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Protein S S460P (Heerlen) Mutation, Blood #83003


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This bulletin from the Mayo Clinic is a useful reminder that medical science is continually evolving, and even if research has highlighted a new understanding, something that is discovered later may render it inaccurate. The (now obsolete) test is still published on their web site. When we learn things about PSD from articles published on the web we should always be open minded about alternatives and avoid becoming overly reliant on our assumptions. From a scientists point of view this is not necessarily bad news, because it merely reflects a better understanding, and eliminating false conclusions is a useful contribution to furthering an end result.



Protein S S460P (Heerlen) Mutation, Blood





EXPLANATION: Early reports suggesting that Protein S S460P (Protein S Heerlen) was associated

with congenital type III protein S deficiency have subsequently been disproven. Consequently,

genotyping for this common Protein S polymorphism is of no clinical value, and Protein S S460P

(Heerlen) Mutation, Blood #83003 will become obsolete immediately.

QUESTIONS: Contact your Mayo Medical Laboratories’ Regional Manager

Kim J. Baker, Mayo Medical Laboratories’ Technologist Support

Telephone: 800-533-1710



Unit Code 83003:

Protein S S460P (Heerlen) Mutation, Blood

Useful For Suggests clinical disorders or settings where the test may be helpful

Among patients with Type III protein S deficiency, testing for protein S Heerlen is useful for establishing an inherited cause for protein S deficiency.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Protein S is a vitamin K-dependent plasma glycoprotein and a part of the natural anticoagulant system. Protein S acts as a necessary cofactor to activated protein C (APC) in the proteolytic inactivation of procoagulant factors Va and VIIIa. In human plasma, protein S forms an equimolar complex with a complement regulatory protein, C4b-binding protein (C4bBP). Of the total plasma protein S, approximately 60% circulates bound to C4bBP, while the remaining 40% circulates as "free" protein S. Only free protein S has an anticoagulant function. Plasma protein S levels vary widely in the normal population depending on age and sex.

Congenital protein S deficiency is an autosomal-dominant disorder that is present in 2% to 6% of patients with thrombosis. Heterozygous protein S carriers have approximately a 10-fold increased risk of thrombosis, particularly venous thromboembolism (VTE).(1)

Three types of protein S deficiency have been described according to the levels of total protein S antigen, free protein S antigen, and protein S activity in plasma.

Over 100 different mutations have been identified in the protein S alpha (PROS1) gene from more than 135 protein S deficient propositi.(2) Most are point mutations or short deletions/insertions scattered throughout the PROS1 coding regions and are associated with Type I protein S deficiency. In contrast, only 6 mutations have been identified in patients with Type II protein S deficiency. The molecular basis for Type III protein S deficiency is complex. To date, most of the mutations identified in Type III protein S deficiency have affected PROS1 regions encoding for the sex hormone binding globulin-like (SHBG) region, particularly exons XII and XIII.

Protein S Heerlen is characterized by a thymine (T) to cytosine © transition at base pair 67 in exon XIII of the PROS1 gene, encoding for a missense serine (S) 460 to proline (P) change (S460P).(3) The protein S S460P substitution results in loss of the N-linked glycosylation site at N458.(4) Protein S Heerlen is associated with a Type III protein S deficiency phenotype.(5) In 1 study, protein S Heerlen was present in 16 of 85 (18.8%) symptomatic patients with protein S deficiency, compared to 1 of 113 (0.8%) healthy subjects.(6) Compared to wild-type protein S, protein S Heerlen is a poor APC cofactor for inactivation of factor VaR506Q (Leiden), suggesting possible synergy between protein S Heerlen and Factor V Leiden in the pathogenesis of thrombosis (7).

Symptomatic homozygous protein S Heerlen patients, and heterozygous protein S Heerlen combined with another inherited thrombophilia (eg, factor V R506Q [Leiden] or prothrombin 20210G->A mutation), should be considered for lifelong oral anticoagulation. Asymptomatic protein S Heerlen family members should receive appropriate prophylaxis if exposed to additional VTE risk factors (eg, surgery, trauma, extended immobilization). Asymptomatic female protein S Heerlen carriers should receive counseling regarding the risks of VTE associated with oral contraceptive use, pregnancy and the postpartum period, and estrogen replacement therapy.

Measurement of free plasma protein S antigen should be performed as the initial testing for protein S deficiency (#83049 "Protein S Antigen, Plasma"). When the free protein S antigen level is below the age- and sex-adjusted reference range, testing for total plasma protein S is automatically performed.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.


Interpretation Provides information to assist in interpretation of the test results

The interpretive report will include specimen information, assay information, background information, and conclusions based on the test results (normal, heterozygous protein S460P, homozygous protein S460P).

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

This test should not be ordered as the initial test for protein S Type III deficiency.

This direct mutation analysis will not detect individuals with protein S deficiency caused by mechanisms other than the protein S Heerlen mutation.

On-site Thrombophilia Center, Special Coagulation Clinic/Laboratory, and/or Medical Genetics consultations are available for registered Mayo Clinic patients and may be especially helpful in complex cases or in situations where the diagnosis is atypical or uncertain. Phone consultations are available for Mayo Medical Laboratories clients.

Clinical Reference Provides recommendations for further in-depth reading of a clinical nature

1. De Stefano V, Finazzi G, Mannucci PM: Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood 1996 May 1;87(9):3531-3544

2. Gandrill S, Borgel D, Ireland H, et al: Protein S deficiency: a database of mutations. For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 1997 June;77(6):1201-1214

3. Bertina RM, Ploos van Amstel HK, van Wijngaarden A, et al: Heerlen polymorphism of protein S, an immunologic polymorphism due to dimorphism of residue 60. Blood 1990 August 1;76:538-548

4. Schwarz HP, Heeb MJ, Lottenberg R, et al: Familial protein S deficiency with a variant protein S molecule in plasma and platelets. Blood 1989 July;74(1):213-221

5. Espinosa-Parrilla Y, Navarro G, Morell M, et al: Homozygosity for the protein S Heerlen allele is associated with Type I PS deficiency in a thrombophilic pedigree with multiple risk factors. Thromb Haemost 2000 January;83(1):102-106

6. Duchemin J, Gandrille S, Borgel D, et al: The Ser 460 to Pro substitution of the protein S alpha (PROS1) gene is a frequent mutation associated with free protein S (type IIa) deficiency. Blood 1995 November 1;86(9):3436-3443

7. Giri TK, Yamazaki T, Sala N, et al: Deficient APC-cofactor activity of protein S Heerlen in degradation of factor Va Leiden: a possible mechanism of synergism between thrombophilic risk factors. Blood 2000 July 15;96(2): 523-531

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Venous thromboembolic risk and protein S deficiency: ethnic difference and remaining issues

Tong Yin,Toshiyuki Miyata.J Geriatr Cardiol 2009,6(1):11~19

Authors: Tong Yin1; Toshiyuki Miyata2

Author Affiliation:1.Institute of Geriatric Cardiology, General Hospital of People’s Liberation Army, Beijing 100853, China;2.National Cardiovascular Center Research Institute, Suita, Osaka, Japan

Abstract: Protein S deficiency is an autosomal dominant disorder that results from mutations in the protein S gene (PROS1). Inherited deficiency of protein S constitutes a risk factor for venous thromboembolism. Protein S functions as a nonenzymatic cofactor for activated protein C in the proteolytic degradation of coagulation factors Ⅴa and Ⅷa. The frequency of protein S deficiency seems to differ between populations. More than 200 rare mutations in PROS1 have been identified in patients with protein S deficiency. Among the prevalent mutations within PROS1, the S460P substitution (known as Heerlen polymorphism) detected in Caucasians and the K196E substitution (known as protein S Tokushima) found in Japanese have been intensively studied for their structures and potential functions in the disorder of protein S deficiency. Until now, causative mutations in PROS1 have been found in only approximately 50% of cases with protein S deficiency. Co-segregation analysis of microsatellite haplotypes with protein S deficiency in families with protein S deficiency suggests that the causative defects in the PROS1 mutation-negative patients are located in or close to the PROS1 gene. Large PROS1 gene deletions have been identified in 3 out of 9 PROS1 mutation-negative Swedish VTE families with protein S deficiency and 1 out of 6 PROS1 mutation-negative Japanese patients with protein S deficiency. Intensive sequencing of the entire PROS1 gene, including introns, may be needed to identify the cryptic mutations in those patients, and these efforts might uncover the pathogenesis of protein S deficiency.

protein S deficiency, PROS1, thrombophilia, mutation, genetic defects

Published Online:March 28, 2009

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