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Correction of Cellular Metachromasia in Cultured Fibroblasts in Several Inherited Mucopolysaccharidoses* B

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Correction of Cellular Metachromasia in Cultured Fibroblasts in Several Inherited Mucopolysaccharidoses* B Proceeding8 of the National Academy of Sciences Vol. 67, No. 1, pp. 357-364, September 1970 Correction of Cellular Metachromasia in Cultured Fibroblasts in Several Inherited Mucopolysaccharidoses* B. Shannon Danest and Alexander G. Bearn DIVISION OF HUMAN GENETICS, DEPARTMENT OF MEDICINE, CORNELL UNIVERSITY MEDICAL COLLEGE, NEW YORK, NEW YORK 10021 Communicated by Henry G. Kunkel, May 15, 1970 This paper is dedicated to Th. Dobzhansky on the occasion of his seventieth birthday. Abstract. Cultured fibroblasts from the genetic mucopolysaccharidoses store higher than normal amounts of the polyanionic glycosaminoglycans (mucopoly- saccharides); histochemical staining with the cationic dyes toluidine blue 0 and Alcian blue detects such intracellular accumulation. With these stains as phenotypic markers, correction of the cellular abnormality by fibroblasts derived from different patients and their heterozygous parents has been observed among several genetic types of mucopolysaccharidoses. In this way, syndromes previ- ously considered clinically homogeneous have been separated into distinct groups. In the absence of detailed knowledge of the primary metabolic abnormality, classification of inherited diseases in man is usually based on their clinical charac- teristics. It is also evident that the observed phenotype may reflect more than one genotype. The technique of mixing cultured fibroblasts to demonstrate genotypic differences, pioneered by Neufeld and her associates,' allows genetic heterogeneity at the cellular level to be explored in finer detail. The genetic mucopolysaccharidoses constitute a group of inborn errors of metabolism of the glycosaminoglycans (mucopolysaccharides), in which glycos- aminoglycans accumulate in various tissues of the body.2 McKusick3 es- tablished a clinical classification of mucopolysaccharidoses-emphasizing that, in all probability, genetic heterogeneity existed within each clinical type. Until the'advent of cultured cell mixing, no experimental technique had been available to detect any genetic variation that might-be-present in these syndromes. Cultured fibroblasts from homozygotes -and heterozygotes for the genetic mucopolysaccharidoses accumulate excessive quantities of glycosaminoglycans.4 The observation' that such accumulation does not result if cultured fibroblasts from the Hunter and Hurler syndromes are mixed, either with each other or with normal fibroblasts, established thl specificity of these two genotypes, which was already well recognized from clinical and pedigree studies. Glycosaminoglycans can be distinguished histochemically by differential staining with Alcian blue in the presence of various concentrations of magnesium eliloride." 6 We have applied this Ihistochemical method to detect in vitro phenotypic correction Witlin this group of glycosaminoglycati disorders. 357 Downloaded by guest on September 30, 2021 358 MEDICAL SCIENCES: DANES AND BEARIN PRoc. N. A. S. Materials and Methods. Skin biopsies were taken from 28 persons with different genetic mucopolysaccharidoses, 6 heterozygous parents for the Hurler syndrome, 4 hetero- zygous mothers for the Hunter syndrome, 3 persons with other genetic disorders, and 6 normal subjects. Only patients with the classical clinical and biochemical phenotype for each disorder were included. The establishment of the cell lines from skin biopsies by standard culture methods7 required about 6 weeks, so that the cells studied had been grown as monolayer cultures from 1 to 2 months (two to six subcultures by trypsinization) before the mixing studies. Prior to each experiment, cell lines were grown in large round bottles on a roller apparatus so that coverslip cultures for each person studied could be obtained from one culture. Approximately 20,000 cells were inoculated into each 2-oz. glass flask, which contained a coverslip. The cultures were grown in reinforced Eagle's medium containing 10% by volume of newborn calf serum. One day after subculturing, the coverslip was removed under aseptic conditions from the flask, a drop of silicone grease was applied to its undersurface, and the coverslip was placed in another culture flask containing a monolayer of cells obtained from the same or a different clinical phenotype. The purpose of the grease drop was to raise the coverslip off the inner surface of the flask and so minimize cell migration during the subsequent culture period. Fourteen days after the mixing of the cells, each coverslip was removed, washed in warm balanced salt solution for 1 min, and cut into three parts. The first part was im- mediately immersed in methanol for 5 min and stained with the metachromatic dye, toluidine blue 0, as previously described in detail.8 The other two parts were stained for the presence of specific glycosaminoglycans in a simple one-step procedure, using Alcian blue 8 GX solutions containing either 0.1 or 0.3 M MgCl2.8 Cell clones were established from patients with the Hunter syndrome and their carrier mothers according to the dilution techniques described by Puck et al.9 and used by us in previous experiments.10 After cultures from individual clones had been established, the procedures for culture mixing were the same as described for the cell lines. Results.' In the following sections the cytoplasmic staining with toluidine blue 0 will be referred to as metachromasia (pink) and orthochromasia (blue) and that with Alcian blue as alcianophilia. All cultures were stained blue with Alcian blue in 0.1 M MgCl2. The staining with Alcian blue in 0.3 M MgCl2 will be referred to as 0.3 M-alcianophilia. The staining properties of cell lines grown with a panel of cultured fibroblasts from normal persons and patients with different syndromes are illustrated in Table 1. Normal cells: Cultured fibroblasts from four normal persons were ortho- chromatic and showed no 0.3 M-alcianophilia. Mixing these cell lines with all other cell lines showed no change in staining properties. Two cell lines derived from normal persons that showed unequivocal metachromasia, no 0.3 M-alcianophilia, and a normal uronic acid content continued to show these staining characteris- tics no matter with what other cell lines they were grown. Hurler syndrome: Fibroblasts derived from five (Group A) of the seven patients with the Hurler syndrome showed no change in their metachromasia or 0.3 M-alcianophilia when mixed with each other. These same cell lines lost their staining properties when grown with fibroblasts from two other Hurler patients, a brother and sister (Group B). The fibroblast cultures established from these two affected sibs were markedly less metachromatic and alcianophilic at 0.3 M MgC4 and had a lower content of uronic acid. Cell lines from Group B similarly lost their staining when mixed with those of Group A but not with each other. Both Group A and B became totally orthochromatic and no longer showed 0.3 M-alcianophilia when grown for up to 2 months with cells from any normal Downloaded by guest on September 30, 2021 VOL. 67, 1970 FIBROBLAAST METAGHROMASIA 359 0 4 0 '4 C, .0~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~C 00 0d 0 z. 0 '4 0~~~~~~~~~~~~9 r Q 0~~ ++~~~~~~+ .' 4~~~~~~~~~~~~~~~~~~~~~~~' '4 .0 0.4)*-~~~~~~~~~~~~~~~~~~~~~~~~~~4 4.0i t44 Cs 0.2 a.. U 0~~~~~~~~~~~~~..4 Cs0. cr2 0. 02 0 '4~~~~~~~~~~~~~~~~~~~. 4)~,4) 9v'-4 4).P w b - r-4 O~~~~~~~~~' 40 0~~~~~~0 0 Z. '0 Downloaded by guest on September 30, 2021 360 MEDICAL SCIENCES: DANES AND BEARN PROC. N. A. S. person or from patients with any of the other syndromes studied except when mixed with Group C Hunter and Group B Scheie syndromes. These cell mix- tures did not influence the staining properties of each other even with prolonged periods of culture. Cultures from the heterozygous parents in Groups A and B gave similar results to those for their homozygous offspring. Hunter syndrome: 11 patients with the classical and one with an atypical phenotype for the Hunter syndrome were studied. On the basis of cell mixing, the cultures from the 11 patients could be divided into two groups: fibroblasts from Group A (6 patients) and Group B (5 patients) could be mixed within each group without any loss of metachromasia or 0.3 M-alcianophilia, whereas these staining reactions were lost when representatives of the two groups were mixed with each other. The cultures in Group B initially showed less metachromasia, 0.3 M-alcianophilia, and uronic acid. Cultures in both groups lost their stain- ing when mixed with all other cell lines studied. Cultures of both white blood cells and fibroblasts derived from the parents of the patient with the atypical Hunter syndrome (Group C) showed that the mode of inheritance was that of an X-linked recessive. Cultures derived from the affected boy showed marked metachromasia, 0.3 M-alcianophilia, and high cel- lular uronic acid. There was no cytoplasmic staining after mixing with Group A or B or any other cells cxcept those derived from the Hurler syndrome and Group B Scheie syndrome. All clones derived from seven boys with the Hunter syndrome showed meta- chromasia and 0.3 M-alcianophilia. Like the initial cell lines, the clones established from Group A consistently showed more intense staining than those of Group B. Clones of each "corrected" clones of the other group but did not correct within the group. Two populations of cells, positive and negative for staining, were found in cloning lines derived from the carrier mothers. The positive clones in Group A, like the initial lines from which they were derived, stained more strongly than those in Group B. Within a group, positive clones from different individuals could be grown together without influencing staining (Table 2), whereas if such clones were from different groups (A or B), all cells lost their stain. Clonal lines that were negative "corrected" all other clones grown with them to the nonstain- ing form (Table 2). Scheie syndrome: Cultures from two of the patients (Group A) with the TrABL}, 2. Staining characteristics* of skin fibroblast clones from seven patients with the Hunter syndrome grown with clones from their carrier mothers.
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