GERMLINE MOSAICISM FOR AN ALANINE TO VALINE SUBSTITUTION AT RESIDUE-BETA-140 IN HEMOGLOBIN PUTTELANGE, A NEW VARIANT WITH HIGH OXYGEN-AFFINITY

Hb Puttelange [beta 140(H18)Ala-->Val] was found as a de novo mutation in two siblings of a French family suffering from polycythemia. Both parents were phenotypically normal and exclusion of paternity has been ruled out by the study of several polymorphic markers located on diff erent chromosomes. The structural modification of Hb Puttelange was es tablished by reversed-phase HPLC analysis of the tryptic digest of the abnormal chain. The amino acid composition of an abnormal beta T14 pe ptide revealed that one of the four residues of Ala was replaced by a Val. Tandem mass spectrometry demonstrated that the substitution conce rned position beta 140 (H18). This hemoglobin displays an increased ox ygen affinity that is responsible for the polycythemia. De novo mutati ons, as demonstrated again in the case of this variant, have the highe st probabilities of detection when they lead to pathological manifesta tions. They may result either from a somatic mutation in a very early stage of the embryological development of the propositus or may have a parental origin with occurrence of a germline mosaicism. The study of the beta-globin gene indicated that this case of Hb Puttelange probab ly arose from a mutation affecting a part of the germline of the fathe r, therefore leading to a true recurrence risk.