Eight disorders of the immune system have been described which
are inherited as X-linked recessive conditions. The aim of this study
has been to improve predictive testing in X-linked agammaglobulinaemia
(XLA) and X-linked severe combined immunodeficiency (XSCID) and to
investigate the underlying defect in XSCID.
Precise genetic localisation is essential for accurate predictive
testing and in order to develop strategies to clone the genes. Before
disease localisation can be improved it is necessary to clarify the
order of a number of probes within the region of interest. Fourteen
genetic markers assigned to the X chromosome between the
pericentromeric region and Xq22 were ordered by family studies and
deletion mapping. Pulsed field gel electrophoresis was used to make a
physical map of the markers linked to XLA.
Knowledge of the order of these anonymous DNA probes led to
finding addditional linked probes for both diseases. This makes
predictive testing possible in more families.
There are X-linked and autosomal recessive forms of severe
combined immunodeficiency. This has caused difficulties in counselling
couples who have an affected male child and where there is no previous
family history of the disease. In this study it has been shown that
female carriers of the X-linked disorder have non-random use of the X
chromosome in T lymphocytes. This provides a means of distinguishing
between the autosomal and X-linked forms which enables more accurate
XSCID has been mapped to Xqll-ql3 using DNA markers which detect
polymorphic variation (de Saint Basile et al, 1987). No recombinations
have been observed between the disease locus and the anonymous DNA
probe cpX289. In this study the PGK1 locus was also shown to be
closely linked to the disease. Using both of these linked markers
predictive tests can be offered to 65% of families.
The probe pSPT/PGK which detects a polymorphism at the PGK1 locus
can also be used to investigate X chromosome usage. In females who are
heterozygous for the polymorphism detected by this probe, carrier
detection and assignment of phase can be carried out in the same
procedure. This is a unique situation and is particularly useful when
the proband could carry a new mutation or when there are no males
available who can be used to assign linkage phase.
It has been thought that XSCID results from a defect in a T
lymphocyte specific gene because the phenotype is predominantly a lack
of T lymphocytes and because host B lymphocytes produce functional
antibody following transplantation and engraftment of T lymphocytes.
Finding a non-random pattern of X chromosome usage in a mature cell
population implies that the defective gene is expressed in that cell
type and this technique was used to investigate gene expression. Nonrandom
X chromosome usage was found in T lymphocytes, B lymphocytes,
monocytes and granulocytes. The pattern of expression suggests that
the underlying defect in XSCID is in a general metabolic pathway
rather than a pathway specific to lymphocytes.