Two patients with protein S deficiency and cerebral venous sinus thrombosis: nonsense mutations of the PROS1 gene may account for these deficiencies

Cerebral venous sinus thrombosis (CVST) is a rare and atypical thrombotic condition, particularly prevalent among young adults, with a complex cause. In July and October 2023, two patients were diagnosed with hereditary protein S deficiency (PSD) presenting with CVST at the Department of Neurology, the first affiliated hospital of Wenzhou Medical University. This study analysed the phenotypes and gene mutations in two hereditary PSD pedigrees to investigate the link between hereditary PSD and CVST. A total of 11 individuals from these two pedigrees were involved. We measured protein S activity (PS:A) and total protein S antigen (TPS:Ag), and free protein S antigen (FPS:Ag) for all participants, screened them for mutations in the protein S1 ( PROS1 ) gene. Both probands with CVST were diagnosed at a young to middle age. The concurrent reductions in PS:A, TPS:Ag, and FPS:Ag levels observed in the probands and their family members (A-I 2 , A-II 1 , A-II 2 , A-II 3 , A-III 1 , A-III 2 , B-I 2 ) indicate type I PSD. Gene analysis unveiled two heterozygous nonsense mutations, c.1687C>T (p. Gln563∗) and c.1680T>A (p. Tyr560∗), in exon 14 of the PROS1 gene for pedigrees A and B, respectively. The reduced protein S levels in the probands and their relatives, along with CVST in both probands, are all linked to nonsense mutations p. Gln563∗ and p. Tyr560∗ in the PROS1 gene.