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Multipoint Linkage Analysis in Menkes Disease T Am. J. Hum. Genet. 50:1012-1017, 1992 Multipoint Linkage Analysis in Menkes Disease T. T0nnesen,* A. Petterson,* T. A. KruseT A.-M. Gerdest and N. Horn* *John F. Kennedy Institute, Glostrup, Denmark; TInstitute of Human Genetics, University of Aarhus, Aarhus, Denmark; and *Department of Clinical Chemistry, Odense Sygehus, Odense, Denmark Summary Linkage analyses were performed in 11 families with X-linked Menkes disease. In each family more than one affected patient had been diagnosed. Forty informative meioses were tested using 11 polymorphic DNA markers. From two-point linkage analyses high lod scores are seen for DXS146 (pTAK-8; maximal lod score 3.16 at recombination fraction [0] = .0), for DXS1 (p-8; maximal lod score 3.44 at 0 = .0), for PGK1 (maximal lod score 2.48 at 0 = .0), and for DXS3 (p19-2; maximal lod score 2.90 at 0 = .0). This indicates linkage to the pericentromeric region. Multilocus linkage analyses of the same data revealed a peak for the location score between DXS146(pTAK-8) and DXYSlX(pDP34). The most likely location is between DXS159 (cpX289) and DXYS1X(pDP34). Odds for this location relative to the second-best-supported region, be- tween DXS146(pTAK-8) and DXS159 (cpX289), are better than 74:1. Visualization of individual recombi- nant X chromosomes in two of the Menkes families showed the Menkes locus to be situated between DXS159(cpX289) and DXS94(pXG-12). Combination of the present results with the reported absence of Menkes symptoms in male patients with deletions in Xq21 leads to the conclusion that the Menkes locus is proximal to DXSYlX(pDP34) and located in the region Xql2 to Xql3.3. Introduction (Wienker et al. 1983). Use of a centromeric chromo- Menkes disease (McKusick 30940) is an inherited dis- somal marker in five Danish families with Menkes as an X-linked disease suggested a close linkage between the Menkes order of copper metabolism transmitted locus and the centromeric region (Horn et al. 1984). recessive trait. Patients show specific copper-defi- man and as lack keratinization and By comparative gene mapping between ciency symptoms, such of mouse, a localization close to the human PGK1 locus pigmentation ofhair, degenerative changes ofthe elas- et al. In a three- in blood and scorbutic at Xql3 was suggested (Horn 1984). tic tissue the aorta and vessels, the Menkes locus was tenta- bone changes (Danks et al. 1972). In addition, pro- point linkage analysis, retardation with seizures and tively localized on the long arm of the X chromosome gressive psychomotor proximal to DXYS1X (Tonnesen et al. 1986, p. 627). temperature instability are seen, and the affected males of Menkes disease more than 3 The incidence is A girl having clinical symptoms rarely survive for years. a translocation with the on the to be live births et al. and having breakpoint estimated 1:300,000 (Tonnesen active X chromosome in Xql3.2-Xql3.3 was recently 1991). found (Kapur et al. 1987; Verga et al. 1991). The The exact localization of the Menkes locus has not have now been extended to 11 A tentative localization has been linkage analyses yet been established. Menkes families, and the results on 40 informative proposed at Xpl 1.2, defined by the locus DXS7 of these data meioses in these families indicate a localization of the (Wieacker et al. 1983). Further analyses Menkes on the part of Xq. defined the Menkes locus to a region distal to DXS7 gene proximal Received October 23, 1991; revision received December 26, Subjects and Methods 1991. Address for correspondence and reprints: Dr. T. T0nnesen, John Subjects F. Kennedy Institute, GI. Landevej 7, DK-2600 Glostrup, Den- Four German, three American, two British, one mark. i 1992 by The American Society of Human Genetics. All rights reserved. Danish, and one Argentinian family were used in this 0002-9297/92/S005-0015$02.00 study. For each of these 11 investigated families, more 1012 Localization of the Menkes Locus 1013 Table I Results Names and Regional Assignments of Probes Two-Point Linkage Analyses Informative in Present Study A number ofX chromosome-specific DNA markers HMG 10.5 Probe Regional have been used in our search for linkage to the Menkes Nomenclature Designation Assignment locus (table 1). Two-point linkage analyses on the data DXS84 ............. L754 Xp21.1 obtained from 40 informative meioses in 11 Menkes DXS146 ............. pTAK-8 Xpl1.22 families are shown in table 2. For some of the DNA DXS14 ............. p58-1 Xpl 1.21 markers (pTAK-8, p-8, pSPT19-1, and pl9-2) high DXS1 ............. p8 Xqll.2-ql2 lod scores are seen, which indicates linkage between DXS159............. cpX289 Xql2 the Menkes locus and the pericentromeric region. DXS106............. cpX203 Xql2 PGK1 ............. pSPT19.1 Xql3 Multilocus Linkage Analyses DXYS1X............. pDP34 Xq21.31 DXS3 ............. p19-2 Xq21.3 When the data are subjected to multilocus linkage DXS94............. pXG-12 Xq22 analyses, the following picture emerges (fig. 1). The DXS91 ............. pXG-17 Xq24-q26 location score shows a peak between pTAK-8 and DXS52 ............. Stl4-1 Xq28 pDP34. But the most likely localization is between cpX289 and pDP34, with a maximal location score of than one affected Menkes patient has been diagnosed. 26.3, equivalent to a multipoint lod score of5.7. Odds Informative individuals are persons for whom pedi- for this location relative to the second-best-supported gree information alone is sufficient to establish the region (between pTAK-8 and cpX289) are greater genotype. A total of 40 informative meioses have been than 74:1. The present results give no indication of investigated. linkage heterogeneity. DNA Analyses Haplotype Analyses The DNA probes applied for this investigation are We next looked in more details on individual recom- listed in table 1. For hybridization, 0.05-0.10 gg puri- binant X chromosomes (fig. 2). In the left-hand panel fied human insert DNA was used as a template in of figure 2 are shown the results of the RFLP analyses oligonucleotide-primed synthesis of 32P-labeled DNA in one Menkes family. It is evident that the healthy (Feinberg and Vogelstein 1983). Subsequent to the boy (III-2) has received the complete X chromosome labeling, the DNA probes were hybridized to nylon of his maternal grandfather. The Menkes boy (111-3) filters onto which 5-10 gg of human genomic DNA has received the alternative X chromosome from his had been Southern blotted, after restriction-endo- mother. This X chromosome must thus carry the nuclease digestion and subsequent separation of the Menkes mutation, as the mother is an obligate carrier. DNA fragments by agarose gel electrophoresis. The Both 111-4 and III-6 have recombinant X chromo- filters were autoradiographed by exposure to X-ray somes, as they carry parts of the Menkes X chromo- films for 2-10 d. some and parts of the healthy X chromosome. From these analyses we may conclude that the Menkes locus Linkage Analyses is on Xq, distal to cpX289. Genotypic data were obtained using the probes For a second Menkes family the results of the RFLP listed in table 1. Pairwise and multilocus (nine-point) analyses are shown in the right-hand panel of figure 2. linkage analyses were performed using the LINKAGE In this Menkes family we know that 111-3 suffered from 4.7 package of computer programs (Lathrop and La- Menkes disease. 111-4 is one ofthe very few girls known louel 1984; Lathrop et al. 1984). Gene order was ex- to express the Menkes gene (Gerdes et al. 1990). In amined by multilocus likelihood calculations using the this family the X chromosome carrying the Menkes ILINK and LINKMAP programs. Genetic distances mutation in the obligate carrier mother (11-3) is derived were calculated using Haldane's mapping function, from her father, probably as a new mutation during which converts recombination fractions to genetic dis- spermatogenesis. II-3 has donated the main part ofher tances in centiMorgans. The frequency of the Menkes Menkes X chromosome to her Menkes boy. Further- gene in the general population was taken to be .0001, more, she has given most of the Menkes X chromo- and the published RFLP allele frequencies were used. some to her Menkes daughter (III-4). The daughter 1014 Tonnesen et al. Table 2 Lod Score Results of Pairwise Linkage Analyses for I I Different Markers. LOD SCORE AT RECOMBINATION FRACTION OF MAXIMUM MAXIMUM 95% DNA LOD RECOMBINATION CONFIDENCE MARKER .00 .001 .01 .05 .1 .2 .3 .4 SCORE FRACTION LIMITS L754 ...... - 2.27 -1.28 -.62 -.36 -.15 -.05 -.01 .00 .50 .02-.50 pTAK-8 ..... 3.16 3.15 3.10 2.87 2.56 1.91 1.20 .49 3.16 .00 .00-.16 p58-1 . - 3.65 - 1.67 -.39 .06 .32 .30 .17 .33 .24 .03-.50 p-8 ....... 3.44 3.44 3.38 3.12 2.78 2.07 1.33 .61 3.44 .00 .00-.15 cpX289 ......... -.95 .05 .71 .88 .79 .51 .21 .89 .12 .01-.50 cpX203 ......... - 2.15 - 1.16 -.50 -.26 -.08 -.02 -.01 .00 .50 .02-.50 pSPT19-1 ... 2.48 2.48 2.44 2.26 2.03 1.53 .98 .42 2.48 .00 .00-.21 pDP34 .......- - 7.63 - 3.80 - 1.21 -.28 .31 .34 .15 .36 .25 .08-.50 p19-2....... 2.90 2.90 2.85 2.62 2.32 1.68 .99 .33 2.90 .00 .00-.17 pXG-12 ......... - 4.59 - 1.90 -.06 .53 .79 .62 .29 .79 .20 .04-.50 pXG-17 ......... - 6.45 - 3.48 - 1.51 -.78 -.22 -.05 -.01 .00 .50 .08-50 111-1 has received the intact Menkes X chromosome 3), the most likely localization of the Menkes locus is from her mother and should be a carrier of this trait.
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