Steroid 21-hydroxylase deficiency is caused by a defect in the CYP21A2
gene. CYP21A2, the adjacent complement C4 gene and parts of the flanking
genes RP1 and TNXB constitute a tandemly duplicated arrangement in the
central (class III) region of the major histocompatibility complex. The
typical number of repeats of the CYP21/C4 region is two, with one repeat
carrying CYP21A2 and the other carrying the highly homologous pseudogene
CYP21A1P. By comparison with this standard, three categories of CYP21A2
defects have traditionally been distinguished: CYP21A2 deletions,
large-scale gene conversions of CYP21A2 into a structure similar to
CYP21A1P, and smaller mutations in CYP21A2 (also derived from CYP21A1P, by
means of small-scale gene conversions). The genetic mechanisms suggested
by these designations have originally been inferred from the layout of the
haplotypes involved and were later confirmed by observation of deletions
and small mutations, but not large-scale conversions, as de novo events.
Apparent large-scale conversions account for the defect in 9 out of 77
chromosomes in our patient group. We here demonstrate that 4 out of these
9 'conversions' extend into the flanking TNXB gene, which encodes
tenascin-X. This implies that approximately 1 in every 10 steroid
21-hydroxylase deficiency patients is a carrier of tenascin-X deficiency,
which is associated with a recessive form of the Ehlers-Danlos syndrome.
Currently available data on the structure of 'deletion' and 'large-scale
conversion' chromosomes strongly suggests that both are the result of the
same mechanism, namely unequal meiotic crossover. Since it is unlikely
that the term 'large-scale gene conversion' describes a mechanism that
actually occurs between the CYP21A2 and CYP21A1P genes, we propose the
discontinuation of that terminology
