What are causes of hereditary protein S deficiency?

Updated: Jan 03, 2021
  • Author: Mohammad Muhsin Chisti, MD, FACP; Chief Editor: Perumal Thiagarajan, MD  more...
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Answer

Researchers have identified 2 genes for human protein S; both are linked closely on chromosome 3p11.1-3q11.2. [22]  One gene is the active gene, PROS-α (ie, PROS1), and the other, PROS-β, is an evolutionarily duplicated nonfunctional gene, which is classified as a pseudogene because it contains multiple coding errors (eg, frameshifts, stop codons). [23]  The expressed (alpha) PROS1 gene is more than 80 kb long and contains 15 exons and 14 introns. The protein S pseudogene (beta) has 97% homology to the PROS-α gene. [24]  Molecular studies into the genetic causes of protein S deficiency are complicated by the presence of the pseudogene, PROS-β, and phenotypic variation.

Over 200 mutations in PROS1 have been identified as causes of protein S deficiency and thrombophilia. Most are point mutations, such as transversion mutations that generate a premature stop codon and thus result in a truncated protein S molecule. [25, 26, 27] A missense mutation in exon 7 of PROS1 in which glycine is replaced with arginine has been reported in a Chinese family. In addition, deletions of large portions of the PROS1 gene have been reported. Researchers located the first such deletion in the central portion of the gene. [28]  The second deletion described (5.3 kb) was a deletion of coding exon 13, which resulted in a truncated protein product. [29]


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