title: Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis.
abstract: Familial haemophagocytic lymphohistiocytosis (FHL), an inherited form of haemophagocytic lymphohistiocytosis (HLH) syndrome, is characterized by the overwhelming activation of T lymphocytes and macrophages invariably leading to death in the absence of treatment. FHL is a heterogeneous autosomal recessive disorder, with one known causative gene which codes for perforin, a cytotoxic effector protein. In this study, we have characterized the genotype and phenotype of 14 unrelated families with perforin deficiency. Four new missense mutations of the perforin gene were identified. In every case, perforin gene mutations led to undetectable intracellular perforin expression within cytotoxic cells, while some residual T-cell cytotoxic activity could be associated with certain missense mutations. Clinical and biological analyses did not differentiate between patients with nonsense or missense mutations, although age at diagnosis, which tended to be similar within members of the same family, was delayed in patients from two families belonging to the second group. In one case, consequences of perforin deficiency, diagnosed at birth, could be assessed prior to onset of clinical manifestations. No evidence for T-cell activation could be shown, suggesting that an exogenous event is required to trigger the disease manifestation. Control assessment of perforin expression and cytotoxic assays by lymphocytes from young children led to the conclusion that perforin content of natural killer cells could be a reliable diagnostic test at any age. Altogether, these data enabled a better characterization of perforin deficiency and its consequences, and defined reliable diagnostic tools.
authors.affiliation: Unité de Recherche sur le développement normal et pathologique du système immunitaire, INSERM U429, Hôpital Necker-Enfants Malades, 149 rue de Sevres, 75743 Paris cedex 15, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Feldmann
authors.forename: Françoise
authors.initials: F
authors.lastname: Le Deist
authors.forename: Marie
authors.initials: M
authors.lastname: Ouachée-Chardin
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Certain
authors.forename: Sarah
authors.initials: S
authors.lastname: Alexander
authors.forename: Pierre
authors.initials: P
authors.lastname: Quartier
authors.forename: Elie
authors.initials: E
authors.lastname: Haddad
authors.forename: Nico
authors.initials: N
authors.lastname: Wulffraat
authors.forename: Jean Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanche
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint Basile
mesh_terms: D018389:Codon, Nonsense; D005260:Female; D005455:Fluorescent Antibody Technique; D005838:Genotype; D015616:Histiocytosis, Non-Langerhans-Cell / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007694:Killer Cells, Natural / Q000737:chemistry; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000172:deficiency / Q000235:genetics*; D020125:Mutation, Missense; D054353:Perforin; D010641:Phenotype; D052899:Pore Forming Cytotoxic Proteins
chemical_list: D018389:Codon, Nonsense; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin