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GENOMICS 4.427-429 (1989)
SHORT COMMUNICATION
The Gene for lncontinentia Pigmenti Is Assigned to Xq28 A. SEFIANI,*+~ L. ABEL,t 5. HEUERTZ,* D. SINNETT,* L. LAVERGNE,$ D. LABUDA,*
AND M. C. HORS-CAYLA*
l lNsERM U-12, HGpital des Enfants.-Malades, 749 rue de S&es, 75743 Paris Cedex 15, France; ttNSERM U-155, ChSteau de Longchamp, Bois de Boulogne, 750 7 6 Paris, France; 4 H6pital Sainte Justine, Mont&l, Quebec, Canada,
and §Laboratoire de G&$tique, Facult4 de Medecine et de Pharmacie, Rabat, Maroc
Received July 11, 1988; revised September 26, 1988
A linkage study of eight families with incontinentia pigmenti (IP) has been performed, and linkage to site DXSBZ has been established. We suggest that the IP locus lies in the Xq terminal region on the long arm of the X chromosome. o 1s~ AC~~~III~ precls, lnc.
Incontinentia pigmenti (IP, McKusick 30830), also known as Bloch-Sulzberger syndrome, is a rare geno- dermatosis. This disease is a multisystem syndrome accompanied by dermatologic and sometimes neuro- logic, ocular, dental, or skeletal defects. Around the time of birth, the infant manifests inflammatory ery- thematous and vesicular skin disorders that evolve into verrucous lesions after a few weeks. Later, these lesions are replaced by linear or blotchy patterns of pigmentary change. Although there are exceptional unexplained cases of affected boys, the most probable mode of in- heritance seems to be sex-linked, dominant, and lethal in males (Lenz, 1961; Carney, 1976). A cytogenetic lo- cation of IP on Xpll has been proposed following ob- servation of six females with IP carrying an X/auto- some translocation (Gilgenkrantz et al., 1985; Hodgson et al., 1985; Kajii et al., 1985; Cannizzaro and Hecht, 1987; McKusick, 1986); in all but one case, the break- point on the X chromosome involved the Xpll region.
We recently excluded a localization on most of the Xp and especially on the Xpll region (Sefiani et al., 1988). In the present paper we exclude several Xq re- gions and assign the gene responsible for the familial form of incontinentia pigmenti to Xq28.
Families in which there were two or more females affected by IP were studied, thus excluding isolated cases possibly arising by new mutation. Eight families with IP were investigated (Fig. 1).
The procedures for DNA extraction, restriction en- zyme digestion, gel electrophoresis, Southern blotting, hybridization to radioactively labeled probes, and au- toradiography have been previously described (Sefiani et al., 1988). DNA samples were digested with several
restriction enzymes and analyzed with six specific sin- gle-copy DNA probes as described in Table 1.
Linkage analysis was conducted assuming X-linked dominant inheritance of IP with 95% penetrance in afl’ected allele carrier females (Prigent, 1984) and 100%
%& %&
21 21 2 13 Family 4 Family 5
.- Family 7 Family 8
FIG. 1. Pedigrees of families with hereditary incontinentia pig- menti and DXS52 marker (effected females are indicated by solid circles; U, unknown genotypes). In order to follow more easily the segregation of different alleles, they have been arbitrarily designated by arabic numerals in each family.
427 OSSS-7543/S9 $3.00 Copyright 0 1989 by Academic Press, Inc.
All rights of reproduction in any form reserved.
428 SHORT COMMUNICATION
TABLE 1
X-Chromosome Markers
Probe Locus Localization Enzyme Heterozygosity Obtained from Ref.
cpx73 pXPGK-PVRI 0.9 ~19-2 pXG12 36B-2 st14-1 F814
DXS159 PGKl DXS3 DXS94 DXSlO DXS52 DXS52
q12-q13
ql3 q21.3-q22
@2 @6 q28
PstI PstI TaqI PstI
TaqI Td BClI
0.44
0.47 0.50 0.44 0.77 0.80
P. L. Pearson (2) A. M. Michelson (11) G. A. Bruns (1) P. Szabo (7) R. Nussbaum (3) J. L. Mandel W-9 J. L. Mandel (9)
penetrance in affected allele carrier males. The mu- tation rate was fixed at lo-’ according to Vogel and Rathenberg (1975). All calculations were performed using the MLink program (Lathrop et aZ., 1984). Con- fidence intervals for the recombination fraction were calculated as described by Conneally et al. (1965). Re- sults are shown in Table 2.
We studied eight families for a total of 59 members and 37 possibly informative meioses. We showed (Table 2) a linkage between IP and site DXS52. Electropho- resis patterns obtained with the probe F814 are shown in Fig. 2. The DXS52 site is multiallelic (Oberl8 et al., 1985; Heilig et al., 1988) and 29 of 37 meioses were informative. A maximal lod score of Z = 3.5 was ob- tained for a recombination fraction 13 = 0.05 (90% con- fidence interval = 0.00-0.22). This result assigns the gene for the familial form of IP to the distal part of the X chromosome long arm.
Moreover, we can exclude a close or medium linkage of the gene responsible for IP with the sites DXS159- PGK-DXS3-DXS94, which are localized in the prox- imal part of Xq, and with the site DXSlO, which is localized in Xq26. Of interest is the observation that
there are X/autosome translocations associated with a phenotype of incontinentia pigmenti. For five of these, the X breakpoint is in Xpll; for two others (McKusick, 1986; S. Gilgenkrantz, to be published), the breakpoint is in Xq21.
We have previously excluded a localization in Xpl 1 (Sefiani et al., 1988). In the present work we also ex- clude a localization in Xq21. Finally, the gene that seg- regates in a family is in a different part of the X chro- mosome. One simple hypothesis is that two other genes in Xpll and Xq21 could be responsible for the incon- tinentia pigmenti phenotype and that we do not observe families with either a gene located in Xpll or Xq21 or a translocation with a breakpoint in Xq28 because of the small number of sporadic and familial cases studied. However, we are not completely satisfied with this hy- pothesis and wonder whether the incontinentia pig- menti phenotype in cases with a translocation could be an indirect, unspecific, and problematic consequence of the translocation itself.
Further work on the Xq28 region of the X chro- mosome in relation to IP is under study with additional pedigrees and probes.
TABLE 2
Linkage Data for Incontinentia Pigmenti Disease and Six Marker Loci
Lod (2) scores at various recombination fractions (0)
Probe Location 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 N
DXS159 q12-q13 -co -1.740 -1.033 -0.653 -0.413 -0.254 -0.146 -0.074 -0.029 -0.005 10 PGKl q13 -co -3.223 -2.105 -1.488 -1.076 -0.777 -0.548 -0.367 -0.220 -0.100 8 DXS3 q21.3-q22 -cc -3.047 -1.864 -1.210 -0.787 -0.498 -0.296 -0.157 -0.067 -0.0016 13 DXS94 @2 -Co -2.346 -1.291 -0.717 -0.363 -0.138 -0.061 0.069 0.089 0.065 15 DXSlO @6 -2.982 -3.746 -2.491 -1.659 -1.073 -0.651 -0.352 -0.152 -0.032 20 DXS52 q28 oZ4 3.583 3.449 3.124 2.706 2.234 1.730 1.215 0.714 0.279 29
0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08
DXS52 s28 0.504 3.142 3.390 3.505 3.561 3.583 3.582 3.566 3.536
Note. N = informative meioses.
SHORT COMMUNICATION 429
FIG. 2. Southern blot of DNA samples from three incontinentia pigmenti families (families 4, 5, and 6). The samples were digested with Bcfl and electrophoresed on 0.9% agarose gels.
ACKNOWLEDGMENTS
We are very grateful to J. L. Mandel and his group for very helpful advice. This work was partially supported by a grant from For& de Recherche en Sax& du Qu&ec and by a grant from Con&l Scien- tifique de la Faculti de M&lecine Necker-Enfants Malades. D. Labuda is a research fellow and D. Sinnet was the recipient of a studentship from the Medical Research Council of Canada.
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REFERENCES
ALDRIDGE, J., KUNKEL, L., BRUNS, G., TANTRAVAHI, U., LALOND, M., BREWSTER, T., MOREAU, E., WILSON, M., BROM- LEY, W., RODERICK, T., AND LA’rr, S. A. (1984). A strategy to reveal high-frequency RFLPs along the human X chromosome. Amer. J. Hum. Gene%. 36: 546-564.
ARVEILER, B., HOFKER, M. H., BERGEN, A. A. B., PEARSON, P., AND MANDEL, J. L. (1987). A P&I RFLP detected by probe cpX73 (DXS159) in Xqll-q22. Nucleic Acids Res. 15: 5903. BOGGS, B., AND NUSSHBAUM, R. L. (1984). Two anonymous X- specific human sequences detecting RFLPs in region Xq26- qter. Somut. Cell Mol. Genet. 10,607-613. CANNIZZARRO, L. A., AND HECHT, F. (1987). Gene for incon- tinentia pigmenti maps to band Xpll with an (X;lO)(pll;q22) translocation. Clin. Genet. 32: 66-69.
CARNEY, R. G. (1976). Incontinentia pigmenti: A world statis- tical analysis. Arch. Dermatol. 112: 535-542.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
CONNEALLY, P. M., EDWARDS, J. H., KIDD, K. K., LALOUEL, J.-M., MORTON, N. E., OTT, J., AND WHITE, R. (1985). Report of the committee on methods of linkage analysis and reporting. Cytogenet. Cell Genet. 40: 356-359.
DAVATELIS, G., SINISCALCO, M., AND SZABO, P. (1987). An anonymous single copy X-chromosome clone DXS94 from Xqll-q21 identifies a common RFLP. Nucleic Acids Res. 16: 4694. GILGENKRANTZ, S., TRIDON, P., PINEL-BRIQUEL, N., BEUREY, J., AND WEBER, M. (1985). Translocation (X,9)(pll;q34) in a girl with incontinentia pigmenti. Ann. Genet. 28: 90-92.
HEILIG, R., OBERLE, I., ARVEILER, B., HANAUER, A., VIDAUD, M., AND MANDEL, J. L. (1988). Improved DNA markers for efficient analysis of fragile X families. Amer. J. Med. Genet.
30: 543-550. HODGSON, S. V., NEVILLE, B., FEAR, R. W. A. C., AND BOBROW, M. (1985). Two cases of X/autosome translocation in female with incontinentia pigmenti. Hum. Genet. 71: 231-234. HUTZ, M. H., MICHELSON, A. M., ANTONARAKIS, S. E., ORKIN, S. H., AND KAZAZIAN, H. H., JR. (1984). Restriction site poly- morphism in the phosphoglycerate kinase gene on the X chro- mosome. Hum. Genet. 68: 217-219. KAJII, T., TSUKAHAF& M., FUKUSHIMA, Y., HATA, A., MATSUO, K., AND KUROKI, Y. (1985). Translocation (X,13)(p11.21;q21.3) in a girl with incontinentia pigmenti and bilateral retinoblas- toma. Ann. Genet. 28: 219-223. LATHROP, G. M., LALOUEL, J. M., JULIER, C., AND OTT, H. (1984). Strategies for multilocus linkage analysis in humans. Proc. Natl. Acad. Sci. USA 81:3443-3446. LENZ, W. (1961). Zur Genetik der Incontinentia Pigmenti. Ann. Paediatr. (Easel) 196: 149-165. MCKUSICK, V. A. (1986). “Mendelian Inheritance in Man: Cat- alogs of Autosomial Dominant, Autosomal Recessive and X Linked Phenotypes,” Johns Hopkins Univ. Press, Baltimore. OBERLB, I., CAMERINO, G., HEILIG, R., GRUNEBAUM, L., CAZENAVE, J., CRAPANZANO, C., MANNUCCI, P., AND MANDEL, J. L. (1985). Genetic screening for hemophilia A with a poly- morphic DNA probe. N. Engl. J. Med. 312: 682-686. PFUGENT, F. (1984). Incontinentia pigmenti. In “Dermatologie,” 12470 AlO, Encycl. Med. Chir., Paris. SEFIANI, A., SINNEW, D., ABEL, L., SZPIRO-TAPIA, S., HEUERTZ, S., CRAIG, I., FRASER, N., KRUSE, T. A., FRYDMAN, M., PETER, M. O., SCHMUTZ, J. L., GILGENKRANTZ, S., MITCHELL, G., FREZAL, J., MELANCON, S., LAVERGNE, L., LABUDA, D., AND HORS-CAYLA, M. C. (1988). Linkage studies don’t confirm the cytogenetic location of Incontinentia pigmenti on Xpll. Hum. Genet. 80: 282-286.
VOGEL, F., AND RATHENBERG, R. (1975). Spontaneous mutation in man. In (H. Harris and K. Hirschhom, Eda.), ‘Aduances in Human Genetics” Vol 5, pp. 232-233, 237-238 (223-305), Plenum, New York.