X-LINKED LIVER PHOSPHORYLASE-KINASE DEFICIENCY IS ASSOCIATED WITH MUTATIONS IN THE HUMAN LIVER PHOSPHORYLASE-KINASE ALPHA-SUBUNIT

Two Dutch patients with liver phosphorylase kinase (PhK) deficiency we re studied for abnormalities in the PhK liver alpha (alpha L) subunit mRNA by reversed-transcribed-PCR (RT-PCR) and RNase protection assays. One patient, belonging to a large Dutch family that expresses X-linke d liver PhK deficiency, had a C3614T mutation in the PhK alpha(L) codi ng sequence. The C3614T mutation leads to replacement of proline 1205 with leucine, which changes the composition of an amino acid region, c ontaining amino acids 1195-1214 of the PhK alpha(L) subunit, that is h ighly conserved in different species. The patient showed normal levels of PhK alpha(L) mRNA. The second patient, from an unrelated family, w as found to have a TCT (bp 419-421) deletion in the PhK alpha(L) codin g sequence, resulting in a phenylalanine 141 deletion. The same deleti on was found in the PhK alpha(L) coding sequence from lymphocytes of t he patient's mother, together with a normal PhK alpha(L) coding sequen ce. The phenylalanine that is absent in the PhK alpha(L) coding sequen ce of the second patient is a highly conserved amino acid between spec ies. Both the C3614T mutation and the TCT (bp 419-421) deletion were n ot found in a panel of 80 control X chromosomes. On the basis of these results, it is postulated that the mutations found are responsible fo r liver PhK deficiency in the two patients investigated.