Biomedical subjects
Publications and source records attributed to J M Friedman.
Data pooled from contributors to a Registry for Cytogenetic Abnormalities and PKU (ReCAP) shows an unbalanced chromosome abnormality rate of 27 per cent (29 fetuses) for 107 fetuses with ultrasonically diagnosed fetal anomalies. Of the abnormal, 12 were trisomic, 6 were monosomy X and 6 were structural abnormalities, 4 were mosaics and one triploid.
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Kallmann syndrome is defined by the association of hypogonadotropic hypogonadism and anosmia. A previously unreported association of Kallmann syndrome and choanal atresia in a family is reported. The mechanism of the embryopathic association of hypogonadotropic hypogonadism, anosmia, and choanal atresia is though to be due to a single developmental field defect in the region of the median forebrain and associated structures. An irregular autosomal dominant mode of inheritance is suspected.
A small-for-gestational age white female infant was noted to have multiple minor anomalies and severe jejunal stenosis. Mild peripheral pulmonic stenosis, skeletal anomalies, and cholestasis with paucity of intrahepatic bile ducts were observed, and she was diagnosed as having arteriohepatic dysplasia. Chromosome analysis of peripheral blood leukocytes showed a 46,XX,del(20)(p11.2) chromosome constitution.
Congenital contractural arachnodactyly (CCA) is an uncommon condition characterized by arachnodactyly, dolichostenomelia, kyphoscoliosis, "crumpled" auricles, and flexion contractures at knees, elbows, fingers, and sometimes other joints. The long-term prognosis for affected individuals is usually relatively good. We report on two newborn infants with severe CCA, both of whom died in the first year of life. One child also had other anomalies not generally associated with this disorder. These observations are consistent with the possibility that CCA is an etiologically and clinically heterogeneous disorder.
A number of viruses have been implicated as being the cause of various forms of myositis, including acute transient myositis, chronic polymyositis, and dermatomyositis. However, the cause of juvenile dermatomyositis (JDM) has remained elusive. Our study of serum samples taken within 4 months of the onset of disease in 12 children with JDM showed that 83% had detectable titers of complement-fixing (CF) antibody to 1 or more coxsackie B viral antigens. Detectable titers were found in only 25% of age-, sex-, and date-matched control sera taken from 24 patients with juvenile rheumatoid arthritis (JRA), and in 25% of serum samples taken from 2,192 "normal" children who had been hospitalized because of viral syndromes. Titers of CF antibody to coxsackie B1, B2, and B4 were positive in 58%, 50%, and 58%, respectively, of the JDM patients. In matched JRA controls, the respective values were 8%, 13%, and 8%. There were no significant antiviral titers and no significant differences in the results of tests for 13 other viral CF antigens, hepatitis B surface antigen, and Mycoplasma pneumoniae CF antigen in the JDM patient sera compared with the JRA patient sera. When titers of neutralizing antibody were determined, 58%, 58%, and 67% of the JDM patients were positive for coxsackie B2, B4, and B5, respectively, whereas 16%, 26%, and 21%, respectively, of the JRA controls were positive for the 3 antigens. These data suggest that the host response to coxsackie B virus might be related to the pathophysiology of JDM.
A boy is described with severe hyperostosis of the cranium and facial bones, and many other abnormalities including macrocephaly, abnormal facies, cleft palate, conductive hearing loss, speech defect, dental and digital anomalies, delayed skeletal development, short fibulas, short stature of postnatal onset, cervical kyphosis, and progressive lumbar lordosis. His mother exhibited craniofacial sclerosis, similar dental defects, and mild osteopathia striata without other abnormalities. This family may represent a previously undescribed inherited syndrome with cranial sclerosis.
As tested by DNase I digestion, the chromatin structure in several regions 5' to the rat serum albumin gene varies in tissues and cell lines that differ in transcription rate of this gene. Three DNase I-hypersensitive regions were found in hepatocyte nuclei but not in kidney cell nuclei. The sites were approximately 2.8 kbp (site 1), 0.2 kbp (site 2), and 0.05 kbp (site 3) upstream from the cap site of the gene. In rat fetal liver tissue and rat hepatoma cell lines (FaO, C2, and C2-rev7), as well as in cultured primary hepatocytes where the rate of albumin gene transcription is lower than in adult liver, hypersensitive site (HSS) 1 was absent while sites 2 and 3 were present. In addition, the C2 cell line, which does not express albumin mRNA, contains a different HSS at position -1.5 kbp. Factors (proteins) bound to sites 2 and 3 may allow cell-specific transcription, but the additional factor interaction at site 1 could be required for a maximal rate of albumin gene transcription.
Recombinant adenoviruses were constructed in which the viral E1A gene was deleted and the E1B promoter was replaced by the rat albumin, mouse beta-major globin, or mouse immunoglobulin heavy-chain promoter. After infection of human or rat hepatoma cells, E1B-containing mRNAs could be detected only from the virus containing the albumin promoter. Conversely, only the immunoglobulin promoter was active in virus-infected myeloma cells. However, in hepatoma cells transcription from the albumin promoter in the virus was much less than that of the endogenous cellular albumin gene or of other viral genes. In primary mouse hepatocytes endogenous albumin gene transcription was high immediately after plating but declined within 24 h. Expression of the albumin promoter in the virus paralleled that of the cellular albumin gene. From these results it appears that cell-specific expression of albumin depends on the presence of tissue-specific trans-acting factors, but the presence of such factors does not suffice for a maximal rate of transcription, a conclusion that requires direct comparison within a differentiated cell of a newly introduced and preexisting active cell gene.
In the accompanying paper (Friedman et al., Mol. Cell. Biol. 6:3791-3797, 1986), hepatoma-specific expression of the rat albumin promoter within the adenovirus genome was demonstrated. However, the rate of transcription was very low compared with that of the endogenous chromosomal albumin gene. Here we show that in hepatoma cells the adenovirus E1A enhancer, especially in the presence of E1A protein, greatly stimulates transcription from the albumin promoter but not the mouse beta-globin promoter. This enhancer-dependent stimulation did not occur in myeloma cells in which a virus containing a immunoglobulin promoter and enhancer did function. These experiments suggest a limited distribution in cultured differentiated cells of cell-specific transcription factors. However, either the regulation of such cell-specific factors breaks down in other cultured cells, or strictly cell-specific factors are not at play in controlling cell-specific transcription, because HeLa cells could transcribe the albumin promoter from the same start site about 10% as well as hepatomas could and 293 cells could transcribe both albumin and globin promoters.
Picosecond time-resolved Raman spectra of hemoglobin generated with blue pulses (20 to 30 picoseconds) that were resonant with the Soret band and of sufficient intensity to completely photodissociate the starting liganded sample are reported. For both R- and T-state liganded hemoglobins, the peak frequencies in the spectrum of the deoxy transient were the same at approximately 25 picoseconds as those observed at 10 nanoseconds subsequent to photodissociation. In particular, the large R-T differences in the frequency of the stretching mode for the iron-proximal histidine bond (VFe-His) detected in previously reported nanosecond-resolved spectra were also evident in the picosecond-resolved spectra. The implications of this finding with respect to the distribution of strain energy in the liganded protein and the origin of the time course for geminate recombination are discussed. On the basis of these results, a microscopic model is proposed in which delocalization of strain energy is strongly coupled to the coordinate of the iron. The model is used to explain the origin of the R-T differences in the rates of ligand dissociation.
The picosecond geminate rebinding of molecular oxygen was monitored in a variety of different human, reptilian, and fish hemoglobins. The fast (100 to 200 picoseconds) component of the rebinding is highly sensitive to protein structure. Both proximal and distal perturbations of the heme affect this rebinding process. The rebinding yield for the fast process correlates with the frequency of the stretching motion of the iron-proximal histidine mode (VFe-His) observed in the transient Raman spectra of photodissociated ligated hemoglobins. The high-affinity R-state species exhibit the highest values for VFe-His and the highest yields for fast rebinding, whereas low affinity R-state species and T-state species exhibit lower values of VFe-His and correspondingly reduced yields for this geminate process. These findings link protein control of ligand binding with events at the heme.
The static structure of hemoglobin and its functional properties are very well characterized. It is still not known how energy is stored and used within the structure of the protein to promote function and functional diversity. An essential part of this question is understanding the mechanism through which the overall protein structure (quaternary structure) couples to the local environment about the oxygen binding sites. Time-resolved resonance Raman spectroscopy has been used to probe the vibrational degrees of the freedom of the binding site as a function of protein structure. Comparison of the spectra from both equilibrium and transient forms of deoxy hemoglobin from a variety of mammalian, reptilian, and fish hemoglobins reveals that for each quaternary structure there exist two tertiary states stabilized by the presence or absence of an iron-bound ligand. Pulse-probe Raman experiments show that for photodissociated, ligated hemoglobins the local tertiary structure relaxes at a solution-dependent rate extending from tens of nanoseconds to microseconds. In this local environment, the linkage between the iron and the proximal histidine proves to be the single observed structural feature that responds in a systematic and substantial manner to structural changes in the protein. The additional finding of a correlation between the frequency of the iron-proximal histidine stretching motion (nu Fe-His) and various parameters of ligand reactivity, including geminate recombination, implicates the associated localized structural element in the mechanism of protein control of ligand binding. On the basis of these and related finds, a model is presented to account for both coarse and fine control of ligand binding by the protein structure.
We describe a child with Wolf-Hirschhorn syndrome with the karyotype 45,XY,inv(9)(p11q13)pat,-4,-21,+der(4),t(4;21)(p15.3;q11.2)mat. This is the second case known to us of Wolf-Hirschhorn syndrome caused by 1:3 segregation of a parental rearrangement. This mode of segregation can be predicted in both cases by a pachytene-diagram model. It is uncertain whether or not the proximal 21q monosomy in this case has affected the phenotype.
Ninety children with definite juvenile dermatomyositis (JDMS), who had been HLA typed, were tested for the presence of tissue or organ-specific antibodies. Sixty had active disease at the time of study. The mean disease duration was 4 years, and 30 had soft tissue calcifications. The following autoantibodies were sought: thyroid, gastric parietal cells, smooth muscle, striated muscle, microsomes, mitochondria, DNA, extractable nuclear antigen, Sm, PM-1, antinuclear antibody (ANA), and rheumatoid factor. Only the ANA and PM-1 were more frequent in patients than in controls (P less than 0.0002 and P less than 0.001, respectively). Higher levels of immune complexes (P less than 0.01) were found in sera from patients with JDMS than in sera from controls and were correlated with the presence of ANA in patients (P less than 0.01). Soft tissue calcification was not associated with any autoantibody or HLA antigen, but with disease duration and activity (P less than 0.001 and P less than 0.05, respectively). There was no association between the occurrence of any autoantibody and the presence of HLA-B8 or DR3 among the white patients with JDMS. The frequency of autoantibodies in 43 full siblings of children with JDMS was not increased. We conclude that children with JDMS, with or without HLA-B8/DR3, do not show evidence of a generalized nonspecific antibody response to tissue antigens. The significance of the increased antibody to nuclear antigens ANA and PM-1 remains to be determined.
The first appearance of an autosomal dominant disease in a family is often attributed to new mutation, and the parents may be given a very low risk of recurrence for future offspring. This counseling is not appropriate if penetrance of the disease is incomplete and the reproductive fitness of affected individuals is close to normal. The risk of recurrence (PR) for an autosomal dominant disease in the sibling of an affected child, neither of whose parents is affected, may be estimated as: (Formula: see text) where f is fitness of the carrier genotype regardless of phenotype, y is penetrance, and mutation-selection equilibrium is assumed to exist. Recurrence risks have been calculated with this formula for various values of f and y. In cases in which penetrance is moderate and fitness is moderate or high, the risk of recurrence in siblings of the proband is often greater than 10%. When fitness is very high (f greater than 0.9), the risk to siblings may be greater than 25%. These observations have important implications for genetic counseling and may also affect mutation rate calculations, demonstration of paternal age effects, and determination of inheritance patterns in genetically heterogeneous conditions.
Characteristic abnormalities of the umbilicus have been noted in children with Aarskog syndrome, Reiger syndrome, and Robinow syndrome. These observations indicate that specific umbilical configurations may be characteristic features of some malformation syndromes. Evaluation of the umbilicus for minor anomalies should be included in the examination of a dysmorphic child.
We report a brother and sister, both of whom have porencephaly, hydrocephalus, optic atrophy, severe mental retardation, and spastic quadriplegia. In the younger child, abnormal intracranial structure was demonstrated by sonography at 32 weeks' gestation and was suspected earlier. Both children had transient severe thrombocytopenia as newborns. The mother is healthy and has never had purpura or other bleeding symptoms. However, her serum was found to react strongly with platelets from the father and from both children. The antibody in the mother's serum is platelet-specific but does not appear to be directed against any of the known antigens associated with neonatal alloimmune thrombocytopenic purpura (NATP) in other families, including PlA1, PlE2, or Baka. Although the mother's serum reacts with platelets from all 47 unrelated normal donors tested and from both the mothers and the fathers of 17 other children with suspected NATP, it does not react with her own platelets or with platelets from a patient with Glanzmann's thrombasthenia. These observations suggest that the serum from this woman identifies a previously undescribed high-frequency platelet-specific alloantigen and that sensitization to this determinant caused severe immune thrombocytopenia in both her children. It is likely that this led to intracranial hemorrhage in utero in these cases.