X-LINKED SIDEROBLASTIC ANEMIA DUE TO A MUTATION IN THE ERYTHROID 5-AMINOLEVULINATE SYNTHASE GENE LEADING TO AN ARGININE(170) TO LEUCINE SUBSTITUTION

DNA sequencing of the coding region of the erythroid 5-aminolaevulinat e synthase (ALAS2) cDNA from a male with pyridoxine-responsive siderob lastic anaemia revealed a missense mutation, a G561T transversion in e xon 5 of the gene. Previously, the mutation G561A has been shown to be responsible for sideroblastic anaemia in females and thought to be le thal in males (1). The mutation G561T results in the loss of an MspA1- I cutting site. Analysis of MspA1-I restriction enzyme digests of ampl ified exon 5 genomic DNA from other family members revealed that the p roband's mother, aunt and youngest sister, who were not anaemic, were heterozygous carriers of the mutation. The G561T mutation results in a n arginine to leucine substitution at amino acid residue 170. This arg inine residue is conserved in both the erythroid and housekeeping ALAS in vertebrates as well as in all other known ALAS proteins and is loc ated in a predicted alpha-helix region close to the amino-terminus of the enzymatic region of the protein.