ALBERT

Description: Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive immune dysregulation disorder associated with Perforin, Munc13-4 and Syntaxin 11 genes. The mutations in the Perforin gene are the most common cause of the disease. Among these mutations, the role of the Alanin91Valin (A91V) alteration in the pathogenesis of the disease has long been controversial. Even though this alteration can be considered as a polymorphism based on its high frequency in normal population (〉3.7%) and homozygous existence in some healthy individuals, it is also considered as a genetic risk factor depending on its much higher frequency observed in FHL patients (22.7%) and compound heterozygous existence with other disease causing mutations in the Perforin gene in some FHL patients. Contrary to the previous publications concerning with the co-existence of heterozygous A91V with homozygous mutations in other described FHL genes, there has been no reports on homozygous co-existence of A91V up until this communication where we present the interesting results of a study which shed light not only on the role of A91V in development of FHL, but also on the etiopathogenesis of genetic diseases in general. The subject of the study was a 12 year old female patient who was a product of a first degree consanguineous marriage. Initial diagnosis was lymphomatoid granulomatosis due to the presence of symptoms associated solely with central nervous system. The correct diagnosis could be made 1 year later upon development of systemic findings of FHL. There was no history of similar disorder in the family. Linkage analysis in the family revealed homozygosity for both Perforin and Munc13-4 genes in the patient and for only Munc13-4 gene in one of the asymptomatic sibling who was heterozygous for Perforin gene. Syntaxin 11 gene was excluded in this analysis. Detected merely in the patient was a homozygous A91V substitution (272C〉T) in the sequencing of the Perforin gene. Sequencing of the complete coding (32 exons) and the flanking sequences, on the other hand, led to the identification of a homozygous three nucleotide in-frame deletion (2135-2137delTCG) in exon 23 of Munc13-4 gene. This novel mutation resulted in the replacement of nonpolar two aminoacids (Ile-Gly) at positions 712-713 with a polar single aminoacid (Ser). It is plausible that the substitution of highly conserved two aminoacids, especially one (Ile) playing important role in the stability of proteins, with a hydrophilic one would alter the three dimensional structure and the stability of the protein, and would lead to FHL. Ironically, however, an asymptomatic sibling who is currently 22 year old was also homozygous for the mutation. This finding led to the assumption that the Munc13-4 mutation alone may not be sufficient for the development of the disease, but may be a genetic risk factor requiring co-existence of additional homozygous genetic risk factor situated in another FHL gene. If this is the case, it is reasonable to state that homozigosity for A91V in Perforin as well as homozygosity for the 2135-2137del mutation in Munc13-4 is a strong genetic susceptibility factor contributing significantly to the pathogenesis of the disease when they are co-existed. However, this notion could be valid as long as the sibling with homozygous Munc13-4 mutation stays asymptomatic. On the other hand, late onset and atypical presentation in the propositus may indicate that the homozygous co-existence of both alterations is not associated with serious clinical course of the disease as far as the presenting age of the disease is concerned.