A son and daughter of unaffected parents had transfusion dependent, pyridoxine-refractory sideroblastic anaemia from birth. Their haemoglobin levels were 4.3 and 6.4 g/dl, respectively. delta-Aminolaevulinate synthase activity in erythroblasts from fractionated marrow of the sister was 135 pmol delta-aminolaevulinate formed/10(6) erythroblasts/hour (normal range = 110-650 pmol). While mutations of the erythroid-specific delta-aminolaevulinate synthase gene (ALAS2) at Xp11.21 have been reported in patients with X linked sideroblastic anaemia, sequence analysis of the ALAS2 gene in the son did not identify any mutations in the coding region, the intron/exon boundaries, or the 1 kb 5' promoter region. A useful polymorphism was found in the 3' region of the ALAS2 gene, a G to A transition, 220 nt 3' of the AATAAA polyadenylation signal. Mismatch PCR at this site and subsequent discrimination by XmnI restriction analysis of 148 alleles identified the gene frequency of this polymorphism to be 25%. Analysis of the inheritance of this intragenic polymorphism showed that the affected sibs received different maternal alleles at the ALAS2 locus, excluding mutations in this gene as the cause of their sideroblastic anaemia. Furthermore, the absence of a dimorphic erythrocyte population in the mother, coupled with the demonstration of random X inactivation in her peripheral leucocytes, showed that the mother was not the carrier of any X linked sideroblastic anaemia mutation. These results strongly suggest that the sideroblastic anaemia in this family is an autosomal recessive trait.
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