A91V perforin variation in healthy subjects and FHLH patients

Summary Familial haemophagocytic lymphohistiocytosis (FHLH) is a heterogeneous autosomal recessive disorder characterized by hyperactivation of monocytes/macrophages. Perforin (PRF1) gene alterations have been documented in 40% of patients with FHLH. Although several mutations have been identified, a clear correlation between the individual molecular alteration and the phenotypic expression of the disease is still unclear. In particular, the role that the A91V substitution plays in the pathogenesis of the disease is still controversial. In the effort to make a conclusive remark to this issue, we here report on the frequency of the A91V mutation in a group of unrelated healthy families obtained from the ‘Centre d’Etude du Polymorphisme Humain’ (CEPH), which are considered representative of the worldwide population. This frequency was compared to that observed in FHLH patients recruited through the Italian National Registry. The frequency in CEPH healthy subjects is 3.7%, thus indicating that the alteration represents a polymorphism. However, the frequency of this alteration in FHLH patients associated with PRF1 mutation is much higher than that observed in controls (26.2%, P = 0.0002), suggesting that the alteration is an important genetic susceptibility factor.