Peter Wieacker

X-linked dominant Charcot-Marie-Tooth disease: Suggestion of linkage with a cloned DNA sequence from the proximal Xq

SummaryA large kindred with the X-linked dominant form of peroneal muscular atrophy (Charcot-Marie-Tooth disease) was analyzed for individual variation in the length of DNA fragments after restriction endonuclease digestion. A systematic search was performed for linkage with a series of cloned single-copy DNA sequences of known regional assignment to the human X chromosome. Close linkage was found with the pDP34 probe (DXYS1 locus, Xq13-q21), suggesting that the gene responsible for the disease is located on the proximal long arm of the X chromosome.

X-linked retinitis pigmentosa: linkage with the centromere and a cloned DNA sequence from the proximal short arm of the X chromosome

SummaryA large Danish pedigree segregating for X-linked retinitis pigmentosa (RPX) (Warburg and Simonsen 1968) was restudied for linkage analysis. Using two markers, i.e. the DNA base sequence polymorphism presented by the probe L1.28 defining the chromosomal segment DXS7, and the C-banding heteromorphism (Xcen) (Friedrich 1982), we were able to localize the RPX gene in Xp close to the centromere rather precisely. The gene order could be deduced by three-point linkage analysis, and the gene distances were determined by pairwise analysis using the LIPED program (Ott 1974). Together with previously published data concerning the RPX:DXS7 linkage (Bhattacharya et al. 1984) a regional gene map is constructed. Xcen-11 cM-RPX-6 cM-DXS7.

Linkage analysis with RFLPs in families with androgen resistance syndromes: evidence for close linkage between the androgen receptor locus and the DXS1 segment

SummaryThree families with androgen resistance syndromes — two with testicular feminization and one with Reifenstein syndrome — have been studied for linkage analysis. Using three cloned DNA sequences from the centromere region and the proximal long arm of the X chromosome (p8, pDP34, and S9, which define respectively the chromosomal segments DXS1, DXYS1, and DXS17), we found no recombination between the DXS1 locus and the mutant genes in the three families. Assuming that these disorders are the result of allelic mutations at the same locus for the androgen receptor, we can conclude that there is a close linkage between DXS1 and the androgen receptor locus, with a maximum lod score ž=3.5 at a recombination fraction θ=0.0 using the LIPED program (Ott 1974).

Pathophysiology of Polyhydramnios in Twin Transfusion Syndrome

In 3 cases of severe twin transfusion syndrome we demonstrate that the concentration of atrial natriuretic factor (ANF) in the cord blood of recipient twins is significantly elevated compared to that of donor twins. The discrepancy between recipient and donor concentration correlates with the volume of transfusion. The following pathophysiological mechanism for explaining polyhydramnios in recipient twins is proposed: chronic overload in recipient twins causes enhanced release of ANF from the fetal heart. Consequently, increased fetal urine production leads to polyhydramnios, which is additionally enhanced by inhibition of ADH release.

Linkage relationships between retinoschisis, Xg, and a cloned DNA sequence from the distal short arm of the X chromosome

SummaryA cloned DNA sequence, RC8, from the short arm of the X chromosome which is linked to the Duchenne muscular dystrophy (DMD) gene has been employed to study linkage relationships with the Xg-linked retinoschisis (RS) locus. Results of three point linkage analyses in two families suggest that the gene order on Xp is Xg-RS-RC8. Moreover, it can be inferred from these data that the genetic distance between Xg and DMD is approximately 55 cM.

Menkes kinky hair disease: a search for closely linked restriction fragment length polymorphism

SummaryIn a large kindred with X-linked Menkes disease, linkage studies were performed with a restriction fragment length polymorphism (RFLP) that had been found with a cloned hybridisation probe from the proximal short arm of the X chromosome. This RFLP was considered as a potential genetic marker since the Menkes gene seems to be located near the centromere. Moreover, there is circumstantial evidence that in the (para) centric region of the X chromosome cross-overs are relatively rare. Unexpectedly, however, at least two cross-overs were detected in this family which suggests that the DNA sequence employed is of limited use for early diagnosis and carrier detection in this fatal hereditary disorder.

Linkage studies in a family with X-linked recessive ichthyosis employing a cloned DNA sequence from the distal short arm of the X chromosome

SummaryRecently linkage has been described between the Duchenne muscular dystrophy (DMD) gene and a cloned DNA sequence, RC8, that detects restriction fragment length polymorphism and is derived from the distal short arm of the X chromosome. Positive lod scores between RC8 and Xg prompted sulfatase-X-linked recessive ichthyosis (XRI) locus which is situated 15 cM proximal from Xg in the subtelomeric region of Xp. Unexpectedly, at least two crossovers were found among nine informative meioses of an informative family, suggesting that RC8 and XRI may be about 25 cM apart. This implies that the genetic distance between the Xg locus and the DMD locus may exced 50 cM.

Evidence that the Menkes locus maps on proximal Xp

There is now convincing evidence that the gene defect responsible for X-linked Menkes kinky hair disease is located near Xcen, as shown by linkage to a centromeric C-banding polymorphism (Horn et al., to be published) and to a restriction fragment length polymorphism (RFLP) defined by a cloned DNA sequence, L1.28, from the proximal short arm of the X chromosome (Wieacker et al. 1983). The precise location of the Menkes gene locus relative to the centromere has not yet been defined, but there is reason to believe that it maps in the vicinity of the PGK gene on proximal Xq (see Wieacker et al. 1983). By using another cloned DNA probe, MGU22, which is located below L1.28 in the Xcen-Xq12 segment, we have now detected a HindIII RFLP in a family with Menkes disease which had been studied previously for linkage with the L 1.28 sequence. Unexpectedly our data indicate that MGU22 may be more closely linked to L 1.28 than to the Menkes locus (MS) (~ = 1.10 at 0 = 0.13 versus ~ = 0.024 at 0 = 0.45). For L 1.28 and MS, lod scores reach their maximum (2 = 0.82) at a recombination fraction of t) = 0.16 (Wieacker et al. 1983). Analysis of individual recombination events (Fig. 1) reveals that of the three possible gene orders (Xpter-L 1.28MGU 22-MS; Xpter-L 1.28-MS-MGU 22; and Xpter-MSL1.28-MGU 22) the last-mentioned is the most probable because it can explain the observed genotypes as the result of three single crossovers. In contrast, each of the two other gene orders would require a double crossover and two single crossovers between the respective external genetic markers. The likelihood of the pedigree has been calculated (a) for each of the three possible gene orders and (b) for each combination of recombination fractions between the three loci. Since only two of these distances can vary independently, a likelihood surface is obtained for each gene order which covers the area between orthogonal axes that define these distances (see Renwick and Bolling 1971; and Sturt 1975). This is illustrat-

On the genetic length of the short arm of the human X chromosome

SummaryPublished estimates of the length of the human X chromosome are unreliable because they are based on scanty linkage data and complex assumptions about the frequency and distribution of chiasmata in female meiosis. In recent months we have established linkage between restriction fragment length polymorphisms (RFLPs) and several genes on the short arm of the X chromosome. These and previous data can be combined to construct a continuous linkage map spanning the short arm from the Xg gene to the centromere. They suggest that the genetic length of the Xg-Xcen segment may be in the order of 75–90 cM.