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Regional Assignment of the Steroid Sulfatase-X-Linked Ichthyosis Locus

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Regional Assignment of the Steroid Sulfatase-X-Linked Ichthyosis Locus Proc. Natl. Acad. Sc. USA Vol. 76, No. 11, pp. 5779-5783, November 1979 Genetics Regional assignment of the steroid sulfatase-X-linked ichthyosis locus: Implications for a noninactivated region on the short arm of human X chromosome (human gene mapping/mouse-human cell hybrids/X-chromosome inactivation/Xg blood group locus/sterol-sulfatase) T. MOHANDAS*t, L. J. SHAPIRO*t, R. S. SPARKESt, AND M. C. SPARKESt *Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California 90509; and *Division of Medical Genetics, Department of Medicine, Pediatrics and Psychiatry, University of California, Los Angeles, California 90024 Communicated by Victor A. McKusick, July 26, 1979 ABSTRACT The expression of steroid sulfatase (SS; sterol- in normal female hematopoietic cells, at least when associated sulfatase; sterol-sulfate sulfohydrolase, EC 3.1.6.2), a microsomal with an intact X chromosome (7, 8). Recent experiments with enzyme that catalyzes the hydrolysis of a variety of 3,B-hy- fibroblast clones from female obligate heterozygotes for SS droxysteroid sulfates, was evaluated in mouse-human hybrid clones. The mouse parental line, A9, was found to have little SS deficiency demonstrate that a gene locus controlling expression as determined by activity measurements. Human SS can be of SS activity is non-Lyonized (9). It is thus of particular interest separated from mouse SS by electrophoresis. Two human fi- that the loci for SS 4nd Xg, both of which appear to escape in- broblast lines, one carrying an X/13 translocation [46,X,t(X; activation, are relatively closely linked. 13Xp22;ql2)] and the other carrying an X/20 translocation Rodent-human somatic cell hybrids have been used exten- 46,X,t(X;20XXp2Oq;Xq2Op)] were used as the human parental sively in recent years for human gene mapping (10). Attempts lines. Several independently derived hybrid clones from each of the two fusion experiments were analyzed for the expression to map the Xg locus on the human X chromosome by using of human SS by activity measurements and electrophoresis. interspecific somatic cell hybrids have not been successful to Cytogenetic analyses were done on these hybrid clones at the date because the expression of Xg on the hybrid cell surface same passage level. The results showed that the expression of cannot be reliably detected (11, 12). With the availability of the human SS in these cell hybrids was concordant only with the new X-linked marker SS, which can be evaluated in cultured presence of the distal half (p22-.pter) of the short arm of the cells (13), it became possible to investigate whether SS could be human X chromosome, thus assigning the locus for SS to Xp22-.Xpter. Earlier studies have shown that the deficiency mapped by using somatic cell hybrid techniques. Preliminary of SS is the basis for the dermatologic condition X-linked ich- studies indicated that the mouse line A9, which is deficient in thyosis, the gene for which is known to be located approximately hypoxanthine phosphoribosyltransferase (HPRT; EC 2.4.2.8) 10 centimorgans from the Xg blood group locus. The localization has very little SS activity. In addition, mouse SS can be separated of SS on the X chromosome indicates that the Xg locus may be from the human enzyme electrophoretically. Hybrid lines on the short arm of X and possibly on its distal half. The Xg derived from the fusion of A9 cells with two different X- locus is thought to escape X-inactivation in man, and recent investigations suggest that the SS locus also escapes X-inacti- autosome translocations were then analyzed. The results show vation. Our results thus provide evidence for the location of an that the SS locus can be assigned to the distal half of the short apparently noninactivated site on the distal half of the short arm of the human X chromosome. arm of the human X-chromosome that contains the locus for SS and possibly the Xg locus. MATERIALS AND METHODS Steroid sulfatase (SS; sterol-sulfatase; sterol-sulfate sulfohy- drolase, EC 3.1.6.2) is a microsomal enzyme that is capable of Cell Lines. Mouse cell line A9 (GM 0346, Institute of Medical catalyzing the hydrolysis of a variety of 33-hydroxysteroid Research, Camden, NJ), deficient in HPRT was used as the sulfates (1). This enzymatic activity has been detected in a va- rodent parent in these experiments. A9 was fused with four riety of tissues but has been most extensively studied in placenta different human parental cells. One human parental fibroblast and liver (2, 3). Individuals genetically deficient in steroid line was derived from a female carrying an apparently balanced sulfatase activity have been identified (4). All have been males translocation between chromosomes X and 13: 46,X,t(X:13)- and pedigree evidence for X-linked inheritance has been pre- (p22;q12) (Fig. 1) (14). The break in the X chromosome appears sented (5). It was initially appreciated that affected patients to be just above the bright band (p21) on the short arm. Chro- were the result of pregnancies in which diminished estriol mosome replication studies with bromodeoxyuridine incor- production and delayed onset of labor were noted. It has sub- poration (unpublished) show that either the normal X or the sequently been established that this enzymatic defect is the basis translocated X can be seen as the late-replicating X chromosome for the relatively common genetic dermatologic condition in different cells from this individual. Hybrids resulting from X-linked ichthyosis (6). the fusion of A9 and the X/13 translocation are identified by Family studies have established that the locus for X-linked the prefix 25. A second fusion utilized fibroblasts from a female ichthyosis is located approximately 10 centimorgans from the carrying an apparently balanced translocation between chro- Xg blood group locus, which specifies an X-linked erythrocyte mosomes X and 20; 46,X,t(X;20)(Xp20q;Xq20p). The exchange surface antigen (7). Several studies have provided evidence that involves whole arms of the X chromosome and chromosome 20. the Xg locus is not subject to X-inactivation ("Lyonization") Abbreviations: SS, microsomal steroid sulfatase; HPRT, hypoxanthine The publication costs of this article were defrayed in part by page phosphoribosyltransferase; G6PD, glucose-6-phosphate dehydrogenase; charge payment. This article must therefore be hereby marked "ad- ESD, esterase D; THAG, thymidine/hypoxanthine/aminopterin/ vertisement" in accordance with 18 U. S. C. §1734 solely to indicate glycine. this fact. t To either of whom reprint requests should be addressed. 5779 Downloaded by guest on September 25, 2021 5780 Genetics: Mohandas et al. Proc. Natl. Acad. Sci. USA 76 (1979) FIG. 1. Q-banded chromosomes. (A) X/13 translocation carrier, showing chromosomes involved in the translocation. A pair of chromosomes 21 from the same cell are shown for size comparison with 13/X. The descriptions ofthe translocated chromosomes are given in footnotes to Table 1. (B) Mouse-human hybrid cell from clone 25-8, which retains the X/13 chromosome and chromosome 21 (arrows). (C) Partial view of metaphase from clone 25-12, showing human chromosomes 13/X, 21, X, 15, and 13 (arrows). (D) Metaphase from clone 25-6 retaining the X chromosome (arrow). This translocation was previously used for regional localization Giles and Ruddle (16). The initial fusion mixture was diluted of markers on human chromosome 20 (15). The normal X and plated in several small culture vessels, and hybrid clones chromosome appears to be the late-labeling one in the majority were selected in growth medium containing thymidine, hy- of the cells in this individual. Hybrids derived from the fusion poxanthine, aminopterin, and glycine (THAG) (16). Ouabain of A9 and the X/20 translocation are identified by the prefix (10 ,kM) was added to this medium to select against the human 31. A third fusion experiment utilized lymphocytes from a male fibroblasts (16). Only one colony was picked from a culture affected with X-linked ichthyosis, who has deficiency of SS vessel; a cloning cylinder was used to ensure the independent activity, as the human parent. A final set of hybrids was made origin of primary hybrid clones. Hybrid clones were back-se- from the fusion of A9 with lymphocytes from the grandfather lected in growth medium containing 8-azaguanine at 3 ug/ml of the affected male referred to above, who is also affected and to select for cells that have lost the X chromosome or the part lacks SS activity. that carries the HPRT gene. Cell Fusion and Isolation of Hybrid Clones. Mouse line A9 Cytogenetic Analysis. Eight independent primary hybrid and the human parental line were fused in suspension with the clones were derived from the fusion of A9 and the cells with the aid of inactivated Sendai virus according to the procedure of X/13 translocation (series 25). Five of these eight clones were Downloaded by guest on September 25, 2021 Genetics: Mohandas et al. Proc. Natl. Acad. Sci. USA 76 (1979) 5781 successfully back-selected in 8-azaguanine. All 13 of the above hybrid clones were analyzed biochemically for the e6t#r0io + of human steroid sulfatase and cytogenetically for the human chromosomes retained in them. Four independent primary hybrid clones derived in THAG medium from the fusion of A9 and the cells with the X/20 translocation were similarly ana- Human lyzed biochemically and cytogenetically. In total, five inde- pendent primary hybrid clones were analyzed from the fusion of A9 with lymphocytes from the two individuals deficient in Origin . , SS; these lines were evaluated for the expression of human SS, but no cytogenetic analysis was performed. All hybrid clones were analyzed for the expression of human glucose-6-phosphate dehydrogenase (G6PD; EC 1.1.1.49), a 1 2 3 4 5 6 known marker for the long arm of thjhuman X chromosome.
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