to beta ratio of 20:80 instead of 0.5:99.5. Gelinas et al and Collins et al have shown a G to A change 117 nucleotides 5' to the A gamma gene in two Greeks with A gamma beta + HPFH. To demonstrate that this change is not a neutral polymorphism, we carried out hybridization with oligonucleotide probes (19mers) specific for the normal and the mutant sequences. While normal probe identified the A gamma fragment in genomic DNA of all subjects studied, mutant probe was positive only in Greeks with A gamma beta + HPFH. In sum, 108 beta-globin gene clusters of individuals without HPFH were negative when tested with mutant probe, but all 11 affected individuals of six families with Greek A gamma beta + HPFH (two previously sequenced and four new families) were positive with mutant probe. These data support the conclusion that the -117 mutation is causative of A gamma beta + HPFH in Greeks.
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DNA sequencing studies of two recently cloned human A gamma globin alleles has revealed a number of base differences which are clustered in the large intron (IVS-2). One allele has a previously undescribed IVS-2 sequence. Most of the allelic differences can be explained as resulting from a gene conversion event involving G gamma as a donor. A novel feature of this event is that three G gamma-like regions occur interspersed among unconverted areas of the A gamma gene. We propose that an alternating purine-pyrimidine run which is located between two of the converted sites is the initiation site of the conversion event. Consistent with models of gene conversion, this poly (purine-pyrimidine) tract has single-stranded characteristics in supercoiled plasmids as assayed by S1-nuclease.
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Hereditary persistence of fetal hemoglobin (HPFH) is a benign condition in which the normal shutoff of fetal hemoglobin (Hb F) production fails to occur. In the G gamma beta+ type of HPFH, erythrocytes of adult heterozygotes contain approximately equal to 20% Hb F, which is almost exclusively of the G gamma-globin variety, without increased levels of gamma-globin chains from the nearby A gamma-globin gene. Unlike some forms of HPFH, no major deletions in the globin gene cluster have been found by genomic blotting in the G gamma beta+ variety. We report here a family with this condition, from which cosmid clones of the beta-globin gene cluster from the G gamma beta+ HPFH allele have been obtained. Sequencing around the fetal genes has identified a point mutation 202 base pairs 5' to the G gamma-globin gene that is present in genomic DNA of 3/3 unrelated individuals with G gamma beta+ HPFH but in none of more than 100 non-HPFH individuals. Although the mutation could represent a tightly linked polymorphism, its location in a region suggested by recent data to be important in tissue-specific control of gene expression suggests the possibility that the -202 mutation accounts for the phenotype. The sequence created resembles elements of other eukaryotic promoters known to be important for efficient transcription.
The principle of a DNA cloning procedure that directionally generates genomic DNA fragments 50-2000 kilobases away from an initial probe is presented. The method depends on partial digestion of high molecular weight genomic DNA and subsequent ligation at very low concentration to generate covalent DNA circles. A library of the junction fragments from these circles can then be constructed. Biological or physical selection of the junction pieces can be achieved by incorporating a marker DNA fragment into the covalent circles. A 45-kilobase cosmid fragment has been successfully used to test the procedure. At appropriately low ligation concentrations (0.8 micrograms/ml), approximately equal to 90% of the ligated DNA is present as monomeric circles. Larger DNA fragments will require reducing the DNA concentration as the inverse square root of the DNA length. A suppressor tRNA gene has been tested as the selectable marker gene. Ligation of the digested circles into an amber-mutated lambda phage and propagation in a sup- host allows only the phage that contain junction fragments to produce plaques. Potential applications of this approach, such as mapping of complex genetic loci or moving from a linked gene toward a gene of interest, are presented and discussed.
Hereditary persistence of fetal hemoglobin (HPFH) is a genetically heterogeneous and clinically benign condition characterized by persistent expression of fetal hemoglobin (Hb F) into adulthood. In the G gamma beta + type, no major deletions in the globin gene cluster occur; adult heterozygotes produce approximately 20% Hb F, which results from overproduction of G gamma chains, with no apparent increase in production from the adjacent A gamma gene. We have recently described a point mutation 202 base pairs 5' to the cap site of the G gamma gene in an individual with G gamma beta + HPFH. This mutation abolishes a normal ApaI restriction endonuclease site, and thus can be detected by blotting of genomic DNA. We present here further data on the ApaI mutation: (1) It occurs in six of seven families with G gamma beta + HPFH. (2) In three families, detailed haplotype analysis using 11 polymorphic restriction sites in the beta globin cluster has been done. The two that carry the missing ApaI site are identical but the third, which has a normal ApaI pattern, differs from the other two in at least two sites, one of which is a new polymorphic Nco I site between the delta and beta globin genes. This suggests the possibility of a different HPFH mutation in the third family. (3) The haplotype of the G gamma beta + HPFH chromosome carrying the ApaI mutation is different from that of 108 beta A chromosomes of black individuals that have been tested. (4) The G gamma ApaI site is normal in 61 beta A and 109 beta S alleles from non-HPFH black individuals, including 22 who share the same haplotype for the intragenic G gamma, A gamma HindIII polymorphisms. These data add support to the possibility that the -202 mutation is actually causative of the G gamma beta + HPFH phenotype.
Infantile myofibromatosis is a distinct clinicalpathologic entity occurring primarily in neonates and infants either as a single nodular lesion or as a multicentric form. We have recently studied two cases of this disorder in neonates, and a third involving the father of one of these infants, all documented by biopsy. Evidence in support of an autosomal-dominant mode of inheritance for infantile myofibromatosis and of its potential to recur after a long period of quiescence is presented.
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Although pulmonary hypertension is frequently mentioned as a complication of the sicklemic state, careful review of the medical literature revealed only a single subject in whom cardiac catheterization data substantiated this diagnosis. In two additional patients, both clinical and autopsy findings of pulmonary vascular disease and cor pulmonale were described, although no hemodynamic studies had been performed. We have therefore detailed the clinical history, cardiac catheterization results, and autopsy findings in three previously undescribed patients. These three patients, along with the three case reports culled from the medical literature, from the substance of this review. Pulmonary hypertension should be suspected in patients with sickle hemoglobinopathy in whom either fixed dyspnea or unexplained syncope develops. Early in the course of the disease, right heart catheterization remains the only way to establish the diagnosis with certainty. Noninvasive studies such as chest x-ray, electrocardiography, and echocardiography tend to be nondiagnostic until late in the course of right ventricular failure. Although specific therapy has yet to be defined, the ominous prognosis of this complication of sickle hemoglobinopathy supports the application of experimental modalities such as continuous oxygen therapy, partial exchange transfusion, or even limited phlebotomy.