Germline mosaicism for an alanine to valine substitution at residue ? 140 in hemoglobin Puttelange, a new variant with high oxygen affinity

Abstract

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 different chromosomes. The structural modification of Hb Puttelange was established by reversed-phase HPLC analysis of the tryptic digest of the abnormal chain. The amino acid composition of an abnormal beta T14 peptide revealed that one of the four residues of Ala was replaced by a Val. Tandem mass spectrometry demonstrated that the substitution concerned position beta 140 (H18). This hemoglobin displays an increased oxygen affinity that is responsible for the polycythemia. De novo mutations, as demonstrated again in the case of this variant, have the highest probabilities of detection when they lead to pathological manifestations. 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 probably arose from a mutation affecting a part of the germline of the father, therefore leading to a true recurrence risk.

A Novel Hemoglobin Variant Found on the α1 Chain: Hb KSVGH (HBA1: p.Lys57_Gly58insSerHisGlySerAlaGlnValLys)

“…The first example of a Hb variant causing erythrocytemia was reported in 1966 (14). Currently, more than 200 articles related to Hb variants with increased oxygen affinity have been published (14)(15)(16)(17)(18)(19)(20)(21)(22)(23). We confirmed that the Hb KSVGH patient has PV due to the high WBC and PLT, and low EPO values.…”

Two new unstable haemoglobins leading to chronic haemolytic anaemia: Hb Caruaru [β122 (GH5) Phe→Ser], a probable case of germ line mutation, and Hb Olinda [β22 (B4) ‐ 25 (B7)], a deletion of a 12 base‐pair sequence

“…To our knowledge, there is only one previously reported case of germ line mosaicism that affects globin genes. Haemoglobin Punttelange [β140 Ala→Val] was found as a de novo mutation in two French siblings suffering from polycythemia, of which both parents were phenotypically normal and had no detectable alterations in the β‐genes (15). In this case, the mutation seemed to have arisen in the germ line cells of the father of the patients.…”

Hemoglobin Loves Park [β68 (E12) Leu→Phe]: Report of five cases including one originating from a de novo mutation

“…If this mutation occurred during meiosis process or as an early post-zygotic event in the proband the risk would be negligible. In contrast, the risk increases significantly if the mutation occurred during an early germ line mitotic division, and one of the parents is a germinal mosaic [22,23]. In theory, the maximum risk for future pregnancies after the birth of one affected child to unaffected parents is 4.8% [23].…”