Identification of 58 Mutations (26 Novel) in 94 of 109 Symptomatic Spanish Probands with Protein C Deficiency

Laura Martos; Álvaro Fernández-Pardo; María F. López-Fernández; Francisco Ibáñez; Sonia Herrero; Dolors Tàssies; José R. González-Porras; María J. Solmoirago; María J. Costa; Juan C. Reverter; Pascual Marco; Vanessa Roldán; Ramón Lecumberri; Francisco Velasco; Julia Oto; Gemma Iruin; María N. Alonso; Amparo Vayá; Santiago Bonanad; Fernando Ferrando; Edelmira Martí; Ana R. Cid; Emma Plana; Francisca Oña; Isabel Cuesta; Tomás J. González-López; Francisco España; Pilar Medina; Silvia Navarro; on behalf of the Working Group of the Spanish Society of Thrombosis Haemostasis (SETH)

doi:10.1055/s-0039-1692440

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2019; 119(09): 1409-1418
DOI: 10.1055/s-0039-1692440

Coagulation and Fibrinolysis

Georg Thieme Verlag KG Stuttgart · New York

Identification of 58 Mutations (26 Novel) in 94 of 109 Symptomatic Spanish Probands with Protein C Deficiency

Laura Martos‡^*

¹Grupo de Investigación en Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Hospital Universitario y Politécnico La Fe, Valencia, Spain

,

Álvaro Fernández-Pardo‡^*

¹Grupo de Investigación en Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Hospital Universitario y Politécnico La Fe, Valencia, Spain

,

María F. López-Fernández

²Complejo Hospitalario Universitario A Coruña, A Coruña, Spain

,

Francisco Ibáñez

³Hospital General Universitario de Valencia, Valencia, Spain

,

Sonia Herrero

⁴Hospital Universitario de Guadalajara, Guadalajara, Spain

,

Dolors Tàssies

⁵Hospital Clinic de Barcelona, Barcelona, Spain

,

José R. González-Porras

⁶Hospital Universitario de Salamanca–IBSAL, Salamanca, Spain

,

María J. Solmoirago

¹Grupo de Investigación en Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Hospital Universitario y Politécnico La Fe, Valencia, Spain

,

María J. Costa

²Complejo Hospitalario Universitario A Coruña, A Coruña, Spain

,

Juan C. Reverter

⁵Hospital Clinic de Barcelona, Barcelona, Spain

,

Pascual Marco

⁷Hospital General Universitario de Alicante, Alicante, Spain

,

Vanessa Roldán

⁸Hospital General Universitario Morales Meseguer, Murcia, Spain

,

Ramón Lecumberri

⁹Clínica Universidad de Navarra, Pamplona, Spain

,

Francisco Velasco

¹⁰Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain

,

Julia Oto

¹Grupo de Investigación en Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Hospital Universitario y Politécnico La Fe, Valencia, Spain

,

Gemma Iruin

¹¹Hospital de Cruces, Baracaldo, Bilbao, Spain

,

María N. Alonso

¹²Hospital Universitario Infanta Cristina, Badajoz, Spain

,

Amparo Vayá

¹Grupo de Investigación en Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Hospital Universitario y Politécnico La Fe, Valencia, Spain

,

Santiago Bonanad

¹Grupo de Investigación en Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Hospital Universitario y Politécnico La Fe, Valencia, Spain

¹³Unidad de Trombosis y Hemostasia, Servicio de Hematología, Hospital Universitario y Politécnico La Fe, Valencia, Spain

,

Fernando Ferrando

¹Grupo de Investigación en Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Hospital Universitario y Politécnico La Fe, Valencia, Spain

¹³Unidad de Trombosis y Hemostasia, Servicio de Hematología, Hospital Universitario y Politécnico La Fe, Valencia, Spain

,

Edelmira Martí

¹⁴Hospital de Manises, Valencia, Spain

,

Ana R. Cid

¹Grupo de Investigación en Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Hospital Universitario y Politécnico La Fe, Valencia, Spain

¹³Unidad de Trombosis y Hemostasia, Servicio de Hematología, Hospital Universitario y Politécnico La Fe, Valencia, Spain

,

Emma Plana

¹Grupo de Investigación en Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Hospital Universitario y Politécnico La Fe, Valencia, Spain

,

Francisca Oña

¹⁵Hospital Universitario de Getafe, Getafe, Madrid, Spain

,

Isabel Cuesta

¹⁶Hospital Obispo Polanco, Teruel, Spain

,

Tomás J. González-López

¹⁷Hospital Universitario de Burgos y Departamento de Ciencias de la Salud, Universidad de Burgos, Burgos, Spain

,

Francisco España

¹Grupo de Investigación en Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Hospital Universitario y Politécnico La Fe, Valencia, Spain

,

Pilar Medina

¹Grupo de Investigación en Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Hospital Universitario y Politécnico La Fe, Valencia, Spain

,

Silvia Navarro

¹Grupo de Investigación en Hemostasia, Trombosis, Arteriosclerosis y Biología Vascular, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Hospital Universitario y Politécnico La Fe, Valencia, Spain

,

on behalf of the Working Group of the Spanish Society of Thrombosis Haemostasis (SETH)

› Institutsangaben

Abstract

Presently, no data on the molecular basis of hereditary protein C (PC) deficiency in Spain is available. We analyzed the PC gene (PROC) in 109 patients with symptomatic PC deficiency and in 342 relatives by sequencing the 9 PROC exons and their flanking intron regions. In 93 probands, we found 58 different mutations (26 novel). Thirty-seven consisted of a nucleotide change, mainly missense mutations, 1 was a 6-nucleotide insertion causing the duplication of 2 amino acids, and 4 were deletions of 1, 3, 4, and 16 nucleotides. Nine mutations caused type II deficiencies, with the presence of normal antigen levels but reduced anticoagulant activity. Using a PC level of 70% as lowest normal limit, we found no mutations in 16 probands and 25 relatives with PC levels ≤ 70%. On the contrary, 4 probands and 12 relatives with PC levels > 70% carried the mutation identified in the proband. The spectrum of recurrent mutations in Spain is different from that found in the Netherlands, where the most frequent mutations were p.Gln174* and p.Arg272Cys, and is more similar to that found in France, where the most frequent were p.Arg220Gln and p.Pro210Leu. In our study, p.Val339Met (9 families), p.Tyr166Cys (7), p.Arg220Gln (6), and p.Glu58Lys (5) were the most prevalent. This study confirms the considerable heterogeneity of the genetic abnormality in PC deficiencies, and allowed genetic counseling to those individuals whose PC levels were close to the lower limit of the normal reference range.

Keywords

protein C deficiency - gene mutations - venous thromboembolism - family study

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Referenzen

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