High frequency of the TARDBP p.Ala382Thr mutation in Sardinian patients with amyotrophic lateral sclerosis.

Recently, rare mutations in the TARDBP gene have been identified in familial and sporadic amyotrophic lateral sclerosis (ALS) patients. The purpose of this study was to characterize the genetic variability of the TARDBP gene in a cohort of Sardinian ALS patients. The coding region of the gene was analyzed in 97 unrelated patients previously tested negative for superoxide dismutase (SOD1) mutations. The p.Ala382Thr (c.1144G>A) mutation was found in 30 patients (30.9%). The mutation was predominant in familial ALS patients (FALS) as it was represented in 24 of 30 FALS cases (80%) (p < 0.0003). Six cases were apparently sporadic (9% of sporadic ALS patients). No further mutation of TARDBP was found in our cohort of ALS patients. Patients carrying the mutation showed spinal site of onset in 24 cases (80%), an average age at onset of 54.7 ± 11.1 years, not significantly different from patients not harboring TARDBP mutations (56.7 ± 9.6) and a female:male gender ratio of 1:1.1. The haplotype analysis carried out using eight microsatellite markers flanking the gene showed a founder effect for this mutation. Finally, we estimated the age-specific penetrance of the TARDBP p.Ala382Thr mutation in an additional sample of 47 carriers (20 affected and 27 unaffected). The average penetrance to 70 years was 60% (95% confidence interval 41-79%). A trend toward a higher penetrance in males was observed. Even in the presence of a causal mutation, most of the ALS clinical heterogeneity, however, draws upon from a multifactorial context.

The role of killer immunoglobulin-like receptor haplotypes on the outcome of unrelated donor haematopoietic SCT for thalassaemia.

Recent insight into the pathophysiology of acute GVHD after allogeneic haematopoietic SCT has led to a growing interest in the role of natural killer (NK) cells. NK cell cytotoxicity is mainly regulated by the interaction of activating and inhibitory killer immunoglobulin-like receptors (KIRs) with their respective ligands. To investigate the impact of KIRs and their ligands on haematopoietic SCT outcome, we performed a retrospective study of 78 transfusion-dependent thalassaemia patients (median age 10 years, range 1-29 years) transplanted from an unrelated donor selected using high-resolution molecular typing for both class I and II loci after a myeloablative conditioning regimen. GVHD prophylaxis consisted of CsA, short-term MTX and anti-thymocyte globulin in all patients. We found that patients transplanted from donors homozygous for KIR haplotype A had a greater risk of developing grade II-IV acute GVHD compared with those transplanted from a donor carrying at least one B haplotype (hazard ratio=4.5, 99% confidence interval=1.2-17.1, P=0.003). Our study suggests that KIR genotyping of donor and recipient pairs could contribute to the identification of patients at high risk for developing severe complications of haematopoietic SCT and thus may help with the choice of intensity of GVHD prophylaxis.