Hemoglobin Philly ( p 35 Tyrosine Phenylalanine ) : Studies in

Received for publication 24 January 1969. INTRODUCTION The severity of the clinical manifestations of the different abnormal hemoglobins is varied. Many of these mutant proteins produce no discernible effect on the patient, while some cause a mild compensated hemolysis, and others are associated with severe hemolytic disease (1). The detection of an abnormal hemoglobin in many patients presenting with clinical states within this spectrum has frequently been straightforward. Since the demonstration of hemoglobin S (2), the widespread use of electrophoresis has resulted in the discovery of over 100 mutant forms of human hemoglobin (3). Recently it has become evident that a proportion of patients with hereditary nonspherocytic hemolytic disease of the Heinz body type possess an abnormal unstable hemoglobin (4). In several instances the electrophoretic or chromatographic separation of a variant protein from hemoglobin A has been difficult or only partially successful (3). Where complete chemical analyses have been performed, several of the mutations have been shown to consist of amino acid substitutions involving no change in charge or occurring in the interior of the hemoglobin molecule, so that surface charge and electrophoretic mobility are unaffected (3). The present report describes a hemoglobinopathy which was discovered in three members of a family, each of whom had evidence of a chronic hemolytic state. The demonstration of a mutant hemoglobin was hampered by the inability to separate a variant protein from hemoglobin A by any of the usual methods of electrophoresis or chromatography. Proof of the presence of hemoglobin Philly, and its isolation and purification, depended upon a unique property of this new abnormal hemoglobin. The properties of hemoglobin Philly have provided an explanation for the pathophysiologic state of the affected The Journal of Clinical Investigation Volume 48 1969 1627 patients. The structural defect of the abnormal hemoglobin has provided information on the importance of one interchain bond in the maintenance of the structural integrity of the normal hemoglobin molecule.