Kwan et al. (1986) were the first to produce data from which the X LA gene could be assigned to a region of the X-chromosome. They showed a localisation to the proximal long arm of the X-chromosome by showing linkage to the DXS3 (Z = 3.65 at 6 = 0.04) and DXS17 (Z = 2.17 at 0 = 0) loci. They also excluded a location on the
short arm of the X-chromosome. Mensink et al. (1986) also showed linkage of the X LA
locus to the DXS3 locus in one extended XLA pedigree (Z = 3.30 at ^ = 0.06). Since this time the identification of new families in which the disease is segregating, the identification of new RFLP loci and the improved mapping and ordering of these loci has
lead to greater and greater refinement of the X LA locus. In 1987, Malcolm et a l (1987) reported linkage to a further marker and confirmed the findings of previous linkage studies. Linkage to DXS17 (Z = 4.44 at 0 = 0), DXS94 (Z = 6.65 at 0 = 0) and DXS3 (Z = 3.63 at ^ = 0.06) was shown. A recombination between the disease locus and the DXS3 locus was identified, excluding this marker from the X L A locus, although it was closely linked. In a large linkage study of the long arm of the X-chromosome using 44 pedigrees, an order for the loci identified as being linked to the X L A locus was determined (Arveiler et a l. , 1987). This study indicated that the most likely order of loci
in the region was: cen-DXS3-DXS94-DXS17-tel. In addition, another locus was
identified as lying in the X L A candidate region, DXS178, showed close linkage to the DXS94 locus (Z = 10.31 at 0 = 0) (Arveiler et aL, 1987). Linkage studies using the
DXS178 marker (Guioli et at., 1989; Kwan et aL, 1990) showed it to have no
recombinations with the disease locus in over 40 informative meioses and a combined two point LOD score of Z = 14.48 at 0 = 0 showed it to be very tightly linked to the XLA locus. In addition, the study by Kwan et at. (1990) identified crossovers between the DXS94 and DXS17 loci and the XLA locus placing these as the distal flanking markers of the X LA locus. A genetic map of the region was produced with positions being as follows: cen- DXS3-6.5cM-(DXS178, XLA)-5cM-DXS94-3.5cM-DXS17-tel.
At around this time several new markers were isolated which mapped to the area of interest for X LA (Dietz-band et aL, 1990; Barker et aL, 1991). Dietz-band et aL (1990) identified five new markers mapping to the Xq21.2-q22 interval. Three of these (DXS265, DXS327, DXS328) were placed in the same interval as the DXS178 and DXS94 loci, and so close to the X LA locus, by Barker et aL (1991), and two additional new loci (DXS366 and DXS442) (Barker et aL, 1991) also mapped to this interval. In addition, the Mspl polymorphism associated with the D X S lO l locus was also mapped in the region of the X LA locus (Barker et aL, 1991). The D X S lO l specific probe had not been used extensively in genetic linkage analyses as it recognises at least five distinct species, all mapping to the same region of the X-chromosome (Hofker et aL, 1987).
A preliminary mapping study (Kwan et aL, 1991) found no recombinations
between the X L A locus and any of the DXS265, DXS327, DXS366 and DXS442 loci in nine X LA pedigrees, this confirmed the placement of these loci in the region of the X LA locus. Close linkage was identified between the DXS265 locus and the X LA locus with
no recombinations in 13 informative meioses (Z = 4.14 at 0 = 0).
Most recently two linkage studies have resulted in the identification of new proximal and distal flanking markers for the X LA locus (Parolini et aL, 1993; Lovering et aL, 1993a). Both studies identified crossovers between the DXS366 and DXS442 loci and the disease locus allowing these to replace DXS3 as the new proximal flanking markers of the X L A locus. A crossover between DXS366 and DXS442 (Barker et al. , 1991) placed DXS366 proximal to DXS442 and thus DXS442 became the proximal flanking marker of the X LA locus. A crossover was also identified between the Mspl polymorphism at the DXSlO l locus and the XLA locus (Lovering et aL, 1993a). This placed the copy of the D XSlO l locus associated with the Mspl polymorphism distal to the X L A locus and thus this became the new distal flanking marker for the X L A locus. Neither study found any recombinations between the DXS178 or DXS265 loci and the
disease locus. There have now been no crossovers between the D X S 178 locus and
the disease locus in over 70 informative meioses and the cumulative two point LOD score is now in excess of 30.
1 .3 .2 .1 .2 Genetic heterogeneity of XLA
X LA families have been reported in whom genetic linkage data was not consistent with a mutation in the Xq22 region of the X-chromosome. This suggested the possibility of a second X LA gene. In one such pedigree (Ott et aL, 1986; Mensink et aL, 1986) two sisters were identified who each had affected sons, and in whom RFLP analysis was not consistent with a mutation in Xq22. Further analysis revealed that the sisters had received a defective X-chromosome from their asymptomatic father. The father was therefore an X-chromosome mosaic, his B cells contained a normal X-chromosome, but his spermatocytes contained a defective gene. When the linkage analysis was repeated taking into account this paternal mode of inheritance the results did not exclude a mutation in Xq22 (Hendricks et aL, 1989).
Mutations arising in the germline of the grandfathers of affected individuals appear to account for a significant proportion of new X L A mutations (Lau et aL, 1988).
Recently there has been a report of females with a phenotype that is identical to
X LA (Conley and Sweinberg, 1992). As these females do not have translocations
suggested that there may be a second gene which causes an X L A type phenotype that is located on an autosome. Mutations in this putative second gene may be responsible for 5-10% of agammaglobulinemia patients (Conley and Sweinberg, 1992).
1 .3 .2 .1 .3 Chromosomal abnormalities
No X LA patients have been detected who have cytogenetically detectable